Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease

Science.gov (United States)

Anway, Matthew D.; Leathers, Charles; Skinner, Michael K.

2018-01-01

The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1–F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1–F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease. PMID:16973726

Endocrine Disruptors and Leydig Cell Function

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K. Svechnikov

2010-01-01

Full Text Available During the past decades, a large body of information concerning the effects of endocrine disrupting compounds (EDCs on animals and humans has been accumulated. EDCs are of synthetic or natural origin and certain groups are known to disrupt the action of androgens and to impair the development of the male reproductive tract and external genitalia. The present overview describes the effects of the different classes of EDCs, such as pesticides, phthalates, dioxins, and phytoestrogens, including newly synthesized resveratrol analogs on steroidogenesis in Leydig cells. The potential impact of these compounds on androgen production by Leydig cells during fetal development and in the adult age is discussed. In addition, the possible role of EDCs in connection with the increasing frequency of abnormalities in reproductive development in animals and humans is discussed.

Dietary exposure to the endocrine disruptor tolylfluanid promotes global metabolic dysfunction in male mice.

Science.gov (United States)

Regnier, Shane M; Kirkley, Andrew G; Ye, Honggang; El-Hashani, Essam; Zhang, Xiaojie; Neel, Brian A; Kamau, Wakanene; Thomas, Celeste C; Williams, Ayanna K; Hayes, Emily T; Massad, Nicole L; Johnson, Daniel N; Huang, Lei; Zhang, Chunling; Sargis, Robert M

2015-03-01

Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.

Cosmetics as endocrine disruptors: are they a health risk?

Science.gov (United States)

Nicolopoulou-Stamati, Polyxeni; Hens, Luc; Sasco, Annie J

2015-12-01

Exposure to chemicals from different sources in everyday life is widespread; one such source is the wide range of products listed under the title "cosmetics", including the different types of popular and widely-advertised sunscreens. Women are encouraged through advertising to buy into the myth of everlasting youth, and one of the most alarming consequences is in utero exposure to chemicals. The main route of exposure is the skin, but the main endpoint of exposure is endocrine disruption. This is due to many substances in cosmetics and sunscreens that have endocrine active properties which affect reproductive health but which also have other endpoints, such as cancer. Reducing the exposure to endocrine disruptors is framed not only in the context of the reduction of health risks, but is also significant against the background and rise of ethical consumerism, and the responsibility of the cosmetics industry in this respect. Although some plants show endocrine-disrupting activity, the use of well-selected natural products might reduce the use of synthetic chemicals. Instruments dealing with this problem include life-cycle analysis, eco-design, and green labels; in combination with the committed use of environmental management systems, they contribute to "corporate social responsibility".

Environmental endocrine disruptors: Effects on the human male reproductive system.

Science.gov (United States)

Sweeney, M F; Hasan, N; Soto, A M; Sonnenschein, C

2015-12-01

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.

Characterization of the interactions between endocrine disruptors and aquatic humic substances from tropical rivers

International Nuclear Information System (INIS)

Botero, Wander G.; Oliveira, Luciana C. de; Cunha, Bruno B.; Oliveira, Lilian K. de; Goveia, Danielle; Fraceto, Leonardo F.; Rosa, Andre Henrique; Rocha, Julio Cesar

2011-01-01

Interactions between two endocrine disruptors (ED) and aquatic humic substances (AHS) from tropical rivers were studied using an ultrafiltration system equipped with a 1 kDa cut-off cellulose membrane to separate free ED from the fraction bound in the AHS. Quantification of 17α-ethynylestradiol and bisphenol A was performed using gas chromatography-mass spectrometry (GC-MS). The times required for establishment of equilibrium between the AHS and the ED were ca. 30 min, and complexation capacities for 17α-ethynylestradiol and bisphenol A were 18.53 and 2.07 mg g -1 TOC, respectively. The greater interaction of AHS with 17α-ethynylestradiol, compared to bisphenol A, was due to the presence of hydrogen in the structure of 17α-ethynylestradiol, which could interact with ionized oxygenated groups of the AHS. The results indicate that AHS can strongly influence the transport and reactivity of endocrine disruptors in aquatic systems. (author)

Characterization of the interactions between endocrine disruptors and aquatic humic substances from tropical rivers

Energy Technology Data Exchange (ETDEWEB)

Botero, Wander G. [Universidade Federal de Alagoas (UFAL), Arapiraca, AL (Brazil); Oliveira, Luciana C. de [Universidade Federal de Sao Carlos (UFSCar), Sorocaba, SP (Brazil); Cunha, Bruno B.; Oliveira, Lilian K. de; Goveia, Danielle; Fraceto, Leonardo F.; Rosa, Andre Henrique, E-mail: ahrosa@sorocaba.unesp.b [UNESP, Sorocaba, SP (Brazil). Dept. de Engenharia do Meio Ambiente; Rocha, Julio Cesar [UNESP, Araraquara, SP (Brazil). Inst. de Quimica. Dept. de Quimica Analitica

2011-07-01

Interactions between two endocrine disruptors (ED) and aquatic humic substances (AHS) from tropical rivers were studied using an ultrafiltration system equipped with a 1 kDa cut-off cellulose membrane to separate free ED from the fraction bound in the AHS. Quantification of 17{alpha}-ethynylestradiol and bisphenol A was performed using gas chromatography-mass spectrometry (GC-MS). The times required for establishment of equilibrium between the AHS and the ED were ca. 30 min, and complexation capacities for 17{alpha}-ethynylestradiol and bisphenol A were 18.53 and 2.07 mg g{sup -1} TOC, respectively. The greater interaction of AHS with 17{alpha}-ethynylestradiol, compared to bisphenol A, was due to the presence of hydrogen in the structure of 17{alpha}-ethynylestradiol, which could interact with ionized oxygenated groups of the AHS. The results indicate that AHS can strongly influence the transport and reactivity of endocrine disruptors in aquatic systems. (author)

The BfR publishes workshop report based on the expert meeting on endocrine disruptors

OpenAIRE

German Federal Institute for Risk Assessment

2016-01-01

On the occasion of an expert meeting organised by the Federal Institute for Risk Assessment (BfR) held in Berlin on 11 and 12 April 2016, a consensus was reached on the identification of endocrine disruptors. The BfR has now published the workshop report from the conference. It contains, among other things, the consensus paper agreed by all participants. The report is published at http://www.bfr.bund.de/cm/349/scientific-principles-for-the-identification-of-endocrine-disrupting-chemicals-a-co...

Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease.

Science.gov (United States)

Anway, Matthew D; Skinner, Michael K

2008-04-01

The ability of an endocrine disruptor exposure during gonadal sex determination to promote a transgenerational prostate disease phenotype was investigated in the current study. Exposure of an F0 gestating female rat to the endocrine disruptor vinclozolin during F1 embryo gonadal sex determination promoted a transgenerational adult onset prostate disease phenotype. The prostate disease phenotype and physiological parameters were determined for males from F1 to F4 generations and the prostate transcriptome was assessed in the F3 generation. Although the prostate in prepubertal animals develops normally, abnormalities involving epithelial cell atrophy, glandular dysgenesis, prostatitis, and hyperplasia of the ventral prostate develop in older animals. The ventral prostate phenotype was transmitted for four generations (F1-F4). Analysis of the ventral prostate transcriptome demonstrated 954 genes had significantly altered expression between control and vinclozolin F3 generation animals. Analysis of isolated ventral prostate epithelial cells identified 259 genes with significantly altered expression between control and vinclozolin F3 generation animals. Characterization of regulated genes demonstrated several cellular pathways were influenced, including calcium and WNT. A number of genes identified have been shown to be associated with prostate disease and cancer, including beta-microseminoprotein (Msp) and tumor necrosis factor receptor superfamily 6 (Fadd). The ability of an endocrine disruptor to promote transgenerational prostate abnormalities appears to involve an epigenetic transgenerational alteration in the prostate transcriptome and male germ-line. Potential epigenetic transgenerational alteration of prostate gene expression by environmental compounds may be important to consider in the etiology of adult onset prostate disease.

Endocrine disruptors in water filters used in the Rio dos Sinos Basin region, Southern Brazil

OpenAIRE

Furtado,CM; von Mühlen,C

2015-01-01

The activated carbon filter is used in residences as another step in the treatment of drinking water, based on a physical-chemical process to absorb pollutants that are not removed in conventional treatment. Endocrine disruptors (EDCs) are exogenous substances or mixtures of substances that acts on the endocrine system similarly to the endogenously produced hormones, triggering malfunctions and harmful changes to human and animal health. The objective of the present work was to study EDCs thr...

Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

OpenAIRE

Lagarde, Fabien; Beausoleil, Claire; Belcher, Scott M; Belzunces, Luc P; Emond, Claude; Guerbet, Michel; Rousselle, Christophe

2015-01-01

International audience; Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that repor...

Endocrine disruptors: Revisiting concepts and dogma in toxicology.

Science.gov (United States)

Barouki, Robert

During the last decades, a large number of observations have shown that some exogenous substances could interfere with hormone levels or hormone action and could induce toxic effects. This has led to the identification of endocrine disruptors more than 25 years ago as a new class of toxic agents (Zoeller et al., 2014). Those widely used agents correspond to a variety of chemical classes, are not identified by their chemical structure or by a specific type of usage, but rather by their mechanisms of action; this is not unprecedented in toxicology since genotoxicants have also been identified by their mechanism of action, i.e. their ability to alter DNA structure and function. Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS.

Science.gov (United States)

Kandaraki, Eleni; Chatzigeorgiou, Antonis; Livadas, Sarantis; Palioura, Eleni; Economou, Frangiscos; Koutsilieris, Michael; Palimeri, Sotiria; Panidis, Dimitrios; Diamanti-Kandarakis, Evanthia

2011-03-01

Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbonate plastics. In experimental animals, neonatal exposure to BPA results in a polycystic ovary-like syndrome (PCOS) in adulthood. A bidirectional interaction between androgens and BPA levels has been disclosed. To determine BPA levels in PCOS women as well as the association between BPA and hormonal/metabolic parameters compared to a control group. Cross-sectional study of 71 PCOS (National Institutes of Health criteria) and 100 normal women, age- and body mass index-matched, in a University hospital setting. Anthropometric, hormonal, metabolic parameters and BPA blood levels were determined. Patients (PCOS) and controls (C) were further subdivided according to body mass index into lean and overweight subgroups, respectively. BPA levels were significantly higher in the total PCOS group compared with the controls (1.05±0.56 vs. 0.72±0.37 ng/ml, P PCOS women, lean (PCOS-L) and overweight (PCOS-OW), had higher BPA levels compared to the corresponding control group lean (C-L) and overweight (C-OW): (PCOS-L = 1.13±0.63 vs. C-L = 0.70±0.36, P PCOS-OW = 0.96 ± 0.46 vs. C-OW = 0.72 ± 0.39, P PCOS (r = 0.497, P PCOS group (r = 0.273, P PCOS women compared to controls and a statistically significant positive association between androgens and BPA point to a potential role of this endocrine disruptor in PCOS pathophysiology.

Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors

Czech Academy of Sciences Publication Activity Database

Ezechiáš, Martin; Janochová, Jana; Filipová, Alena; Křesinová, Zdena; Cajthaml, Tomáš

2016-01-01

Roč. 152, JUNE (2016), s. 284-291 ISSN 0045-6535 R&D Projects: GA TA ČR TE01020218; GA ČR GA13-28283S Institutional support: RVO:61388971 Keywords : Endocrine disruptor * Anti-estrogenic * Anti-androgenic Subject RIV: EE - Microbiology, Virology Impact factor: 4.208, year: 2016

Comparative anti-androgenic actions of vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis

OpenAIRE

Anway, Matthew D.; Rekow, Stephen S.; Skinner, Michael K.

2008-01-01

Exposure of gestating female rats to the anti-androgenic endocrine disruptor vinclozolin has been shown to induce transgenerational adult onset disease phenotypes. The current study, was designed to compare the actions of vinclozolin to the known anti-androgenic compound flutamide. The gestating female rats were exposed to intraperitoneal injections during embryonic day 8–14 (E8–E14) to 100 mg/kg/day vinclozolin or flutamide at either 5mg or 20 mg/kg/day. As previously observed, vinclozolin i...

Nuevos disruptores endocrinos: su importancia en la población pediátrica New endocrine disruptors: their importance in pediatric population

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Juan Manuel Alfaro Velásquez

2005-04-01

Full Text Available Los cambios de nuestro hábitat en los últimos 40 años han generado contactos frecuentes con sustancias químicas tanto naturales como sintéticas que funcionan como disruptores endocrinos; son ejemplos los pesticidas ampliamente usados tras la introducción del DDT, los derivados petroquímicos en la industria del plástico, las medicinas sintéticas, y el volumen creciente de artículos de vestuario, aseo, cosmética y transporte. En cada uno de los grupos anotados hay señales de actividad de algún disruptor endocrino sea directamente o a través de sus derivados. La controversia inicial se centró principalmente en los compuestos químicamente similares a los estrógenos y en todos aquellos con actividad antiandrógenos o antitiroidea, debido a que se sospechaba que dañaban el ADN; recientemente se han estudiado otros compuestos y condiciones de vida que no lesionan el genoma pero sí interactúan con enzimas y sus metabolitos. Entre los efectos potenciales de estas sustancias cabe mencionar los siguientes: anomalías intrauterinas por daños del tejido fetal en formación; cambios del fenotipo genital al nacer y diversas manifestaciones clínicas durante la adolescencia; además, no pueden perderse de vista los efectos sobre las generaciones futuras. Los disruptores endocrinos son compuestos que pueden modular tanto la expresión endocrina e inmune del afectado como la homeostasis, la reproducción, el desarrollo y el comportamiento y tienen efectos sobre los tejidos reproductivos masculino y femenino, la fertilidad, la función tiroidea y el sistema nervioso central. Changes in the environment that have taken place during the last 40 years have generated frequent contacts with natural and synthetic chemical products with potential endocrine-disrupting roles; among them: the intensive use of pesticides after the introduction of DDT, the petrochemical derivatives of the plastic industry, the synthetic medicines and the growing market of

Exposición a disruptores endocrinos y alteraciones del tracto urogenital masculino (criptorquidia e hipospadias Exposure to endocrine disruptors and male urogenital tract malformations [cryptorchidism and hypospadias

Directory of Open Access Journals (Sweden)

Mariana F. Fernández

2007-12-01

Full Text Available Antecedentes: Se ha sugerido que la exposición maternoinfantil a compuestos hormonalmente activos (disruptores endocrinos tiene en la etapa intrauterina una de sus fases más comprometidas. Objetivo: Revisar los estudios epidemiológicos, nacionales e internacionales, publicados entre 1990 y el primer trimestre de 2006, que tuvieran como hipótesis la asociación entre la exposición humana a disruptores endocrinos y el riesgo de criptorquidia e hipospadias. Métodos: Se han buscado artículos en MEDLINE/PubMed mediante las palabras clave: disruptores endocrinos, xenoestrógenos, pesticidas organoclorados y criptorquidia e hipospadias. La selección de los 16 trabajos incluidos se hizo atendiendo al diseño y la población de estudio, las medidas de exposición empleadas, los criterios de exclusión e inclusión establecidos y el análisis estadístico utilizado. Resultados y conclusiones: Aunque los estudios aquí revisados no son concluyentes para confirmar la asociación entre disruptores endocrinos y riesgo de malformación del tracto genitourinario, tampoco demuestran la falta de tal asociación. Por este motivo parece razonable sugerir que este aspecto de la patología hormonal debería investigarse más en profundidad, resolviendo, al menos, el diagnóstico adecuado de los individuos y la estimación de la exposición a múltiples compuestos químicos, contaminantes ambientales, que actúan conjuntamente a través de mecanismos similares a las hormonas endógenas.Background: It has been proposed that the intrauterine period of child-mother exposure to hormonally active compounds (endocrine disruptors is of critical importance. Objective: We reviewed all Spanish and English-language epidemiological studies published between 1990 and the first trimester of 2006 that studied the possible association between human exposure to chemical compounds and the risk of cryptorchidism and/or hypospadias. Methods: The MEDLINE (PubMed database was

Exposure to Endocrine Disruptor Induces Transgenerational Epigenetic Deregulation of MicroRNAs in Primordial Germ Cells

Czech Academy of Sciences Publication Activity Database

Brieno-Enriguez, M. A.; García-López, J.; Cárdenas, D.B.; Guibert, S.; Cleroux, E.; Děd, Lukáš; de Dios Hourcade, J.; Pěknicová, Jana; Weber, M.; del Mazo, J.

2015-01-01

Roč. 10, č. 4 (2015) E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GAP503/12/1834; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : endocrine disruptor * epigenetic s * primordial germ cells * vinclozolin * TUNEL analysis * methylation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.057, year: 2015

Inhibitor of Differentiation-3 and Estrogenic Endocrine Disruptors: Implications for Susceptibility to Obesity and Metabolic Disorders

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Mayur Doke

2018-01-01

Full Text Available The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3 promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.

Androgenic endocrine disruptors in wastewater treatment plant effluents in India: Their influence on reproductive processes and systemic toxicity in male rats

International Nuclear Information System (INIS)

Kumar, Vikas; Chakraborty, Ajanta; Viswanath, Gunda; Roy, Partha

2008-01-01

Endocrine-disrupting chemicals (EDC) are linked to human health and diseases as they mimic or block the normal functioning of endogenous hormones. The present work dealt with a comparative study of the androgenic potential of wastewater treatment plant (WWTP) influents and effluents in Northern region of India, well known for its polluted water. Water samples were screened for their androgenic potential using the Hershberger assay and when they were found positive for androgenicity, we studied their mode of action in intact rats. The data showed a significant change in the weight and structure of sex accessory tissues (SATs) of castrated and intact rats. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis demonstrated a significant change in the expression patterns of the major steroidogenic enzymes in adrenal and testis: cytochrome P450 SCC , cytochrome P450 C17 , 3β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase. This was further supported by increased enzymatic activities measured in vitro spectrophotometrically. Serum hormone profile showed a decreased level of gonadotrophic hormones and increased testosterone level. Further, increase in the serum level of alkaline phosphatase, SGPT and SGOT and histopathological changes in kidney and liver of treated animals, confirmed the toxic effects of contaminating chemicals. Analysis of water samples using HPLC and GC-MS showed the presence of various compounds and from them, four prominent aromatic compounds viz. nonylphenol, hexachlorobenzene and two testosterone equivalents, were identified. Our data suggest that despite rigorous treatment, the final treated effluent from WWTP still has enough androgenic and toxic compounds to affect general health

Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action.

Directory of Open Access Journals (Sweden)

Alison M Anderson

Full Text Available BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods.

Disruptores endocrinos utilizados en la industria textil-confección en España Endocrine disruptors used in textile industry in Spain

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Rafael Gadea

2009-03-01

Full Text Available Introducción: Los disruptores endocrinos son sustancias químicas que pueden alterar el sistema hormonal. Estas sustancias se utilizan en distintos procesos de la industria del textil-confección. Objetivos: Identificar las sustancias con efectos de disrupción endocrina utilizados en la industria del textil y la confección en España para prevenir la exposición de los trabajadores a estas sustancias. Material y métodos: En el estudio participaron 65 empresas de siete comunidades autónomas, seleccionadas mediante acuerdo entre las organizaciones empresariales y sindicales del sector. Técnicos de salud laboral de las federaciones sindicales visitaron las empresas participantes y recogieron información sobre los productos químicos utilizados mediante observación de etiquetas y fichas de datos de seguridad y mediante entrevistas con técnicos de prevención, trabajadores designados, delegados de prevención y trabajadores utilizando cuestionarios estandarizados. Resultados: Las empresas participantes cubren un amplio rango de actividades propias del sector, siendo la mayoría de ellas de tamaño medio (entre 51 y 250 trabajadores, n=39. Se identificaron diecisiete sustancias diferentes con efectos de disrupción endocrina utilizadas en distintos puestos de trabajo, incluyendo preparación de fibras y tejidos, lavado, tintado o acabado textil, entre otros. Conclusiones: Serían necesarios estudios que permitieran cuantificar el nivel de exposición en los puestos identificados para priorizar las medidas preventivas necesarias.Introduction: Endocrine disruptors are chemicals which can affect hormonal system in human beings. These substances are used in several processes in the textile industry. Objectives: Identifying chemicals with endocrine disruption potential used in Spanish textile industry to promoting risk prevention in exposed workers. Material and methods: The study includes 65 companies located in seven different Spanish regions

Endocrine disruptors and asthma-associated chemicals in consumer products.

Science.gov (United States)

Dodson, Robin E; Nishioka, Marcia; Standley, Laurel J; Perovich, Laura J; Brody, Julia Green; Rudel, Ruthann A

2012-07-01

Laboratory and human studies raise concerns about endocrine disruption and asthma resulting from exposure to chemicals in consumer products. Limited labeling or testing information is available to evaluate products as exposure sources. We analytically quantified endocrine disruptors and asthma-related chemicals in a range of cosmetics, personal care products, cleaners, sunscreens, and vinyl products. We also evaluated whether product labels provide information that can be used to select products without these chemicals. We selected 213 commercial products representing 50 product types. We tested 42 composited samples of high-market-share products, and we tested 43 alternative products identified using criteria expected to minimize target compounds. Analytes included parabens, phthalates, bisphenol A (BPA), triclosan, ethanolamines, alkylphenols, fragrances, glycol ethers, cyclosiloxanes, and ultraviolet (UV) filters. We detected 55 compounds, indicating a wide range of exposures from common products. Vinyl products contained > 10% bis(2-ethylhexyl) phthalate (DEHP) and could be an important source of DEHP in homes. In other products, the highest concentrations and numbers of detects were in the fragranced products (e.g., perfume, air fresheners, and dryer sheets) and in sunscreens. Some products that did not contain the well-known endocrine-disrupting phthalates contained other less-studied phthalates (dicyclohexyl phthalate, diisononyl phthalate, and di-n-propyl phthalate; also endocrine-disrupting compounds), suggesting a substitution. Many detected chemicals were not listed on product labels. Common products contain complex mixtures of EDCs and asthma-related compounds. Toxicological studies of these mixtures are needed to understand their biological activity. Regarding epidemiology, our findings raise concern about potential confounding from co-occurring chemicals and misclassification due to variability in product composition. Consumers should be able to avoid

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

Energy Technology Data Exchange (ETDEWEB)

Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei, E-mail: hongfeixia@yahoo.com.cn; Ma, Xu

2012-08-15

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

International Nuclear Information System (INIS)

Hao, Chan-Juan; Cheng, Xue-Jia; Xia, Hong-Fei; Ma, Xu

2012-01-01

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.

Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study.

Science.gov (United States)

Brophy, James T; Keith, Margaret M; Watterson, Andrew; Park, Robert; Gilbertson, Michael; Maticka-Tyndale, Eleanor; Beck, Matthias; Abu-Zahra, Hakam; Schneider, Kenneth; Reinhartz, Abraham; Dematteo, Robert; Luginaah, Isaac

2012-11-19

Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. 1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case-control design, exposure effects were estimated using conditional logistic regression. Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5). These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work

Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case–control study

Science.gov (United States)

2012-01-01

Background Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. Methods 1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression. Results Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5). Conclusions These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and

Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case–control study

Directory of Open Access Journals (Sweden)

Brophy James T

2012-11-01

Full Text Available Abstract Background Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. Methods 1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case–control design, exposure effects were estimated using conditional logistic regression. Results Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration. Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82; bars-gambling (OR = 2.28; 95% CI, 0.94-5.53; automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88, food canning (OR = 2.35; 95% CI, 1.00-5.53, and metalworking (OR = 1.73; 95% CI, 1.02-2.92. Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4 and food canning (OR = 5.70; 95% CI, 1.03-31.5. Conclusions These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and

The effects of different endocrine disruptors defining compound-specific alterations of gene expression profiles in the developing testis

NARCIS (Netherlands)

López-Casas, Pedro P.; Mizrak, Sefika C.; López-Fernández, Luis A.; Paz, María; de Rooij, Dirk G.; del Mazo, Jesús

2012-01-01

Environmental contaminants considered endocrine disruptors have been shown to affect testis development and function but the mechanisms of action are not clear. We now have analyzed the effects on the transcriptome in testes of mice exposed to mono-(2-ethylhexyl)-phthalate (9.2; 46.3 or 92.7

Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease

OpenAIRE

Nilsson, Eric E; Anway, Matthew D; Stanfield, Jacob; Skinner, Michael K

2008-01-01

Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1–F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with vinclozolin (i.e., fungicide with anti...

Polymorphic variation in the androgen receptor gene: association with risk of testicular germ cell cancer and metastatic disease

DEFF Research Database (Denmark)

Västermark, Åke; Giwercman, Yvonne Lundberg; Hagströmer, Oskar

2011-01-01

Increasing incidence of testicular germ cell cancer (TGCC) is most probably related to environment and lifestyle. However, an underlying genetic predisposition may play a role and since sex steroids are assumed to be important for the rise and progression of TGCC, a study of androgen receptor (AR...... of endocrine disruptors. From a biological point of view, our findings strengthen the hypothesis of the importance of androgen action in the aetiology and pathogenesis of testicular malignancy. Future studies should focus on the impact of sex hormones on foetal germ cell development and the interaction between...

Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part II: Triphenyltin as a xeno-androgen.

Science.gov (United States)

Schulte-Oehlmann, U; Tillmann, M; Markert, B; Oehlmann, J; Watermann, B; Scherf, S

2000-12-01

In laboratory experiments the effects of suspected endocrine disrupting chemicals on freshwater and marine prosobranch species were analysed. In this second of three publications the responses of the freshwater ramshorn snail Marisa cornuarietis and of two marine prosobranchs (the dogwhelk Nucella lapillus and the netted whelk Hinia reticulata) to the xeno-androgenic model compound triphenyltin (TPT) are presented. Marisa and Nucella were exposed via water (nominal concentrations 5-500 ng TPT-Sn/L) and Hinia via sediments (nominal concentrations 50-500 micrograms TPT-Sn/kg dry wt.) for up to 4 months. Female ramshorn snails but not the two marine species developed imposex in a time and concentration dependent manner (EC10 4 months: 12.3 ng TPT-Sn/L) with a comparable intensity as described for tributyltin. TPT reduced furthermore the fecundity of Marisa at lower concentrations (EC10 4 months: 5.59 ng TPT-Sn/L) with a complete inhibition of spawning at nominal concentrations > or = 250 ng TPT-Sn/L (mean measured +/- SD: > or = 163 +/- 97.0 ng TPT-Sn/L). The extension of the pallial sex organs (penis with accessory structures and prostate gland) of male ramshorn snails and dogwhelks were reduced by up to 25% compared to the control but not in netted whelks. Histopathological analyses for M. cornuarietis and H. reticulata provide evidence for a marked impairment of spermatogenesis (both species) and oogenesis (only netted whelks). The test compound induced a highly significant and concentration independent increase in the incidence of hyperplasia on gills, osphradia and other organs in the mantle cavity of N. lapillus indicating a carcinogenic potential of TPT. The results show that prosobranchs are sensitive to endocrine disruption at environmentally relevant concentrations of TPT. Also, M. cornuarietis is a promising candidate for a future organismic invertebrate system to identify endocrine-mimetic test compounds.

Stimulatory effects of combined endocrine disruptors on MA-10 Leydig cell steroid production and lipid homeostasis

International Nuclear Information System (INIS)

Jones, Steven; Boisvert, Annie; Naghi, Andrada; Hullin-Matsuda, Françoise; Greimel, Peter; Kobayashi, Toshihide; Papadopoulos, Vassilios; Culty, Martine

2016-01-01

Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from individual exposures. These studies identified fetal and adult Leydig cells as sensitive targets for low dose endocrine disruptor (ED) mixtures. To further investigate the direct effects and mechanisms of toxicity of GEN and DEHP, MA-10 mouse tumor Leydig cells were exposed in-vitro to varying concentrations of GEN and MEHP, the principal bioactive metabolite of DEHP. Combined 10 μM GEN + 10 μM MEHP had a stimulatory effect on basal progesterone production. Consistent with increased androgenicity, the mRNA of steroidogenic and cholesterol mediators Star, Cyp11a, Srb1 and Hsl, as well as upstream orphan nuclear receptors Nr2f2 and Sf1 were all significantly increased uniquely in the mixture treatment group. Insl3, a sensitive marker of Leydig endocrine disruption and cell function, was significantly decreased by combined GEN + MEHP. Lipid analysis by high-performance thin layer chromatography demonstrated the ability of combined 10 μM combined GEN + MEHP, but not individual exposures, to increase levels of several neutral lipids and phospholipid classes, indicating a generalized deregulation of lipid homeostasis. Further investigation by qPCR analysis revealed a concomitant increase in cholesterol (Hmgcoa) and phospholipid (Srebp1c, Fasn) mediator mRNAs, suggesting the possible involvement of upstream LXRα agonism. These results suggest a deregulation of MA-10 Leydig function in response to a combination of GEN + MEHP. We propose a working model for GEN + MEHP doses relevant to human exposure involving LXR agonism and activation of other transcription factors. Taken more broadly, this research highlights the importance of assessing the impact of ED mixtures in multiple toxicological models across a range of environmentally

In Vitro Effects of the Endocrine Disruptor p,p’-DDT on Human Follitropin Receptor

Science.gov (United States)

Munier, Mathilde; Grouleff, Julie; Gourdin, Louis; Fauchard, Mathilde; Chantreau, Vanessa; Henrion, Daniel; Coutant, Régis; Schiøtt, Birgit; Chabbert, Marie; Rodien, Patrice

2016-01-01

Background: 1-chloro-4-[2,2,2-trichloro-1-(4-chlorophenyl)ethyl]benzene (p,p′-DDT) is a persistent environmental endocrine disruptor (ED). Several studies have shown an association between p,p′-DDT exposure and reproductive abnormalities. Objectives: To investigate the putative effects of p,p′-DDT on the human follitropin receptor (FSHR) function. Methods and Results: We used Chinese hamster ovary (CHO) cells stably expressing human FSHR to investigate the impact of p,p′-DDT on FSHR activity and its interaction with the receptor. At a concentration of 5 μM p,p′-DDT increased the maximum response of the FSHR to follitropin by 32 ± 7.45%. However, 5 μM p,p′-DDT decreased the basal activity and did not influence the maximal response of the closely related LH/hCG receptor to human chorionic gonadotropin (hCG). The potentiating effect of p,p′-DDT was specific for the FSHR. Moreover, in cells that did not express FSHR, p,p′-DDT had no effect on cAMP response. Thus, the potentiating effect of p,p′-DDT was dependent on the FSHR. In addition, p,p′-DDT increased the sensitivity of FSHR to hCG and to a low molecular weight agonist of the FSHR, 3-((5methyl)-2-(4-benzyloxy-phenyl)-5-{[2-[3-ethoxy-4-methoxy-phenyl)-ethylcarbamoyl]-methyl}-4-oxo-thiazolidin-3-yl)-benzamide (16a). Basal activity in response to p,p′-DDT and potentiation of the FSHR response to FSH by p,p′-DDT varied among FSHR mutants with altered transmembrane domains (TMDs), consistent with an effect of p,p′-DDT via TMD binding. This finding was corroborated by the results of simultaneously docking p,p′-DDT and 16a into the FSHR transmembrane bundle. Conclusion: p,p′-DDT acted as a positive allosteric modulator of the FSHR in our experimental model. These findings suggest that G protein–coupled receptors are additional targets of endocrine disruptors. Citation: Munier M, Grouleff J, Gourdin L, Fauchard M, Chantreau V, Henrion D, Coutant R, Schiøtt B, Chabbert M, Rodien P. 2016

Efficiencies of freshwater and estuarine constructed wetlands for phenolic endocrine disruptor removal in Taiwan.

Science.gov (United States)

Hsieh, Chi-Ying; Yang, Lei; Kuo, Wen-Chien; Zen, Yi-Peng

2013-10-01

We examined the distribution and removal efficiencies of phenolic endocrine disruptors (EDs), namely nonylphenol diethoxylates (NP2EO), nonylphenol monoethoxylates (NP1EO), nonylphenol (NP), and octylphenol (OP), in wastewater treated by estuarine and freshwater constructed wetland systems in Dapeng Bay National Scenic Area (DBNSA) and along the Dahan River in Taiwan. Water samples were taken bimonthly at 30 sites in three estuarine constructed wetlands (Datan, Pengcun and Linbian right bank (A and B)) in DBNSA, for eight sampling campaigns. The average removal efficiencies were in the range of 3.13-97.3% for wetlands in DBNSA. The highest average removal occurred in the east inlet to the outlet of the Tatan wetland. The most frequently detected compound was OP (57.7%), whose concentration was up to 1458.7 ng/L in DBNSA. NP was seen in only 20.5% of the samples. The temporal variation of EDs showed a decrease across seasons, where summer>spring>winter>autumn in these constructed wetlands. The removal efficiencies of EDs by estuarine wetlands, in decreasing order, were Datan>Pengcun>Linbian right bank in DBNSA. Water samples collected at 18 sites in three freshwater constructed wetlands (Daniaopi, Hsin-Hai I, and Hsin-Hai II) along the riparian area of Dahan River. NP2EO was the most abundant compound, with a concentration of up to 11,200 ng/L. Removal efficiencies ranged from 55% to 91% for NP1EO, NP2EO, and NP in Hsin-Hai I. The average removal potential of EDs in freshwater constructed wetlands, in decreasing order, was Hsin-Hai II>Daniaopi>Hsin-Hai I constructed wetlands. The lowest concentrations of the selected compounds were observed in the winter. The highest removal efficiency of the selected phenolic endocrine disruptors was achieved by Hsin-Hai I wetland. The calculated risk quotients used to evaluate the ecological risk were up to 30 times higher in the freshwater wetlands along Dahan River than in the estuarine (DBNSA) constructed wetlands, indicating

Occurrence and Profiles of the Artificial Endocrine Disruptor Bisphenol A and Natural Endocrine Disruptor Phytoestrogens in Urine from Children in China

Directory of Open Access Journals (Sweden)

Mingyue Zhang

2015-11-01

Full Text Available Background: Exposure to artificial or natural endocrine disruptors, such as bisphenol A (BPA and phytoestrogens has been demonstrated to have health effects, especially in children. Biomonitoring of BPA and phytoestrogens in human urine can be used to assess the intake levels of these compounds. Methods: In this study, BPA and phytoestrogens in urine specimens (n = 256 collected from children in China were measured by liquid chromatography (LC-tandem mass spectrometry (MS/MS. Results: BPA was detected in most specimens, with a geometric mean concentration of 1.58 ng/mL. For the first time, levels of urinary phytoestrogens in Chinese children were reported. Daidzein and enterolactone are the typical isoflavones and lignans compounds in urine, respectively. Conclusions: Relatively high levels of urinary BPA indicate an increasing risk of BPA exposure to Chinese children. Urinary concentrations of daidzein in Chinese children are higher when compared with those reported in the U.S. children, while concentrations of urinary enterolactone and enterodiols are significantly lower. This suggests a significant difference in phytoestrogen intake between the children from China and from the U.S.

The immune system of geriatric mice is modulated by estrogenic endocrine disruptors (diethylstilbestrol, α-zearalanol, and genistein): Effects on interferon-γ

International Nuclear Information System (INIS)

Calemine, Jillian; Zalenka, Julie; Karpuzoglu-Sahin, Ebru; Ward, Daniel L.; Lengi, Andrea; Ahmed, S. Ansar

2003-01-01

The immune system is a potential target for estrogenic endocrine disrupters. To date, there is limited information on whether estrogenic endocrine disruptors modulate the immune system of aged individuals. To address this issue, groups of 74-week-old mice were given nine oral doses of selected estrogenic endocrine disrupters: diethylstilbestrol (DES, 3 μg/100 g bw), α-zearalanol (0.5 mg/100 g bw), or genistein (0.15 mg/100 g bw) in corn oil, or corn oil alone, over 2.5 weeks. Both developmental (thymus) and mature (spleen) lymphoid organs were affected, although specific effects varied with the chemical. DES significantly decreased thymocyte numbers. However, relative percentages of thymocyte subsets were not altered. While splenic cellularity and percentages of T and B cells were unchanged, splenocytes from DES-exposed mice had significantly decreased ability to proliferate in response to Concanavalin-A (Con-A). Con-A-activated splenocytes from mice treated with genistein or α-zearalanol had decreased levels of interferon-γ (IFNγ) protein in their culture supernatants compared to similar cultures from oil-treated mice. RT-PCR analysis of Con-A-activated splenocytes revealed that the expression of IFNγ gene is altered by DES or genistein treatment. Together, these results suggest that estrogenic endocrine disruptors modulate the immune system of aged mice

Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Science.gov (United States)

Yang, Oneyeol; Kim, Hye Lim; Weon, Jong-Il; Seo, Young Rok

2015-01-01

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors. PMID:25853100

The endocrine disruptors among the environmental risk factors for stillbirth

International Nuclear Information System (INIS)

Roncati, Luca; Piscioli, Francesco; Pusiol, Teresa

2016-01-01

Persistent organic pollutants have been lately taken into consideration for their adverse effects, as possible stillbirth contributors; stillbirth can be in fact considered the most dramatic pregnancy complication. Congenital abnormalities account for few stillbirths and many related disorders are potentially modifiable or often coexist, such as maternal infections, non-communicable diseases, lifestyle factors and maternal age. Causal pathways for stillbirth frequently involve impaired placental function, either with fetal growth restriction or preterm labour. For this reason, many current efforts are focusing on the study of endocrine disruptor (ED) placental transfer, to better understand the in utero exposure dynamics. In this regard, our research group has investigated, by gas chromatography–mass spectrometry, the EDs presence in brain samples of 24 stillbirths, collected over a 3-year period (2012–2014), coming from the Northeast Italy, a notorious area devoted to apple cultivation. Surprisingly, organochlorine pesticides (OCPs), well-known EDs, have been detected in 11 samples. Apart from the noteworthy evidence of pesticides' bio-persistence, this finding implies a redefinition of the placental barrier concept: not a real safety system, but a time-deferral mechanism of absorption. The term ‘placental barrier’ in fact refers to a 4-membrane structure, made up by two epithelial layers, which exactly lining the chorionic villi, and by two endothelial layers, belonging to the feeding vessels for the fetus. It is an effective barrier only for a low administration of water-soluble substances, which encounter obstacle to cross four instead of two membranes. High doses of water-soluble compounds can reach appreciable concentration in the fetal blood, and the lipid-soluble chemicals, such as EDs, are able to pass the placental barrier, through a simple mechanism of passive diffusion, even in minimal concentrations. After crossing the placental barrier, it is

The endocrine disruptors among the environmental risk factors for stillbirth

Energy Technology Data Exchange (ETDEWEB)

Roncati, Luca, E-mail: emailmedical@gmail.com [Provincial Health Care Services, Institute of Pathology, Santa Maria del Carmine Hospital, Rovereto, TN (Italy); Department of Diagnostic and Clinical Medicine and of Public Health, University of Modena and Reggio Emilia, Modena, MO (Italy); Piscioli, Francesco; Pusiol, Teresa [Provincial Health Care Services, Institute of Pathology, Santa Maria del Carmine Hospital, Rovereto, TN (Italy)

2016-09-01

Persistent organic pollutants have been lately taken into consideration for their adverse effects, as possible stillbirth contributors; stillbirth can be in fact considered the most dramatic pregnancy complication. Congenital abnormalities account for few stillbirths and many related disorders are potentially modifiable or often coexist, such as maternal infections, non-communicable diseases, lifestyle factors and maternal age. Causal pathways for stillbirth frequently involve impaired placental function, either with fetal growth restriction or preterm labour. For this reason, many current efforts are focusing on the study of endocrine disruptor (ED) placental transfer, to better understand the in utero exposure dynamics. In this regard, our research group has investigated, by gas chromatography–mass spectrometry, the EDs presence in brain samples of 24 stillbirths, collected over a 3-year period (2012–2014), coming from the Northeast Italy, a notorious area devoted to apple cultivation. Surprisingly, organochlorine pesticides (OCPs), well-known EDs, have been detected in 11 samples. Apart from the noteworthy evidence of pesticides' bio-persistence, this finding implies a redefinition of the placental barrier concept: not a real safety system, but a time-deferral mechanism of absorption. The term ‘placental barrier’ in fact refers to a 4-membrane structure, made up by two epithelial layers, which exactly lining the chorionic villi, and by two endothelial layers, belonging to the feeding vessels for the fetus. It is an effective barrier only for a low administration of water-soluble substances, which encounter obstacle to cross four instead of two membranes. High doses of water-soluble compounds can reach appreciable concentration in the fetal blood, and the lipid-soluble chemicals, such as EDs, are able to pass the placental barrier, through a simple mechanism of passive diffusion, even in minimal concentrations. After crossing the placental barrier

In vitro steroid profiling system for the evaluation of endocrine disruptors.

Science.gov (United States)

Nakano, Yosuke; Yamashita, Toshiyuki; Okuno, Masashi; Fukusaki, Eiichiro; Bamba, Takeshi

2016-09-01

Endocrine disruptors (ED) are chemicals that affect various aspects of the endocrine system, often leading to the inhibition of steroidogenesis. Current chemical safety policies that restrict human exposure to such chemicals describe often time-consuming and costly methods for the evaluation of ED effects. We aimed to develop an effective tool for accurate phenotypic chemical toxicology studies. We developed an in vitro ED evaluation system using gas chromatography/mass spectrometry (GC/MS/MS) methods for metabolomic analysis of multi-marker profiles. Accounting for sample preparation and GC/MS/MS conditions, we established a screening method that allowed the simultaneous analysis of 17 steroids with good reproducibility and a linear calibration curve. Moreover, we applied the developed system to H295R human adrenocortical cells exposed to forskolin and prochloraz in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines and observed dose-dependent variations in steroid profiles. While the OECD guidelines include only testosterone and 17β-estradiol, our system enabled a comprehensive and highly sensitive analysis of steroid profile alteration due to ED exposure. The application of our ED evaluation screen could be economical and provide novel insights into the hazards of ED exposure to the endocrine system. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Endocrine disruptors: from Wingspread to environmental developmental biology.

Science.gov (United States)

Markey, Caroline M; Rubin, Beverly S; Soto, Ana M; Sonnenschein, Carlos

2002-12-01

The production and release of synthetic chemicals into the environment has been a hallmark of the "Second Industrial Revolution" and the "Green Revolution." Soon after the inception of these chemicals, anecdotal evidence began to emerge linking environmental contamination of rivers and lakes with a variety of developmental and reproductive abnormalities in wildlife species. The accumulation of evidence suggesting that these synthetic chemicals were detrimental to wildlife, and potentially humans, as a result of their hormonal activity, led to the proposal of the endocrine disruptor hypothesis at the 1991 Wingspread Conference. Since that time, experimental and epidemiological data have shown that exposure of the developing fetus or neonate to environmentally-relevant concentrations of certain synthetic chemicals causes morphological, biochemical, physiological and behavioral anomalies in both vertebrate and invertebrate species. The ubiquitous use, and subsequent human exposure, of one particular chemical, the estrogen mimic bisphenol A (BPA), is the subject of this present review. We have highlighted this chemical since it provides an arresting model of how chemical exposure impacts developmental processes involved in the morphogenesis of tissues and organs, including those of the male and female reproductive systems, the mammary glands and the brain.

Application of biotests for the characterization of exposure pathways for endocrine disrupters from plastics; Anwendung von Biotests zur Charakterisierung der Expositionspfade fuer Umwelthormone aus Kunststoffen

Energy Technology Data Exchange (ETDEWEB)

Wagner, Martin; Oehlmann, Joerg [Frankfurt Univ., Frankfurt am Main (Germany). Abteilung Aquatische Oekotoxikologie

2011-12-15

The present project aims to characterise the exposure pathways for endocrine disruptors from plastic materials. A bioassay-based approach was employed to investigate and characterise the endocrine activity. Migration studies with food packaging and plastic preforms document the leaching of estrogen-like compounds from several types of plastic in the Yeast Estrogen Screen and the E-Screen. Additionally, anti-estrogenic activity was predominant in many samples. The detection of complex migration profiles provides evidence for the leaching of several, diverse-acting endocrine disruptors. Moreover, extracts of plastic food packaging exhibited agonistic activity on the estrogen receptor, retinoid X receptor, and vitamin D receptor. A theoretical exposure assessment for marine molluscs implies that endocrine disruptors from plastic might induce relevant effect in the environment. Within the exemplary investigation of bottled mineral water, 60% of the products were characterised as significantly estrogenic using the YES and E-Screen. These in vitro data point to the plastic packaging being one source of estrogenic contamination. An in vivo study employing the estrogen-sensitive model organism Potamopyrgus antipodarum supports this hypothesis. By using several analytical techniques (GC-MS, LC-MS/MS) we identified several well-known endocrine disruptors in bottled water and the plastic material, e.g. numerous phthalates and phenols. Moreover, potent antagonists of the estrogen and androgen receptor were extracted from bottled water. In a non-target analysis (Orbitrap-MS) a compound with the exact mass of 363.1992 [M+H{sup +}] correlated highly significantly with the biological activity. On the basis of the methods optimised and applied within the project we elaborated a set of aspects that are crucial for the applicability of bioassays to characterise the endocrine activity of complex samples. Employing a bioassay-based approach we provide evidence for the presence and

Development of a new adsorbent from agro-industrial waste and its potential use in endocrine disruptor compound removal.

Science.gov (United States)

Rovani, Suzimara; Censi, Monique T; Pedrotti, Sidnei L; Lima, Eder C; Cataluña, Renato; Fernandes, Andreia N

2014-04-30

A new activated carbon (AC) material was prepared by pyrolysis of a mixture of coffee grounds, eucalyptus sawdust, calcium hydroxide and soybean oil at 800°C. This material was used as adsorbent for the removal of the endocrine disruptor compounds 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) from aqueous solutions. The carbon material was characterized by scanning electron microscopy (SEM), infrared spectroscopy (FTIR), N2 adsorption/desorption curves and point of zero charge (pHPZC). Variables including the initial pH of the adsorbate solutions, adsorbent masses and contact time were optimized. The optimum range of initial pH for removal of endocrine disruptor compounds (EDC) was 2.0-11.0. The kinetics of adsorption were investigated using general order, pseudo first-order and pseudo-second order kinetic models. The Sips isotherm model gave the best fits of the equilibrium data (298K). The maximum amounts of E2 and EE2 removed at 298K were 7.584 (E2) and 7.883mgg(-1) (EE2) using the AC as adsorbent. The carbon adsorbent was employed in SPE (solid phase extraction) of E2 and EE2 from aqueous solutions. Copyright © 2014 Elsevier B.V. All rights reserved.

Negative role of the environmental endocrine disruptors in the human neurodevelopment

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Luca Roncati

2016-08-01

Full Text Available The endocrine disruptors (EDs are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS and 8 cases of sudden infant death syndrome (SIDS, collected by centralization in the last year (2015. More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides (OCPs, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs, chlorpyrifos and chlorfenvinfos, have been found in 7 and 3 samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers, but simply time-deferral mechanisms of absorption.

Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease.

Science.gov (United States)

Nilsson, Eric E; Anway, Matthew D; Stanfield, Jacob; Skinner, Michael K

2008-05-01

Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1-F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with vinclozolin (i.e., fungicide with anti-androgenic activity) on embryonic (E) days E8-E14 of gestation. F1 control and vinclozolin generation offspring from different litters were mated to produce F2 offspring, and similarly F2 generation animals produced F3 generation offspring. Observations demonstrated that 9 out of 105 pregnant rats (8.6%) from the vinclozolin F1-F3 generations exhibited uterine hemorrhage and/or anemia late in pregnancy. None (0 out of 82) of the control F1-F3 generation females had similar pregnancy problems. Complete blood cell counts and serum chemistry profiles demonstrated that selected vinclozolin generation animals, but not controls, exhibited marked regenerative anemia in late pregnancy. Examination of kidney histology revealed moderate or severe glomerular abnormalities in 67% of the vinclozolin F2 and F3 generation adult females compared with 18% of the controls. Adult female vinclozolin generation animals also developed various types of tumors in 6.5% of the animals (11 out of 170), while 2% of control-line animals (3 out of 151) developed mammary tumors. Observations demonstrate that vinclozolin exposure during gonadal sex determination promotes a transgenerational increase in pregnancy abnormalities and female adult onset disease states.

Exposure to paper mill effluent at a site in North Central Florida elicits molecular-level changes in gene expression indicative of progesterone and androgen exposure.

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Erica K Brockmeier

Full Text Available Endocrine disrupting compounds (EDCs are chemicals that negatively impact endocrine system function, with effluent from paper mills one example of this class of chemicals. In Florida, female Eastern mosquitofish (Gambusia holbrooki have been observed with male secondary sexual characteristics at three paper mill-impacted sites, indicative of EDC exposure, and are still found at one site on the Fenholloway River. The potential impacts that paper mill effluent exposure has on the G. holbrooki endocrine system and the stream ecosystem are unknown. The objective of this study was to use gene expression analysis to determine if exposure to an androgen receptor agonist was occurring and to couple this analysis with in vitro assays to evaluate the presence of androgen and progesterone receptor active chemicals in the Fenholloway River. Focused gene expression analyses of masculinized G. holbrooki from downstream of the Fenholloway River paper mill were indicative of androgen exposure, while genes related to reproduction indicated potential progesterone exposure. Hepatic microarray analysis revealed an increase in the expression of metabolic genes in Fenholloway River fish, with similarities in genes and biological processes compared to G. holbrooki exposed to androgens. Water samples collected downstream of the paper mill and at a reference site indicated that progesterone and androgen receptor active chemicals were present at both sites, which corroborates previous chemical analyses. Results indicate that G. holbrooki downstream of the Fenholloway River paper mill are impacted by a mixture of both androgens and progesterones. This research provides data on the mechanisms of how paper mill effluents in Florida are acting as endocrine disruptors.

Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor

International Nuclear Information System (INIS)

Mikamo, Eriko; Harada, Shingo; Nishikawa, Jun-ichi; Nishihara, Tsutomu

2003-01-01

Pregnane X receptor (PXR) is a nuclear receptor that regulates the expression of genes for cytochrome P450 3A (CYP3A), multidrug resistance 1 (MDR1), and organic anion-transporting peptide 2 (OATP2). These genes control the metabolism (CYP3A subfamily) and aspects of the pharmacokinetics (MDR1 and OATP2) of both endogenous and xenobiotic compounds. Since PXR is important in understanding the actions of endocrine disruptors (EDs), we determined the ability of suspected EDs to interact with PXR. In our study, 7 of 54 xenobiotics compounds interacted with PXR, including methoxychlor and benzophenone. All of the chemicals activated PXR in vitro and induced CYP3A mRNA in the male rat liver. In addition, CYP2C11 was also induced by some PXR agonists and converted methoxychlor into xenoestrogen. These findings suggest that some EDs affect sex hormone receptor indirectly by induction of metabolic enzyme via PXR, to produce rapidly higher concentrations of effective metabolites, leading to disturbance of the endocrine system

NMR WaterLOGSY Reveals Weak Binding of Bisphenol A with Amyloid Fibers of a Conserved 11 Residue Peptide from Androgen Receptor.

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Julia Asencio-Hernández

Full Text Available There is growing evidence that bisphenol A (BPA, a molecule largely released in the environment, has detrimental effects on ecosystems and on human health. It acts as an endocrine disruptor targeting steroid hormone receptors, such as the estrogen receptor (ER, estrogen-related receptor (ERR and androgen receptor (AR. BPA-derived molecules have recently been shown to interact with the AR N-terminal domain (AR-NTD, which is known to be largely intrinsically disordered. This N-terminal domain contains an 11 residue conserved domain that forms amyloid fibers upon oxidative dimerisation through its strictly conserved Cys240 residue. We investigate here the interaction of BPA, and other potential endocrine disruptors, with AR-NTD amyloid fibers using the WaterLOGSY NMR experiment. We observed a selective binding of these compounds to the amyloid fibers formed by the AR-NTD conserved region and glutamine homopolymers. This observation suggests that the high potency of endocrine disruptors may result, in part, from their ability to bind amyloid forms of nuclear receptors in addition to their cognate binding sites. This property may be exploited to design future therapeutic strategies targeting AR related diseases such as the spinal bulbar muscular atrophy or prostate cancer. The ability of NMR WaterLOGSY experiments to detect weak interactions between small ligands and amyloid fibers may prove to be of particular interest for identifying promising hit molecules.

Endocrine disrupting chemicals: harmful substances and how to test them

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Olea-Serrano Nicolás

2002-01-01

Full Text Available This paper presents an analysis of the opinions of different groups from: scientists, international regulatory bodies, non-governmental organizations and industry; with an interest in the problem of identifying chemical substances with endocrine disrupting activity. There is also discussion of the consequences that exposure to endocrine disruptors may have for human health, considering concrete issues related to: the estimation of risk; the tests that must be used to detect endocrine disruption; the difficulties to establish an association between dose, time of exposure, individual susceptibility, and effect; and the attempts to create a census of endocrine disruptors. Finally, it is proposed that not all hormonal mimics should be included under the single generic denomination of endocrine disruptors.

Proposal of how to update the standard information requirements in REACH, PPPR and BPR – a testing strategy for identification of endocrine disruptors

DEFF Research Database (Denmark)

Holbech, Henrik; Bjerregaard, Poul; Hass, Ulla

to these, new test methods that include endocrine sensitive endpoints have been included with regard to human health and the environment. Similar data requirements and new test methods that include endocrine sensitive endpoints are included in the guidance on Regulation (EU) No 528/2012 on how to fulfil...... review on EDs and the revised strategy for the future work on endocrine disruptors, focusing on adequate detection of substances with endocrine disrupting properties under various legislative frameworks, including REACH (EC No 1907/2006), the Plant Protection Products Regulation (PPPR) (EC No 1107....../2009) and the Biocidal Products Regulation (BPR) (EC No 528/2012). There are currently no specific information requirements or testing strategies with regard to endocrine disruption in REACH and other relevant legislations. However, in relation to biocides and recently also to plant protection products, indications...

Endocrine Disruptors and Health Effects in Africa: A Call for Action.

Science.gov (United States)

Bornman, Maria S; Aneck-Hahn, Natalie H; de Jager, Christiaan; Wagenaar, Gesina M; Bouwman, Hindrik; Barnhoorn, Irene E J; Patrick, Sean M; Vandenberg, Laura N; Kortenkamp, Andreas; Blumberg, Bruce; Kimmins, Sarah; Jegou, Bernard; Auger, Jacques; DiGangi, Joseph; Heindel, Jerrold J

2017-08-22

Africa faces a number of unique environmental challenges. Unfortunately, it lacks the infrastructure needed to support the comprehensive environmental studies that could provide the scientific basis to inform environmental policies. There are a number of known sources of endocrine-disrupting chemicals (EDCs) and other hazardous chemicals in Africa. However, a coordinated approach to identify and monitor these contaminants and to develop strategies for public health interventions has not yet been made. This commentary summarizes the scientific evidence presented by experts at the First African Endocrine Disruptors meeting. We describe a "call to action" to utilize the available scientific knowledge to address the impact of EDCs on human and wildlife health in Africa. We identify existing knowledge gaps about exposures to EDCs in Africa and describe how well-designed research strategies are needed to address these gaps. A lack of resources for research and a lag in policy implementation slows down intervention strategies and poses a challenge to advancing future health in Africa. To address the many challenges posed by EDCs, we argue that Africans should take the lead in prioritization and evaluation of environmental hazards, including EDCs. We recommend the institution of education and training programs for chemical users, adoption of the precautionary principle, establishment of biomonitoring programs, and funding of community-based epidemiology and wildlife research programs led and funded by African institutes and private companies. https://doi.org/10.1289/EHP1774.

[Determination of four phenolic endocrine disruptors in environmental water samples by high performance liquid chromatography-fluorescence detection using dispersive liquid-liquid microextraction coupled with derivatization].

Science.gov (United States)

Wang, Xiaoyan; Qi, Weimei; Zhao, Xian'en; Lü, Tao; Wang, Xiya; Zheng, Longfang; Yan, Yehao; You, Jinmao

2014-06-01

To achieve accurate, fast and sensitive detection of phenolic endocrine disruptors in small volume of environmental water samples, a method of dispersive liquid-liquid microextraction (DLLME) coupled with fluorescent derivatization was developed for the determination of bisphenol A, nonylphenol, octylphenol and 4-tert-octylphenol in environmental water samples by high performance liquid chromatography-fluorescence detection (HPLC-FLD). The DLLME and derivatization conditions were investigated, and the optimized DLLME conditions for small volume of environmental water samples (pH 4.0) at room temperature were as follows: 70 microL chloroform as extraction solvent, 400 microL acetonitrile as dispersing solvent, vortex mixing for 3 min, and then high-speed centrifugation for 2 min. Using 2-[2-(7H-dibenzo [a, g] carbazol-7-yl)-ethoxy] ethyl chloroformate (DBCEC-Cl) as precolumn derivatization reagent, the stable derivatives of the four phenolic endocrine disruptors were obtained in pH 10.5 Na2CO3-NaHCO3 buffer/acetonitrile at 50 degrees C for 3 min, and then separated within 10 min by HPLC-FLD. The limits of detection (LODs) were in the range of 0.9-1.6 ng/L, and the limits of quantification (LOQs) were in the range of 3.8-7.1 ng/L. This method had perfect linearity, precision and recovery results, and showed obvious advantages and practicality comparing to the previously reported methods. It is a convenient and validated method for the routine analysis of phenolic endocrine disruptors in waste water of paper mill, lake water, domestic wastewater, tap water, etc.

The use and acceptance of Other Scientifically Relevant Information (OSRI) in the U.S. Environmental Protection Agency (EPA) Endocrine Disruptor Screening Program.

Science.gov (United States)

Bishop, Patricia L; Willett, Catherine E

2014-02-01

The U.S. Environmental Protection Agency (EPA) Endocrine Disruptor Screening Program (EDSP) currently relies on an initial screening battery (Tier 1) consisting of five in vitro and six in vivo assays to evaluate a chemical's potential to interact with the endocrine system. Chemical companies may request test waivers based on Other Scientifically Relevant Information (OSRI) that is functionally equivalent to data gathered in the screening battery or that provides information on a potential endocrine effect. Respondents for 47 of the first 67 chemicals evaluated in the EDSP submitted OSRI in lieu of some or all Tier 1 tests, seeking 412 waivers, of which EPA granted only 93. For 20 of the 47 chemicals, EPA denied all OSRI and required the entire Tier 1 battery. Often, the OSRI accepted was either identical to data generated by the Tier 1 assay or indicated a positive result. Although identified as potential sources of OSRI in EPA guidance, Part 158 guideline studies for pesticide registration were seldom accepted by EPA. The 93 waivers reduced animal use by at least 3325 animals. We estimate 27,731 animals were used in the actual Tier 1 tests, with additional animals being used in preparation for testing. Even with EPA's shift toward applying 21st-century toxicology tools to screening of endocrine disruptors in the future, acceptance of OSRI will remain a primary means for avoiding duplicative testing and reducing use of animals in the EDSP. Therefore, it is essential that EPA develop a consistent and transparent basis for accepting OSRI. © 2013 Wiley Periodicals, Inc.

Effect of an endocrine disruptor on mammalian fertility. Application of monoclonal antibodies against sperm protein as marker for testing sperm damage

Czech Academy of Sciences Publication Activity Database

Pěknicová, Jana; Kyselová, Vendula; Buckiová, Daniela; Boubelík, Michael

2002-01-01

Roč. 2002, č. 47 (2002), s. 311-318 ISSN 1046-7408 R&D Projects: GA ČR GV524/96/K162; GA ČR GA303/00/1651; GA MZd NJ5851 Institutional research plan: CEZ:AV0Z5039906; CEZ:AV0Z5052915 Keywords : acrosome integrity * bisphenol -A * endocrine disruptor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.413, year: 2002

The endocrine disruptor bisphenol A may play a role in the aetiopathogenesis of polycystic ovary syndrome in adolescent girls.

Science.gov (United States)

Akın, Leyla; Kendirci, Mustafa; Narin, Figen; Kurtoglu, Selim; Saraymen, Recep; Kondolot, Meda; Koçak, Selda; Elmali, Ferhan

2015-04-01

Experimental in vitro studies have shown that bisphenol A affects steroidogenesis, folliculogenesis and ovarian morphology. The aim of this study was to investigate the role of the endocrine disruptor bisphenol A in the aetiopathogenesis of polycystic ovary syndrome (PCOS) in adolescents and its relationship with metabolic parameters, insulin resistance and obesity in this population. A total of 112 girls with PCOS and 61 controls between 13 and 19 years of age were enrolled in the study. Serum bisphenol A levels were measured by high-pressure liquid chromatography. An oral glucose tolerance test was also performed. Adolescents with PCOS had markedly increased serum bisphenol A levels (mean: 1.1 ng/mL 95% CI: 1.0-1.2) than controls (mean: 0.8 ng/mL 95% CI: 0.6-0.9, p = 0.001). When we compared the subgroups according to obesity, the main factor determining the significant increase in bisphenol A was the presence of PCOS, but not obesity (p = 0.029). Bisphenol A was significantly correlated with total testosterone (r = 0.52), free testosterone (r = 0.44), dehydroepiandrosterone sulphate (r = 0.37) and Ferriman-Gallwey score (r = 0.43) (p bisphenol A levels than controls, independent of obesity. Bisphenol A concentrations were significantly correlated with androgen levels, leading us to consider that bisphenol A might play a role in the aetiopathogenesis of PCOS in adolescents. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

The effect of endocrine disruptors on reproductive parameters and expression of selected testicular genes in male mice in vivo

Czech Academy of Sciences Publication Activity Database

Pěknicová, Jana; Elzeinová, Fatima; Žatecká, Eva; Děd, Lukáš; Dorosh, Andriy

2012-01-01

Roč. 67, Issue Supplement s1 (2012), s. 20 ISSN 1046-7408. [13th International Symposium for Immunology of reproduction "From the roots to the tops of Reproductive Immunology". 22.06.2012-24.06.2012, Varna] R&D Projects: GA ČR(CZ) GA523/09/1793; GA ČR(CZ) GAP503/12/1834 Institutional research plan: CEZ:AV0Z50520701 Keywords : endocrine disruptors * testicular gene * reproductive parameters * reproduction Subject RIV: DN - Health Impact of the Environment Quality

IFPA meeting 2015 workshop report III: nanomedicine applications and exosome biology, xenobiotics and endocrine disruptors and pregnancy, and lipid.

Science.gov (United States)

Albrecht, C; Caniggia, I; Clifton, V; Göhner, C; Harris, L; Hemmings, D; Jawerbaum, A; Johnstone, E; Jones, H; Keelan, J; Lewis, R; Mitchell, M; Murthi, P; Powell, T; Saffery, R; Smith, R; Vaillancourt, C; Wadsack, C; Salomon, C

2016-12-01

Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology; 2) xenobiotics and endocrine disruptors and pregnancy; 3) lipid mediators and placental function. Copyright © 2016. Published by Elsevier Ltd.

The molecular mechanism of bisphenol A (BPA as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD simulations.

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Lanlan Li

Full Text Available Bisphenol A (BPA can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA.

Development of a new adsorbent from agro-industrial waste and its potential use in endocrine disruptor compound removal

International Nuclear Information System (INIS)

Rovani, Suzimara; Censi, Monique T.; Pedrotti, Sidnei L.; Lima, Éder C.; Cataluña, Renato; Fernandes, Andreia N.

2014-01-01

Highlights: • Development of a new adsorbent from agro-industrial waste. • Characterization by chemical and spectroscopic methods. • Alternative for the treatment of effluents that contain estrogens. • The AC adsorbent was successfully employed as solid phase adsorbent for the preconcentration of E2 and EE2 from aqueous solutions. - Abstract: A new activated carbon (AC) material was prepared by pyrolysis of a mixture of coffee grounds, eucalyptus sawdust, calcium hydroxide and soybean oil at 800 °C. This material was used as adsorbent for the removal of the endocrine disruptor compounds 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) from aqueous solutions. The carbon material was characterized by scanning electron microscopy (SEM), infrared spectroscopy (FTIR), N 2 adsorption/desorption curves and point of zero charge (pH PZC ). Variables including the initial pH of the adsorbate solutions, adsorbent masses and contact time were optimized. The optimum range of initial pH for removal of endocrine disruptor compounds (EDC) was 2.0–11.0. The kinetics of adsorption were investigated using general order, pseudo first-order and pseudo-second order kinetic models. The Sips isotherm model gave the best fits of the equilibrium data (298 K). The maximum amounts of E2 and EE2 removed at 298 K were 7.584 (E2) and 7.883 mg g −1 (EE2) using the AC as adsorbent. The carbon adsorbent was employed in SPE (solid phase extraction) of E2 and EE2 from aqueous solutions

Development of a new adsorbent from agro-industrial waste and its potential use in endocrine disruptor compound removal

Energy Technology Data Exchange (ETDEWEB)

Rovani, Suzimara; Censi, Monique T.; Pedrotti, Sidnei L.; Lima, Éder C.; Cataluña, Renato; Fernandes, Andreia N., E-mail: andreia.fernandes@ufrgs.br

2014-04-01

Highlights: • Development of a new adsorbent from agro-industrial waste. • Characterization by chemical and spectroscopic methods. • Alternative for the treatment of effluents that contain estrogens. • The AC adsorbent was successfully employed as solid phase adsorbent for the preconcentration of E2 and EE2 from aqueous solutions. - Abstract: A new activated carbon (AC) material was prepared by pyrolysis of a mixture of coffee grounds, eucalyptus sawdust, calcium hydroxide and soybean oil at 800 °C. This material was used as adsorbent for the removal of the endocrine disruptor compounds 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) from aqueous solutions. The carbon material was characterized by scanning electron microscopy (SEM), infrared spectroscopy (FTIR), N{sub 2} adsorption/desorption curves and point of zero charge (pH{sub PZC}). Variables including the initial pH of the adsorbate solutions, adsorbent masses and contact time were optimized. The optimum range of initial pH for removal of endocrine disruptor compounds (EDC) was 2.0–11.0. The kinetics of adsorption were investigated using general order, pseudo first-order and pseudo-second order kinetic models. The Sips isotherm model gave the best fits of the equilibrium data (298 K). The maximum amounts of E2 and EE2 removed at 298 K were 7.584 (E2) and 7.883 mg g{sup −1} (EE2) using the AC as adsorbent. The carbon adsorbent was employed in SPE (solid phase extraction) of E2 and EE2 from aqueous solutions.

Preparation and characterization of sodium dodecyl sulfate doped polypyrrole solid phase micro extraction fiber and its application to endocrine disruptor pesticide analysis

OpenAIRE

Korba, Korcan; Pelit, Levent; Okçu Pelit, Füsun; Özdokur, K. Volkan; Ertaş, Hasan; Eroğlu, Ahmet E.; Ertaş, Fatma Nil

2013-01-01

A robust in house solid-phase micro extraction (SPME) surface has been developed for the headspace (HS)-SPME determination of endocrine disruptor pesticides, namely, Chlorpyrifos, Penconazole, Procymidone, Bromopropylate and Lambda-Cyhalothrin in wine sample by using sodium dodecylsulfate doped polypyrrole SPME fiber. Pyrrole monomer was electrochemically polymerized on a stainless steel wire in laboratory conditions in virtue of diminishing the cost and enhancing the analyte retention on its...

Endocrine disruptors in water filters used in the Rio dos Sinos Basin region, Southern Brazil

Directory of Open Access Journals (Sweden)

CM Furtado

Full Text Available The activated carbon filter is used in residences as another step in the treatment of drinking water, based on a physical-chemical process to absorb pollutants that are not removed in conventional treatment. Endocrine disruptors (EDCs are exogenous substances or mixtures of substances that acts on the endocrine system similarly to the endogenously produced hormones, triggering malfunctions and harmful changes to human and animal health. The objective of the present work was to study EDCs through semi-quantitative analysis of residential water filters collected in the region of Rio dos Sinos basin, focusing on two specific classes: hormones and phenols. The solid phase extraction principle was used for the extraction of compounds and gas chromatography coupled with mass spectrometry for the separation and characterization of EDCs. Four samples of residential filters collected from public water distribution and artesian wells, from the cities of Novo Hamburgo and São Leopoldo were analysed. Using the developed methodology, it was possible to detect and comparatively quantify selected EDCs in all studied samples, which indicates the presence of these contaminants in drinking water from different sources.

Recent advances in sample preparation methods for analysis of endocrine disruptors from various matrices.

Science.gov (United States)

Singh, Baljinder; Kumar, Ashwini; Malik, Ashok Kumar

2014-01-01

Due to the high toxicity of endocrine disruptors (EDs), studies are being undertaken to design effective techniques for separation and detection of EDs in various matrices. Recently, research activities in this area have shown that a diverse range of chromatographic techniques are available for the quantification and analysis of EDs. Therefore, on the basis of significant, recent original publications, we aimed at providing an overview of different separation and detection methods for the determination of trace-level concentrations of selected EDs. The biological effects of EDs and current pretreatment techniques applied to EDs are also discussed. Various types of chromatographic techniques are presented for quantification, highlighting time- and cost-effective techniques that separate and quantify trace levels of multiple EDs from various environmental matrices. Reports related to methods for the quantification of EDs from various matrices primarily published since 2008 have been cited.

Removal of endocrine disruptors PAEs in drinking water by gamma-ray irradiation

International Nuclear Information System (INIS)

Zhao Yongfu; Zheng Zheng; Zheng Binguo; Wang Changbao; Li Lili

2012-01-01

Phthalic acid esters (PAEs) belong to environmental endocrine disruptor. The dimethyl phthalate (DMP), diethyl phthalate (DEP) and di-n-butyl phthalate (DBP) were selected for the radiation study. The removal efficiencies of DMP, DEP and DBP in drinking water by gamma-ray irradiation are discussed. The results show that these PAEs could be efficiently removed by gamma-ray irradiation. The removal efficiencies of DMP, DEP and DBP (12 mg/L) in aqueous solutions by 0.8 kGy gamma-ray treatment were 96.6%, 94.5% and 86.2%. The absorbed dose needed for the removal of total carbon in aqueous solutions was much larger than the doses for PAEs degradation. When 2 kGy was selected, the removal efficiencies of TC for DMP, DEP and DBP were only 23.6%, 14.3% and 12.9%. The study results also show that the radiation degradation reaction of PAEs should be divided into two stages: low dose addition reaction and high dose ring-opening reaction. This study is of significance in the disposal of micro-polluted drinking water. (authors)

Estrogenic and anti-androgenic endocrine disrupting chemicals and their impact on the male reproductive system.

Directory of Open Access Journals (Sweden)

Maria eDe Falco

2015-02-01

Full Text Available Endocrine disrupting chemicals (EDCs are identified for their ability to perturb the homeostasis of endocrine system and hormonal balance. The male reproductive system is under close control of hormones and each change in their concentration and time of exposition and action can induce a deregulation of its physiology. In this review we summarize the most recent studies on two main categories of EDCs with different action: the estrogenic bisphenol A and alkylphenols and the anti-androgenic phthalates. This review describes the main effects of these substances on male reproductive system.

Nuclear receptors and endocrine disruptors in fetal and neonatal testes: a gapped landscape.

Directory of Open Access Journals (Sweden)

Virginie eRouiller-Fabre

2015-05-01

Full Text Available During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment. Among the chemicals present in the environment (air, water, food and many consumer products, several can act as endocrine disrupting compounds (EDCs, thus interfering with the endocrine system. Phthalates, bisphenol A (BPA and diethylstilbestrol (DES have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development. As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review we discuss the role of classical nuclear receptors (genomic pathway in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA and DES. Among the nuclear receptors we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR, androgen receptor (AR, estrogen receptors (ERα and β, liver X receptors (LXR and small heterodimer partner (SHP. First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s. We also point-out the involvement of other receptors and nuclear receptor-independent pathways.

Per- and polyfluoroalkyl substances (PFASs) - New endocrine disruptors in polar bears (Ursus maritimus)?

Science.gov (United States)

Pedersen, Kathrine Eggers; Letcher, Robert J; Sonne, Christian; Dietz, Rune; Styrishave, Bjarne

2016-11-01

Per- and polyfluoroalkyl substances (PFASs) are emerging in the Arctic and accumulate in brain tissues of East Greenland (EG) polar bears. In vitro studies have shown that PFASs might possess endocrine disrupting abilities and therefore the present study was conducted to investigate potential PFAS induced alterations in brain steroid concentrations. The concentrations of eleven steroid hormones were determined in eight brain regions from ten EG polar bears. Pregnenolone (PRE), the dominant progestagen, was found in mean concentrations of 5-47ng/g (ww) depending on brain region. PRE showed significantly (pbears. Dehydroepiandrosterone (DHEA) found in mean concentrations 0.67-4.58ng/g (ww) was the androgen found in highest concentrations. Among the estrogens estrone (E1) showed mean concentrations of 0.90-2.21ng/g (ww) and was the most abundant. Remaining steroid hormones were generally present in concentrations below 2ng/g (ww). Steroid levels in brain tissue could not be explained by steroid levels in plasma. There was however a trend towards increasing estrogen levels in plasma resulting in increasing levels of androgens in brain tissue. Correlative analyses showed positive associations between PFASs and 17α-hydroxypregnenolone (OH-PRE) (e.g. perflouroalkyl sulfonates (∑PFSA): ppolar bears. It is, however, not possible to determine whether alterations in brain steroid concentrations arise from interference with de novo steroid synthesis or via disruption of peripheral steroidogenic tissues mainly in gonads and feedback mechanisms. Steroids are important for brain plasticity and gender specific behavior as well as postnatal development and sexually dimorph brain function. The present work indicates an urgent need for a better mechanistic understanding of how PFASs may affect the endocrine system of polar bears and potentially other mammal species. Copyright © 2016 Elsevier Ltd. All rights reserved.

Does Cancer Start in the Womb? Altered Mammary Gland Development and Predisposition to Breast Cancer due to in Utero Exposure to Endocrine Disruptors

OpenAIRE

Soto, Ana M.; Brisken, Cathrin; Schaeberle, Cheryl; Sonnenschein, Carlos

2013-01-01

We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary ...

Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

NARCIS (Netherlands)

Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

2015-01-01

Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

Evaluation of organic endocrine disruptors in water at Brazilian Multipurpose Reactor - RMB installation area

Energy Technology Data Exchange (ETDEWEB)

Silva, Larissa L.; Martins, Elâine A.J.; Cotrim, Marycel E.B.; Pires, Maria A.F., E-mail: larissa.limeira07@gmail.com, E-mail: elaine@ipen.br, E-mail: mecotrim@ipen.br, E-mail: mapires@ipen.br [Instituto de Pesquisas Energéticas e Nucleares (IPEN/CNEN-SP), São Paulo, SP (Brazil)

2017-07-01

The study of pollutants with organic and inorganic characteristics in groundwater and surface waters of a given region is an important tool in the assessment of pollution. Endocrine interferers are synthetic or natural chemicals that have the ability to act on the endocrine system of humans and animals by mimetizing natural hormones and may produce adverse effects on organisms, even in low concentrations (μg or ng.L{sup -1}). Anthropic activities are the major source of input of endocrine disruptors into the environment. The Brazilian government has a project to construct a multipurpose reactor, Brazilian Multipurpose Reactor (RMB), at the Iperó city, to improve the nuclear research Brazilian capacity. The object of this research in to analyze 14 organic compounds that may be present in the groundwater and surface waters of the RMB installation area. This is an unprecedented and extremely important study for the evaluated region; since it will provide guidance on the degree of contamination of the local waters before the construction begins. The study will also make it possible to verify if the construction of the RMB will offer environmental issues to the place. For the determination of the compounds of interest, a developed and validated analytical method was used. This methodology consists of the concentration of the samples by solid phase extraction (SPE) followed by quantification by gas chromatography coupled to the mass spectrometry detector (GC/MS). The water column particulate was also evaluated by ultrasonic extraction, followed by quantification by GC/MS. The results reveal that some of the compounds were found and it was due to anthropic activities in the vicinity of the regions. By initial analysis it was possible verify river that cross the RMB area present values below 0.05 μg L{sup -1}. (author)

Evaluation of organic endocrine disruptors in water at Brazilian Multipurpose Reactor - RMB installation area

International Nuclear Information System (INIS)

Silva, Larissa L.; Martins, Elâine A.J.; Cotrim, Marycel E.B.; Pires, Maria A.F.

2017-01-01

The study of pollutants with organic and inorganic characteristics in groundwater and surface waters of a given region is an important tool in the assessment of pollution. Endocrine interferers are synthetic or natural chemicals that have the ability to act on the endocrine system of humans and animals by mimetizing natural hormones and may produce adverse effects on organisms, even in low concentrations (μg or ng.L -1 ). Anthropic activities are the major source of input of endocrine disruptors into the environment. The Brazilian government has a project to construct a multipurpose reactor, Brazilian Multipurpose Reactor (RMB), at the Iperó city, to improve the nuclear research Brazilian capacity. The object of this research in to analyze 14 organic compounds that may be present in the groundwater and surface waters of the RMB installation area. This is an unprecedented and extremely important study for the evaluated region; since it will provide guidance on the degree of contamination of the local waters before the construction begins. The study will also make it possible to verify if the construction of the RMB will offer environmental issues to the place. For the determination of the compounds of interest, a developed and validated analytical method was used. This methodology consists of the concentration of the samples by solid phase extraction (SPE) followed by quantification by gas chromatography coupled to the mass spectrometry detector (GC/MS). The water column particulate was also evaluated by ultrasonic extraction, followed by quantification by GC/MS. The results reveal that some of the compounds were found and it was due to anthropic activities in the vicinity of the regions. By initial analysis it was possible verify river that cross the RMB area present values below 0.05 μg L -1 . (author)

Endocrine disruptors in freshwater streams of Hesse, Germany: changes in concentration levels in the time span from 2003 to 2005.

Science.gov (United States)

Quednow, Kristin; Püttmann, Wilhelm

2008-03-01

Four small freshwater streams in the region known as Hessisches Ried in Germany were investigated with respect to the temporal and spatial concentration variations of the endocrine disruptors bisphenol A (BPA), 4-tert-octylphenol (4-tert-OP), and the technical isomer mixture of 4-nonylphenol (tech.-4-NP). Measured concentrations of the target compounds in the river water samples ranged from marketing and use of nonylphenols. Results from the analysis of additionally collected water samples from sewage treatment plant (STP) effluents indicate that the STPs cannot be the only sources for tech.-4-NP found in the river water.

Exposure of rats to exogenous endocrine disruptors 17alpha-ethinylestradiol and benzo(a) pyrene and an estrogenic hormone estradiol induces expression of cytochromes P450 involved in their metabolism

Czech Academy of Sciences Publication Activity Database

Bořek-Dohalská, L.; Klusoňová, Z.; Holecová, J.; Martinková, M.; Bárta, F.; Dračínská, H.; Cajthaml, Tomáš; Stiborová, M.

2016-01-01

Roč. 37, Sup 1 (2016), s. 84-94 ISSN 0172-780X R&D Projects: GA ČR(CZ) GA15-02328S Institutional support: RVO:61388971 Keywords : endocrine disruptor * 17 alpha-ethinylestradiol * cytochrome P450 Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 0.918, year: 2016

Endocrine Disruptors (Chapter 14) in Mammalian Toxicology Book

Science.gov (United States)

Endocrine disrupting chemicals (EDCs) are exogenous substances that alter endocrine system function(s) and consequently cause adverse health effects in intact organisms or its progeny. The endocrine system is important for a wide range of biological processes, from normal cell si...

Mixture Effects of 3 Mechanistically Different Steroidogenic Disruptors (Prochloraz, Genistein, and Ketoconazole) in the H295R Cell Assay

DEFF Research Database (Denmark)

Nielsen, Frederik Knud; Hansen, Cecilie Hurup; Fey, Jennifer Anna

2015-01-01

Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol......Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β...

Presence of endocrine disruptors in freshwater in the northern Antarctic Peninsula region.

Science.gov (United States)

Esteban, S; Moreno-Merino, L; Matellanes, R; Catalá, M; Gorga, M; Petrovic, M; López de Alda, M; Barceló, D; Silva, A; Durán, J J; López-Martínez, J; Valcárcel, Y

2016-05-01

The increasing human presence in Antarctica and the waste it generates is causing an impact on the environment at local and border scale. The main sources of anthropic pollution have a mainly local effect, and include the burning of fossil fuels, waste incineration, accidental spillage and wastewater effluents, even when treated. The aim of this work is to determine the presence and origin of 30 substances of anthropogenic origin considered to be, or suspected of being, endocrine disruptors in the continental waters of the Antarctic Peninsula region. We also studied a group of toxic metals, metalloids and other elements with possible endocrine activity. Ten water samples were analyzed from a wide range of sources, including streams, ponds, glacier drain, and an urban wastewater discharge into the sea. Surprisingly, the concentrations detected are generally similar to those found in other studies on continental waters in other parts of the world. The highest concentrations of micropollutants found correspond to the group of organophosphate flame retardants (19.60-9209ngL(-1)) and alkylphenols (1.14-7225ngL(-1)); and among toxic elements the presence of aluminum (a possible hormonal modifier) (1.7-127µgL(-1)) is significant. The concentrations detected are very low and insufficient to cause acute or subacute toxicity in aquatic organisms. However, little is known as yet of the potential sublethal and chronic effects of this type of pollutants and their capacity for bioaccumulation. These results point to the need for an ongoing system of environmental monitoring of these substances in Antarctic continental waters, and the advisability of regulating at least the most environmentally hazardous of these in the Antarctic legislation. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparative anti-androgenic actions of vinclozolin and flutamide on transgenerational adult onset disease and spermatogenesis.

Science.gov (United States)

Anway, Matthew D; Rekow, Stephen S; Skinner, Michael K

2008-10-01

Exposure of gestating female rats to the anti-androgenic endocrine disruptor vinclozolin has been shown to induce transgenerational adult onset disease phenotypes. The current study, was designed to compare the actions of vinclozolin to the known anti-androgenic compound flutamide. The gestating female rats were exposed to intraperitoneal injections during embryonic day 8-14 (E8-E14) to 100mg/kg/day vinclozolin or flutamide at either 5mg or 20mg/kg/day. As previously observed, vinclozolin induced a transgenerational testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm number. In contrast, the flutamide exposures resulted in a testis phenotype of increased spermatogenic cell apoptosis and decreased epididymal sperm numbers in the F1 generation only, and not the F2 and F3 generation adult males. Interestingly, some of the low dose (5mg/kg) flutamide F2 generation offspring developed spinal agenesis and supernummery development (polymelia) of limbs. Although the actions of vinclozolin and flutamide appear similar in the F1 generation males, the transgenerational effects of vinclozolin do not appear to be acting through the same anti-androgenic mechanism as flutamide.

Electrochemical performance of porous diamond-like carbon electrodes for sensing hormones, neurotransmitters, and endocrine disruptors.

Science.gov (United States)

Silva, Tiago A; Zanin, Hudson; May, Paul W; Corat, Evaldo J; Fatibello-Filho, Orlando

2014-12-10

Porous diamond-like carbon (DLC) electrodes have been prepared, and their electrochemical performance was explored. For electrode preparation, a thin DLC film was deposited onto a densely packed forest of highly porous, vertically aligned multiwalled carbon nanotubes (VACNT). DLC deposition caused the tips of the carbon nanotubes to clump together to form a microstructured surface with an enlarged surface area. DLC:VACNT electrodes show fast charge transfer, which is promising for several electrochemical applications, including electroanalysis. DLC:VACNT electrodes were applied to the determination of targeted molecules such as dopamine (DA) and epinephrine (EP), which are neurotransmitters/hormones, and acetaminophen (AC), an endocrine disruptor. Using simple and low-cost techniques, such as cyclic voltammetry, analytical curves in the concentration range from 10 to 100 μmol L(-1) were obtained and excellent analytical parameters achieved, including high analytical sensitivity, good response stability, and low limits of detection of 2.9, 4.5, and 2.3 μmol L(-1) for DA, EP, and AC, respectively.

A computational model to predict rat ovarian steroid secretion from in vitro experiments with endocrine disruptors.

Directory of Open Access Journals (Sweden)

Nadia Quignot

Full Text Available A finely tuned balance between estrogens and androgens controls reproductive functions, and the last step of steroidogenesis plays a key role in maintaining that balance. Environmental toxicants are a serious health concern, and numerous studies have been devoted to studying the effects of endocrine disrupting chemicals (EDCs. The effects of EDCs on steroidogenic enzymes may influence steroid secretion and thus lead to reproductive toxicity. To predict hormonal balance disruption on the basis of data on aromatase activity and mRNA level modulation obtained in vitro on granulosa cells, we developed a mathematical model for the last gonadal steps of the sex steroid synthesis pathway. The model can simulate the ovarian synthesis and secretion of estrone, estradiol, androstenedione, and testosterone, and their response to endocrine disruption. The model is able to predict ovarian sex steroid concentrations under normal estrous cycle in female rat, and ovarian estradiol concentrations in adult female rats exposed to atrazine, bisphenol A, metabolites of methoxychlor or vinclozolin, and letrozole.

Impact of three endocrine disruptors, Bisphenol A, Genistein and Vinclozolin on female rat enamel.

Science.gov (United States)

Jedeon, K; Berdal, A; Babajko, A

2016-06-28

Concerns about the potential adverse effectsof endocrine disruptors (EDs) have been increasingover the last three decades. BisphenolA (BPA), genistein (G) and vinclozolin (V) arethree widely used EDs sharing similar effects.Since populations are exposed to many diverseEDs simultaneously, we demonstratedrecently their impact alone or combined onmale rat tooth enamel. The purpose of thisstudy was therefore to assess their effects onfemale rat tooth enamel in order to understandwhy they are differentially sensitive. Ratswere exposed daily in utero and after birth tolow doses of EDs during the critical fetal andsuckling periods when amelogenesis takesplace. Enamel of rats exposed to EDs presentedopaque areas of hypomineralization. Theproportion of affected rats was the highestin the groups of rats treated with BPA aloneand higher in males than in females (in all thegroups). Comparison of enamel key gene expressionlevels showed modulations of Klk4and Enamelin in males but no significant variationsin females. These findings show thatfemale rats are less affected than males bythe three EDs chosen in this study and suggestthat enamel hypomineralization may differbetween males and females.

Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles.

Science.gov (United States)

Wagner, Martin; Oehlmann, Jörg

2009-05-01

Food consumption is an important route of human exposure to endocrine-disrupting chemicals. So far, this has been demonstrated by exposure modeling or analytical identification of single substances in foodstuff (e.g., phthalates) and human body fluids (e.g., urine and blood). Since the research in this field is focused on few chemicals (and thus missing mixture effects), the overall contamination of edibles with xenohormones is largely unknown. The aim of this study was to assess the integrated estrogenic burden of bottled mineral water as model foodstuff and to characterize the potential sources of the estrogenic contamination. In the present study, we analyzed commercially available mineral water in an in vitro system with the human estrogen receptor alpha and detected estrogenic contamination in 60% of all samples with a maximum activity equivalent to 75.2 ng/l of the natural sex hormone 17beta-estradiol. Furthermore, breeding of the molluskan model Potamopyrgus antipodarum in water bottles made of glass and plastic [polyethylene terephthalate (PET)] resulted in an increased reproductive output of snails cultured in PET bottles. This provides first evidence that substances leaching from plastic food packaging materials act as functional estrogens in vivo. Our results demonstrate a widespread contamination of mineral water with xenoestrogens that partly originates from compounds leaching from the plastic packaging material. These substances possess potent estrogenic activity in vivo in a molluskan sentinel. Overall, the results indicate that a broader range of foodstuff may be contaminated with endocrine disruptors when packed in plastics.

Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.

Science.gov (United States)

Lv, Xuan; Pan, Liumeng; Wang, Jiaying; Lu, Liping; Yan, Weilin; Zhu, Yanye; Xu, Yiwen; Guo, Ming; Zhuang, Shulin

2017-03-01

Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC 50 ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC 50 of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R 2 between 0.83 and 0.97, p pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Rat α-Fetoprotein Binding Activity Prediction Model to Facilitate Assessment of the Endocrine Disruption Potential of Environmental Chemicals.

Science.gov (United States)

Hong, Huixiao; Shen, Jie; Ng, Hui Wen; Sakkiah, Sugunadevi; Ye, Hao; Ge, Weigong; Gong, Ping; Xiao, Wenming; Tong, Weida

2016-03-25

Endocrine disruptors such as polychlorinated biphenyls (PCBs), diethylstilbestrol (DES) and dichlorodiphenyltrichloroethane (DDT) are agents that interfere with the endocrine system and cause adverse health effects. Huge public health concern about endocrine disruptors has arisen. One of the mechanisms of endocrine disruption is through binding of endocrine disruptors with the hormone receptors in the target cells. Entrance of endocrine disruptors into target cells is the precondition of endocrine disruption. The binding capability of a chemical with proteins in the blood affects its entrance into the target cells and, thus, is very informative for the assessment of potential endocrine disruption of chemicals. α-fetoprotein is one of the major serum proteins that binds to a variety of chemicals such as estrogens. To better facilitate assessment of endocrine disruption of environmental chemicals, we developed a model for α-fetoprotein binding activity prediction using the novel pattern recognition method (Decision Forest) and the molecular descriptors calculated from two-dimensional structures by Mold² software. The predictive capability of the model has been evaluated through internal validation using 125 training chemicals (average balanced accuracy of 69%) and external validations using 22 chemicals (balanced accuracy of 71%). Prediction confidence analysis revealed the model performed much better at high prediction confidence. Our results indicate that the model is useful (when predictions are in high confidence) in endocrine disruption risk assessment of environmental chemicals though improvement by increasing number of training chemicals is needed.

Long term impact of the endocrine disruptor tributyltin on male fertility following a single acute exposure.

Science.gov (United States)

Mitra, Sumonto; Srivastava, Ankit; Khandelwal, Shashi

2017-10-01

Declining rate of human fertility is a growing concern, where lifestyle and environmental factors play an important role. We recently demonstrated that tributyltin (TBT), an omnipresent endocrine disruptor, affects testicular cells in vitro. In this study, male Wistar rats were gavaged a single dose of 10, 20, and 30 mg/kg TBT-chloride (TBTC) (to mimic accidental exposure in vivo) and sacrificed on day 3 and day 7, respectively. TBT bioavailability was evaluated by estimating total tin content, and essential metal levels were analyzed along with redox molecules (ROS and GSH/GSSG) to understand the effect on physiological conditions. Blood-testicular barrier (BTB) disruption, levels of associated proteins and activity of proteolytic enzymes were evaluated to understand the effect on BTB. Histological analysis of tissue architecture and effect on protein expression of steroidogenic, stress and apoptotic markers were also evaluated. Widespread TBTC pollution can be an eventual threat to male fertility worldwide. © 2017 Wiley Periodicals, Inc.

Simultaneous effects of endocrine disruptor bisphenol A and flavonoid fisetin on progesterone production by granulosa cells.

Science.gov (United States)

Bujnakova Mlynarcikova, Alzbeta; Scsukova, Sona

2018-04-01

In the present study, we aimed to examine effects of different concentrations of the endocrine disruptor Bisphenol A (BPA; 1 nM, 1 μM, 100 μM) and the flavonoid fisetin (1, 10, 25, 50 μM), individually and in combinations, on steroidogenic function of porcine ovarian granulosa cells (GCs) represented by progesterone production. We confirmed that BPA inhibited progesterone production by GCs at the highest concentration. Fisetin reduced gonadotropin-stimulated progesterone synthesis dose-dependently, and in this manner, fisetin impaired progesterone production when added to BPA-treated GCs. The mechanisms of the inhibitory effects of the combinations included a significant down-regulation of the key steroidogenesis-related genes (STAR, CYP11A1, HSD3B). Our findings suggest for the first time that fisetin might interfere with ovarian steroidogenesis, and might not have beneficial but rather aggravating effects in terms of modulating progesterone synthesis altered by high concentrations of BPA. Copyright © 2018 Elsevier B.V. All rights reserved.

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

DEFF Research Database (Denmark)

Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

2011-01-01

Background: Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine disrupting compounds (EDCs) share a high...... suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades....

Bioindication in natural-like aquatic ecosystems: endocrine disruptors in outdoor microcosms. Status-report

Energy Technology Data Exchange (ETDEWEB)

Schramm, K.W.; Severin, G.F.

2002-07-01

Over the past few decades scientists have shown that the hormone system of a wide range of organisms can be affected by numerous environmental chemicals. Society strongly demands studies about the fate and effects of such endocrine disruptors on the aquatic environment. It has been scientifically accepted that risk assessment studies done in aquatic microcosms can be used to extrapolate the potential impact of the tested compound on natural ecosystems. Realistic exposure situations were simulated and screening methods as well as analytical methods with high accuracy were applied on water and sediment. For the comprehensive risk assessment as many trophic levels as possible have to be investigated. Changes in the population dynamics and the community structure serve as ecotoxicological endpoints. Modelling the concentrations of the chemicals in the different aquatic compartments complements and confirms the analytical diagnostics. A directed design of the analytical procedures according to amount of sample and limits of determination becomes possible. Bridging acute and chronic time scales in effect diagnostics the 'area under the curve' - approach has been followed in combination with multivariate statistics. Haber's rule have been applied to the results about complex effect- and exposure-conditions. In some cases the interpretation of results becomes more easy and clear by this approach. (orig.)

Endocrine active agents: implications of adverse and non-adverse changes.

Science.gov (United States)

Foster, Paul M D; McIntyre, Barry S

2002-01-01

and should always be compared using bodyweight as a covariate. The historical control database for such changes is gradually growing, albeit that if pups are not individually identified it becomes problematic to associate any change with a specific malformation or to assess whether a delay or advance in, for example, developmental landmarks is biologically significant. Agents that significantly reduce AGD in males (it is an androgen-dependent variable) frequently have other more adverse changes associated with this end point (eg, reproductive tract malformations), but a 2 to 3% change in AGD although measurable is unlikely to be biologically of importance and in isolation would not necessarily be considered adverse. Retention of thoracic nipples in male rat pups is also an indicator of impaired androgen status. Recent studies have also shown that this retention for some endocrine active chemicals is permanent. Thus, the presence of a permanent structural change that is rarely found in adult control animals could be considered a malformation and therefore a developmental adverse effect on which risk assessment decisions could be made. The advent of multigeneration reproduction studies as the definitive studies for the assessment of the dose-response relationships and risk assessment for endocrine disruptors has shown that current testing protocols may be inadequate to reliably detect the adverse effects of concern as only 1 adult/sex/litter is examined. A number of the effects on reproductive development although, due to an in utero exposure, will not be manifest until after puberty or at adulthood. The use of only a limited number of animals to examine such changes, particularly for weaker acting materials indicates that some agents may have been examined in well-conducted, modern protocols but have insufficient power to detect low incidence phenomena (eg, a 5% incidence of malformations).

Spreeta-based biosensor for endocrine disruptors

NARCIS (Netherlands)

Marchesini, G.R.; Koopal, K.; Meulenberg, E.; Haasnoot, W.; Irth, H.

2007-01-01

The construction and performance of an automated low-cost Spreeta¿-based prototype biosensor system for the detection of endocrine disrupting chemicals (EDCs) is described. The system consists primarily of a Spreeta miniature liquid sensor incorporated into an aluminum flow cell holder, dedicated to

Application of endocrine disruptor screening program fish short-term reproduction assay: Reproduction and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus) exposed to Bermuda pond sediment.

Science.gov (United States)

Fort, Douglas J; Mathis, Michael; Fort, Chelsea E; Fort, Hayley M; Bacon, Jamie P

2015-06-01

A modified tier 1 Endocrine Disruptor Screening Program (EDSP) 21-d fish short-term reproduction assay (FSTRA) was used to evaluate the effects of sediment exposure from freshwater and brackish ponds in Bermuda on reproductive fecundity and endocrine function in fathead minnow (Pimephales promelas) and killifish (Fundulus heteroclitus). Reproductively active male and female fish were exposed to control sediment and sediment from 2 freshwater ponds (fathead minnow) and 2 marine ponds (killifish) contaminated with polyaromatic hydrocarbons and metals via flow-through exposure for 21 d. Reproductive fecundity was monitored daily. At termination, the status of the reproductive endocrine system was assessed by the gonadosomatic index, gonadal histology, plasma steroids (estrogen [E2], testosterone [T], and 11-ketotestosterone [11-KT]), steroidogenic enzymes (aromatase and combined 3β/17β -hydroxysteroid dehydrogenase [3β/17β-HSD]), and plasma vitellogenin (VTG). Decreased reproductive fecundity, lower male body weight, and altered endocrinological measures of reproductive status were observed in both species. Higher plasma T levels in female minnows and 11-KT levels in both male and female minnows and female killifish exposed to freshwater and brackish sediments, respectively. Decreased female E2 and VTG levels and gonadal cytochrome P19 (aromatase) activity were also found in sediment exposed females from both species. No effect on female 3β/17β-HSD activity was found in either species. The FSTRA provided a robust model capable of modification to evaluate reproductive effects of sediment exposure in fish. © 2015 SETAC.

Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study.

Science.gov (United States)

Ormond, Gillian; Nieuwenhuijsen, Mark J; Nelson, Paul; Toledano, Mireille B; Iszatt, Nina; Geneletti, Sara; Elliott, Paul

2009-02-01

Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. We designed a case-control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997-30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40-4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04-11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44-0.93). Vegetarianism was not associated with hypospadias risk. Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.

Biodegradation of pharmaceuticals and endocrine disruptors with oxygen, nitrate, manganese (IV), iron (III) and sulfate as electron acceptors

Science.gov (United States)

Schmidt, Natalie; Page, Declan; Tiehm, Andreas

2017-08-01

Biodegradation of pharmaceuticals and endocrine disrupting compounds was examined in long term batch experiments for a period of two and a half years to obtain more insight into the effects of redox conditions. A mix including lipid lowering agents (e.g. clofibric acid, gemfibrozil), analgesics (e.g. diclofenac, naproxen), beta blockers (e.g. atenolol, propranolol), X-ray contrast media (e.g. diatrizoic acid, iomeprol) as well as the antiepileptic carbamazepine and endocrine disruptors (e.g. bisphenol A, 17α-ethinylestradiol) was analyzed in batch tests in the presence of oxygen, nitrate, manganese (IV), iron (III), and sulfate. Out of the 23 selected substances, 14 showed a degradation of > 50% of their initial concentrations under aerobic conditions. The beta blockers propranolol and atenolol and the analgesics pentoxifylline and naproxen showed a removal of > 50% under anaerobic conditions. In particular naproxen proved to be degradable with oxygen and under most anaerobic conditions, i.e. with manganese (IV), iron (III), or sulfate. The natural estrogens estriol, estrone and 17β-estradiol showed complete biodegradation under aerobic and nitrate-reducing conditions, with a temporary increase of estrone during transformation of estriol and 17β-estradiol. Transformation of 17β-estradiol under Fe(III)-reducing conditions resulted in an increase of estriol as well. Concentrations of clofibric acid, carbamazepine, iopamidol and diatrizoic acid, known for their recalcitrance in the environment, remained unchanged.

78 FR 57859 - Draft Guidance for Industry on Endocrine Disruption Potential of Drugs: Nonclinical Evaluation...

Science.gov (United States)

2013-09-20

... the endocrine system. This draft guidance also discusses factors to consider in determining the need... interfere with some aspect of the endocrine system of an organism or its progeny. Any component of the endocrine system can be a target of endocrine disruptors, although the systems most commonly affected...

Toxicity of compounds with endocrine activity in the OECD 421 reproductive toxicity screening test

NARCIS (Netherlands)

Piersma AH; Verhoef A; Elvers LH; Wester PW; LEO; LPI

1998-01-01

The issue of endocrine disruption has, in view of human risk assessment, raised the question on whether more sensitive test methods are needed to detect the reproductive toxic properties of xenobiotic compounds with endocrine properties. We studied six known and alleged endocrine disruptors in an

Impact of androgenic/antiandrogenic compounds (AAC) on human sex steroid metabolizing key enzymes

International Nuclear Information System (INIS)

Allera, A.; Lo, S.; King, I.; Steglich, F.; Klingmueller, D.

2004-01-01

Various pesticides, industrial pollutants and synthetic compounds, to which human populations are exposed, are known or suspected to interfere with endogenous sex hormone functions. Such interference potentially affect the development and expression of the male and female reproductive system or both. Chemicals in this class are thus referred to as endocrine disruptors (ED). This emphazises on the relevance of screening ED for a wide range of sex hormone-mimicking effects. These compounds are believed to exert influence on hormonal actions predominantly by (i) interfering with endogenous steroids in that they functionally interact with plasma membrane-located receptors as well as with nuclear receptors both for estrogens and androgens or (ii) affecting the levels of sex hormones as a result of their impact on steroid metabolizing key enzymes. Essential sex hormone-related enzymes within the endocrine system of humans are aromatase, 5α-reductase 2 as well as specific sulfotransferases and sulfatases (so-called phase I and phase II enzymes, respectively). Using suitable human tissues and human cancer cell lines (placenta, prostate, liver and JEG-3, lymph node carcinoma of prostate (LnCaP) cells) we investigated the impact of 10 widely used chemicals suspected of acting as ED with androgenic or antiandrogenic activity (so-called AAC) on the activity of these sex hormone metabolizing key enzymes in humans. In addition, the respective effects of six substances were also studied as positive controls due to their well-known specific hormonal agonistic/antagonistic activities. The aim of this report and subsequent investigations is to improve human health risk assessment for AAC and other ED

Assessment of endocrine disruption potential of essential oils of culinary herbs and spices involving glucocorticoid, androgen and vitamin D receptors.

Science.gov (United States)

Bartoňková, Iveta; Dvořák, Zdeněk

2018-04-25

Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine-disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti-glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR.

Environmental Analysis of Endocrine Disrupting Effects from Hydrocarbon Contaminants in the Ecosystem - Final Report - 09/15/1996 - 09/14/2000

International Nuclear Information System (INIS)

McLachlan, John A.

2000-01-01

The three major components of the research included: (a) a biotechnology based screening system to identify potential hormone mimics and antagonists (b) an animal screening system to identify biomarkers of endocrine effects and (c) a literature review to identify compounds at various DOE sites that are potential endocrine disruptors. Species of particular interest in this study were those that can serve as sentinel species (e.g., amphibians) and thus provide early warning signals for more widespread impacts on an ecosystem and its wildlife and human inhabitants. The objective of this basic research is to characterize the potential of common hydrocarbon contaminants in ecosystems to act as endocrine disruptors. Although the endocrine disrupting effects of contaminants such as dioxin and PCBs have been well characterized in both animals and humans, little is known about the capacities of other hydrocarbon contaminants to act as endocrine disruptors. Results obtained from this research project have provided information on endocrine disrupting contaminants for consideration in DOE's risk analyses for determining clean-up levels and priorities at contaminated DOE sites

Environmental Analysis of Endocrine Disrupting Effects from Hydrocarbon Contaminants in the Ecosystem - Final Report - 09/15/1996 - 09/14/2000

Energy Technology Data Exchange (ETDEWEB)

McLachlan, John A.

2000-09-14

The three major components of the research included: (a) a biotechnology based screening system to identify potential hormone mimics and antagonists (b) an animal screening system to identify biomarkers of endocrine effects and (c) a literature review to identify compounds at various DOE sites that are potential endocrine disruptors. Species of particular interest in this study were those that can serve as sentinel species (e.g., amphibians) and thus provide early warning signals for more widespread impacts on an ecosystem and its wildlife and human inhabitants. The objective of this basic research is to characterize the potential of common hydrocarbon contaminants in ecosystems to act as endocrine disruptors. Although the endocrine disrupting effects of contaminants such as dioxin and PCBs have been well characterized in both animals and humans, little is known about the capacities of other hydrocarbon contaminants to act as endocrine disruptors. Results obtained from this research project have provided information on endocrine disrupting contaminants for consideration in DOE's risk analyses for determining clean-up levels and priorities at contaminated DOE sites.

Endocrine-disrupting chemicals: associated disorders and mechanisms of action.

Science.gov (United States)

De Coster, Sam; van Larebeke, Nicolas

2012-01-01

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

Directory of Open Access Journals (Sweden)

Sam De Coster

2012-01-01

Full Text Available The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

CDNA CLONING OF FATHEAD MINNOW (PIMEPHALES PROMELAS) ESTROGEN AND ANDROGEN RECEPTORS FOR USE IN STEROID RECEPTOR EXTRAPOLATION STUDIES FOR ENDOCRINE DISRUPTING CHEMICALS

Science.gov (United States)

cDNA Cloning of Fathead minnow (Pimephales promelas) Estrogen and Androgen Receptors for Use in Steroid Receptor Extrapolation Studies for Endocrine Disrupting Chemicals. Wilson, V.S.1,, Korte, J.2, Hartig P. 1, Ankley, G.T.2, Gray, L.E., Jr 1, , and Welch, J.E.1. 1U.S...

Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

Directory of Open Access Journals (Sweden)

Sung Won Lee

2015-06-01

Full Text Available Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

Effects of 2,4-D and DCP on the DHT-induced androgenic action in human prostate cancer cells.

Science.gov (United States)

Kim, Hyun-Jung; Park, Young In; Dong, Mi-Sook

2005-11-01

2,4-Dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (DCP) are used extensively in agriculture as herbicides, and are suspected of potential endocrine disruptor activity. In a previous study, we showed that these compounds exhibited synergistic androgenic effects by co-treatment with testosterone in the Hershberger assay. To elucidate the mechanisms of the synergistic effects of these compounds on the androgenicity of testosterone, the androgenic action of 2,4-D and DCP was characterized using a mammalian detection system in prostate cancer cell lines. In in vitro assay systems, while 2,4-D or DCP alone did not show androgenic activity, 2,4-D or DCP with 5alpha-dihydroxytestosterone (DHT) exhibited synergistic androgenic activities. Co-treatment of 10 nM 2,4-D or DCP with 10 nM DHT was shown to stimulate the cell proliferation by 1.6-fold, compared to 10 nM DHT alone. In addition, in transient transfection assays, androgen-induced transactivation was also increased to a maximum of 32-fold or 1.28-fold by co-treatment of 2,4-D or DCP with DHT, respectively. However, 2,4-D and DCP exerted no effects on either mRNA or protein levels of AR. In a competitive AR binding assay, 2,4-D and DCP inhibited androgen binding to AR, up to 50% at concentrations of approximately 0.5 microM for both compounds. The nuclear translocation of green fluorescent protein-AR fusion protein in the presence of DHT was promoted as the result of the addition of 2,4-D and DCP. Collectively, these results that 2,4-D and DCP enhanced DHT-induced AR transcriptional activity might be attributable, at least in part, to the promotion of AR nuclear translocation.

Endocrine disruptors in female reproductive tract development and carcinogenesis

OpenAIRE

Ma, Liang

2009-01-01

Growing concerns over endocrine disrupting chemicals (EDCs) and their effects on human fetal development and adult health have promoted research into the underlying molecular mechanisms of endocrine disruption. Gene targeting technology has allowed insight into the genetic pathways governing reproductive tract development and how exposure to EDCs during a critical developmental window can alter reproductive tract development, potentially forming the basis for adult diseases. This review prima...

In silico tools to aid risk assessment of endocrine disrupting chemicals

International Nuclear Information System (INIS)

Jacobs, M.N.

2004-01-01

In silico or computational tools could be used more effectively in endocrine disruptor risk assessment for prescreening potential endocrine disruptors, improving experimental in vitro screening assay design and facilitating more thorough data analyses. The in silico tools reviewed here are three-fold and include the use of: (1) nuclear receptor (NR) crystal structures and homology models to examine potential modes of ligand binding by different representative compounds; (2) multivariate principal component analyses (PCA) techniques to select best predicted cell lines for endocrine disrupting chemicals (EDC) risk assessment purposes; (3) NR quantitative structure-activity relationships (QSARs) that can be constructed from varied biological data sources, using multivariate partial least squares (PLS) techniques and specific descriptors. The cytosolic and NR examples discussed here include the Ah receptor (AhR), the human oestrogen receptor α (hERα) and the human pregnane X receptor (PXR). The varied biological data sets can be compared to give a more integrated dimension to receptor cross talk mechanisms, with further support from molecular modelling studies

European Union's strategy on endocrine disrupting chemicals and the current position of Slovenia.

Science.gov (United States)

Perharič, Lucija; Fatur, Tanja; Drofenik, Jernej

2016-06-01

In view of the European Union regulations 1107/2009 and 528/2012, which say that basic substances in plant protection and biocidal products marketed in the European Union (EU) should not have an inherent capacity to cause endocrine disruption, an initiative was started to define scientific criteria for the identification of endocrine disruptors (EDs). The objectives of the EU strategy on EDs are to protect human health and the environment, to assure the functioning of the market, and to provide clear and coherent criteria for the identification of EDs that could have broad application in the EU legislation. Policy issues were to be addressed by the Ad-hoc group of Commission Services, EU Agencies and Member States established in 2010, whereas the scientific issues were to be addressed by the Endocrine Disruptors Expert Advisory Group (ED EAG), established in 2011. The ED EAG adopted the 2002 World Health Organization (WHO) definition of endocrine disruptor and agreed that for its identification it is necessary to produce convincing evidence of a biologically plausible causal link between an adverse effect and endocrine disrupting mode of action. In 2014, the European Commission proposed four ED identification criteria options and three regulatory options, which are now being assessed for socio-economic, environmental, and health impact. Slovenia supports the establishing of identification criteria and favours option 4, according to which ED identification should be based on the WHO definition with the addition of potency as an element of hazard characterisation. As for regulatory options, Slovenia favours the risk-based rather than hazard-based regulation.

A hierarchical testing strategy for micropollutants in drinking water regarding their potential endocrine-disrupting effects-towards health-related indicator values.

Science.gov (United States)

Kuckelkorn, Jochen; Redelstein, Regine; Heide, Timon; Kunze, Jennifer; Maletz, Sibylle; Waldmann, Petra; Grummt, Tamara; Seiler, Thomas-Benjamin; Hollert, Henner

2018-02-01

In Germany, micropollutants that (may) occur in drinking water are assessed by means of the health-related indicator value (HRIV concept), developed by the German Federal Environment Agency. This concept offers five threshold values (≤ 0.01 to ≤ 3 μg l -1 ) depending on availability and completeness of data regarding genotoxicity, neurotoxicity, and germ cell-damaging potential. However, the HRIV concept is yet lacking integration of endocrine disruptors as one of the most prominent toxicological concerns in water bodies, including drinking water. Thresholds and proposed bioassays hence urgently need to be defined. Since endocrine disruption of ubiquitary chemicals as pharmaceuticals, industrial by-products, or pesticides is a big issue in current ecotoxicology, the aim of this study was to explore endocrine effects, i.e., estrogenic and androgenic effects, as an important, additional toxicological mode of action for the HRIV concept using a hierarchical set of well-known but improved bioassays. Results indicate that all of the 13 tested substances, industrial chemicals and combustion products (5), pharmaceuticals and medical agents (4), and pesticides and metabolites (4), have no affinity to the estrogen and androgen receptor in human U2OS cells without metabolic activation, even when dosed at their water solubility limit, while in contrast some of these substances showed estrogenic effects in the RYES assay, as predicted in pre-test QSAR analysis. Using a specifically developed S9-mix with the U2OS cells, those micropollutants, i.e., Benzo[a]pyrene, 2,4-Dichlorophenol, 3,3-Dichlorbenzidin, 3,4-Dichloranilin, and diclofenac, they show estrogenic effects at the same concentration range as for the yeast cells. Three of the drinking water-relevant chemicals, i.e., atrazine, tributyltin oxide, and diclofenac, caused effects on hormone production in the H295R assay, which can be correlated with changes in the expression of steroidogenic genes. One chemical, 17

Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4

International Nuclear Information System (INIS)

Kucka, Marek; Pogrmic-Majkic, Kristina; Fa, Svetlana; Stojilkovic, Stanko S.; Kovacevic, Radmila

2012-01-01

Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazine did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward c

Androgen Receptor Involvement in Rat Amelogenesis: An Additional Way for Endocrine-Disrupting Chemicals to Affect Enamel Synthesis.

Science.gov (United States)

Jedeon, Katia; Loiodice, Sophia; Salhi, Khaled; Le Normand, Manon; Houari, Sophia; Chaloyard, Jessica; Berdal, Ariane; Babajko, Sylvie

2016-11-01

Endocrine-disrupting chemicals (EDCs) that interfere with the steroid axis can affect amelogenesis, leading to enamel hypomineralization similar to that of molar incisor hypomineralization, a recently described enamel disease. We investigated the sex steroid receptors that may mediate the effects of EDCs during rat amelogenesis. The expression of androgen receptor (AR), estrogen receptor (ER)-α, and progesterone receptor was dependent on the stage of ameloblast differentiation, whereas ERβ remained undetectable. AR was the only receptor selectively expressed in ameloblasts involved in final enamel mineralization. AR nuclear translocation and induction of androgen-responsive element-containing promoter activity upon T treatment, demonstrated ameloblast responsiveness to androgens. T regulated the expression of genes involved in enamel mineralization such as KLK4, amelotin, SLC26A4, and SLC5A8 but not the expression of genes encoding matrix proteins, which determine enamel thickness. Vinclozolin and to a lesser extent bisphenol A, two antiandrogenic EDCs that cause enamel defects, counteracted the actions of T. In conclusion, we show, for the first time, the following: 1) ameloblasts express AR; 2) the androgen signaling pathway is involved in the enamel mineralization process; and 3) EDCs with antiandrogenic effects inhibit AR activity and preferentially affect amelogenesis in male rats. Their action, through the AR pathway, may specifically and irreversibly affect enamel, potentially leading to the use of dental defects as a biomarker of exposure to environmental pollutants. These results are consistent with the steroid hormones affecting ameloblasts, raising the issue of the hormonal influence on amelogenesis and possible sexual dimorphism in enamel quality.

In vitro screening of the endocrine disrupting potency of brominated flame retardants and their metabolites

Energy Technology Data Exchange (ETDEWEB)

Hamers, T.; Kamstra, J.H. [Inst. for Environmental Studies (IVM), Amsterdam (Netherlands); Sonneveld, E. [BioDetection Systems (BDS), Amsterdam (Netherlands); Murk, A.J. [Wageningen Univ., Toxicology Group, Wageningen (Netherlands); Zegers, B.N.; Boon, J.P. [Royal Netherlands Inst. for Sea Research (NIOZ), Den Burg (Netherlands); Brouwer, A. [Umea Univ., Umea (Sweden)

2004-09-15

Substantial evidence is recently becoming available that brominated flame retardants (BFRs) are potential endocrine disruptors. The toxicological profile of BFRs, however, is too incomplete and insufficient to perform human and ecological risk assessment. To fill these gaps, the EU funded research program FIRE was started in December 2002. This program aims at the identification and toxicological characterization of the most potent and environmentally relevant BFRs and their possible risk for human and wildlife health. As part of a hazard identification approach, twenty seven BFRs have been selected within the framework of FIRE for pre-screening their endocrinedisrupting potencies. Selection of test compounds was based on a maximal variation in physicochemical characteristics of BFRs within the test set, allowing the establishment of quantitative structure-activity relationships (QSARs). In addition, environmental relevance (e.g. high production volumes and persistence) and availability for testing were used as selection criteria. BFRs were tested in seven different in vitro bioassays for their potency to interfere via estrogenic, thyroidal, androgenic, progestagenic, and Ah-receptor mediated pathways. Metabolisation rates of BFRs were determined using phenobarbital-induced rat liver microsomes. Finally, the endocrine disrupting potency of the metabolites was determined in the same in vitro bio-assays and compared to the potency of the parent compounds.

Reporter cell lines for the characterization of the interactions between nuclear receptors and endocrine disruptors

Directory of Open Access Journals (Sweden)

marina egrimaldi

2015-05-01

Full Text Available Endocrine-disrupting chemicals (EDCs are exogenous substances interfering with hormone biosynthesis, metabolism, or action, and consequently causing disturbances in the endocrine system. Various pathways are activated by EDCs, including interactions with nuclear receptors (NRs which are primary targets of numerous environmental contaminants.The main NRs targeted by environmental contaminants are the estrogen (ER α, β and the androgen (AR receptors. ERs and AR have pleiotropic regulatory roles in a diverse range of tissues, notably in the mammary gland, the uterus and the prostate. Thus, dysfunctional ERs and AR signaling due to inappropriate exposure to environmental pollutants may lead to hormonal cancers and infertility. The pregnane X receptor (PXR is also recognized by many environmental molecules. PXR has a protective role of the body through its ability to regulate proteins involved in the metabolism, the conjugation and the transport of many exogenous and endogenous compounds. However, the permanent activation of this receptor by xenobiotics may lead to premature drug metabolism, the formation and accumulation of toxic metabolites and defects in hormones homeostasis. The activity of other NRs can also be affected by environmental molecules. Compounds capable of inhibiting or activating the estrogen related (ERRγ, the thyroid hormone (TRα, β, the retinoid X receptors (RXRα, β, γ and peroxisome proliferator-activated (PPAR α, γ receptors have been identified and are highly suspected to promote developmental, reproductive, neurological, or metabolic diseases in humans and wildlife.In this review we provide an overview of reporter cell lines established to characterize the human NR activities of a large panel of EDCs including natural as well as industrial compounds such as pesticides, plasticizers, surfactants, flame retardants and cosmetics.

Effects of endocrine disrupting heavy metals on pituitary and ...

African Journals Online (AJOL)

Association of hypogonadism and visceral obesity (VO) was recently demonstrated in male auto-mechanics occupationally exposed to endocrine disruptors (ED)-lead, cadmium, mercury and arsenic, known to alter the hypothalamic-pituitary-testicular axis. The effects of exposure to these EDs on pituitary and gonadal ...

Endocrine Disruptor Screening Program: Tier I Screening Battery

Science.gov (United States)

In response to emerging concerns that environmental chemicals may have adverse effects on human health by altering the function of the endocrine system,' the Food Quality Protection Act and subsequent amendments to the Safe Drinking Water Act and Federal Food, Drug and Cosmetic A...

A predictive data-driven framework for endocrine prioritization: a triazole fungicide case study

Science.gov (United States)

Paul Friedman, Katie; Papineni, Sabitha; Marty, M. Sue; Yi, Kun Don; Goetz, Amber K.; Rasoulpour, Reza J.; Kwiatkowski, Pat; Wolf, Douglas C.; Blacker, Ann M.; Peffer, Richard C.

2016-01-01

Abstract The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3–5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and between in vivo mammalian bioactivity and EPA chronic human exposure estimates for these products’ registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potential in vivo effects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information. PMID:27347635

Optimization and Application of a GC-MS Method for the Determination of Endocrine Disruptor Compounds in Natural Water

Directory of Open Access Journals (Sweden)

José Gustavo Ronderos-Lara

2018-06-01

Full Text Available Bisphenol A (BPA, 4-nonylphenol (4NP, estradiol (E2, and ethinylestradiol (EE2 are considered as endocrine disruptors or mutagens. These compounds are commonly called endocrine disrupter chemicals (EDCs. BPA and 4NP are widely used as plastic additives, lacquers, resins, or surfactants, while E2 is one of the predominant female sex hormones during the reproductive years, and EE2 is an estrogen derived from estradiol, used in the production of contraceptive pills. All of these can be usually found in wastewater. In Mexico, it is common for water from rivers, lakes, and canyons to be reused for different purposes. Unfortunately, there is little information on the concentration of many of the pollutants present in such bodies of water. To determine the presence of these compounds in samples of wastewater in the Apatlaco River, an accurate and reproducible method was developed by coupling gas chromatography to mass spectrometry (GC-MS. A solid-phase extraction with Chromabond RP-18 cartridges was carried out, and the elution was performed with an acetone/methanol mixture. After isolation, the solvent was removed and a silylation step was carried out using N,O-bis(trimethylsilyltrifluoroacetamide (BSTFA. Recoveries for spiked samples were between 71.8% and 111.0%. The instrumental limits of detection (IDL ranged between 24.7 and 37.0 ng mL−1. In total, 16 samples were taken in 2015 at the microbasin of the Apatlaco River, located in the state of Morelos. The maximum concentrations found were 4NP (85.5 ng mL−1, BPA (174.6 ng mL−1, E2 103.6 (ng mL−1, and EE2 (624.3 ng mL−1.

Prevalent flucocorticoid and androgen activity in US water sources

Science.gov (United States)

Stavreva, Diana A.; George, Anuja A.; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C.; Schiltz, R. Louis; Blazer, Vicki; Iwanowiczl, Luke R.; Hager, Gordon L.

2012-01-01

Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

Prevalent glucocorticoid and androgen activity in US water sources.

Science.gov (United States)

Stavreva, Diana A; George, Anuja A; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C; Schiltz, R Louis; Blazer, Vicki S; Iwanowicz, Luke R; Hager, Gordon L

2012-01-01

Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

International Nuclear Information System (INIS)

Frizzell, Caroline; Ndossi, Doreen; Kalayou, Shewit; Eriksen, Gunnar S.; Verhaegen, Steven; Sørlie, Morten; Elliott, Christopher T.; Ropstad, Erik; Connolly, Lisa

2013-01-01

Alternariol (AOH) is a mycotoxin commonly produced by Alternaria alternata on a wide range of foods. Few studies to date have been performed to evaluate the effects of AOH on endocrine activity. The present study makes use of in vitro mammalian cellular based assays and gene expression to investigate the ability of AOH to act as an endocrine disruptor by various modes of action. Reporter gene assays (RGAs), incorporating natural steroid hormone receptors for oestrogens, androgens, progestagens and glucocorticoids were used to identify endocrine disruption at the level of nuclear receptor transcriptional activity, and the H295R steroidogenesis assay was used to assess endocrine disruption at the level of gene expression and steroid hormone production. AOH exhibited a weak oestrogenic response when tested in the oestrogen responsive RGA and binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of AOH. H295R cells when exposed to 0.1–1000 ng/ml AOH, did not cause a significant change in testosterone and cortisol hormones but exposure to 1000 ng/ml (3.87 μM) AOH resulted in a significant increase in estradiol and progesterone production. In the gene expression study following exposure to 1000 ng/ml (3.87 μM) AOH, only one gene NR0B1 was down-regulated, whereas expression of mRNA for CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2 and CYP19 was up-regulated. Expression of the other genes investigated did not change significantly. In conclusion AOH is a weak oestrogenic mycotoxin that also has the ability to interfere with the steroidogenesis pathway. - Highlights: • Alternariol was investigated for endocrine disrupting activity. • Reporter gene assays and the H295R steroidogenesis assay have been used. • An oestrogenic effect of alternariol was observed. • This can lead to an increase in expression of the progesterone receptor. • Alternariol is capable of modulating hormone production and gene expression

An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol

Energy Technology Data Exchange (ETDEWEB)

Frizzell, Caroline [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Ndossi, Doreen [Section of Experimental Biomedicine, Norwegian School of Veterinary Science, Oslo (Norway); Sokoine University of Agriculture, Morogoro (Tanzania, United Republic of); Kalayou, Shewit [Section of Experimental Biomedicine, Norwegian School of Veterinary Science, Oslo (Norway); Mekelle University College of Veterinary Medicine, Mekelle (Ethiopia); Eriksen, Gunnar S. [Norwegian Veterinary Institute, Oslo (Norway); Verhaegen, Steven [Section of Experimental Biomedicine, Norwegian School of Veterinary Science, Oslo (Norway); Sørlie, Morten [Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås (Norway); Elliott, Christopher T. [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Ropstad, Erik [Section of Experimental Biomedicine, Norwegian School of Veterinary Science, Oslo (Norway); Connolly, Lisa, E-mail: l.connolly@qub.ac.uk [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom)

2013-08-15

Alternariol (AOH) is a mycotoxin commonly produced by Alternaria alternata on a wide range of foods. Few studies to date have been performed to evaluate the effects of AOH on endocrine activity. The present study makes use of in vitro mammalian cellular based assays and gene expression to investigate the ability of AOH to act as an endocrine disruptor by various modes of action. Reporter gene assays (RGAs), incorporating natural steroid hormone receptors for oestrogens, androgens, progestagens and glucocorticoids were used to identify endocrine disruption at the level of nuclear receptor transcriptional activity, and the H295R steroidogenesis assay was used to assess endocrine disruption at the level of gene expression and steroid hormone production. AOH exhibited a weak oestrogenic response when tested in the oestrogen responsive RGA and binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of AOH. H295R cells when exposed to 0.1–1000 ng/ml AOH, did not cause a significant change in testosterone and cortisol hormones but exposure to 1000 ng/ml (3.87 μM) AOH resulted in a significant increase in estradiol and progesterone production. In the gene expression study following exposure to 1000 ng/ml (3.87 μM) AOH, only one gene NR0B1 was down-regulated, whereas expression of mRNA for CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2 and CYP19 was up-regulated. Expression of the other genes investigated did not change significantly. In conclusion AOH is a weak oestrogenic mycotoxin that also has the ability to interfere with the steroidogenesis pathway. - Highlights: • Alternariol was investigated for endocrine disrupting activity. • Reporter gene assays and the H295R steroidogenesis assay have been used. • An oestrogenic effect of alternariol was observed. • This can lead to an increase in expression of the progesterone receptor. • Alternariol is capable of modulating hormone production and gene expression.

Liquid-phase exfoliated graphene as highly-sensitive sensor for simultaneous determination of endocrine disruptors: Diethylstilbestrol and estradiol

Energy Technology Data Exchange (ETDEWEB)

Hu, Lintong; Cheng, Qin [Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China); Chen, Danchao; Ma, Ming [Ningbo Entry-exit Inspection and Quarantine Bureau of China, Ningbo 315012 (China); Wu, Kangbing, E-mail: kbwu@hust.edu.cn [Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074 (China)

2015-02-11

Graphical abstract: - Highlights: • A novel electrochemical sensor was developed for diethylstilbestrol and estradiol. • Graphene prepared by solvent exfoliation greatly enhances the detection sensitivity. • The newly-developed method has promising application and the accuracy is good. - Abstract: It is quite important to develop convenient and rapid analytical methods for trace levels of endocrine disruptors because they heavily affect health and reproduction of humans and animals. Herein, graphene was easily prepared via one-step exfoliation using N-methyl-2-pyrrolidone as solvent, and then used to construct an electrochemical sensor for highly-sensitive detection of diethylstilbestrol (DES) and estradiol (E2). On the surface of prepared graphene film, two independent and greatly-increased oxidation waves were observed at 0.28 V and 0.49 V for DES and E2. The remarkable signal enlargements indicated that the detection sensitivity was improved significantly. The influences of pH value, amount of graphene and accumulation time on the oxidation signals of DES and E2 were discussed. As a result, a highly-sensitive and rapid electrochemical method was newly developed for simultaneous detection of DES and E2. The values of detection limit were evaluated to be 10.87 nM and 4.9 nM for DES and E2. Additionally, this new method was successfully used in lake water samples and the accuracy was satisfactory.

A Demonstration Study on Decomposition of Anntibiotics and Endocrine Disrupters Contained in Sewage Effluent by Mobile Electron Beam Accelerator

Energy Technology Data Exchange (ETDEWEB)

Lee, Myun Joo; Kim, Tae Hoon; Jung, In Ha [Korea Atomic Energy Research Institute (Korea, Republic of)

2012-07-01

This report described a work plan on advanced sewage treatments focusing on reduction of antibiotics and endocrine disruptors and sterilization by radiation in Korea. It included a demonstration study on decomposition of antibiotics and endocrine disruptor contained in sewage effluent by MEB(Mobile Electron Beam accelerator). According to the KAERI’s national research plan, basic radiation application working on sterilization, decomposition of antibiotics and endocrine disruptor contained in effluent by using radiation were conducted in KAERI’s laboratory for three years. In 2011, a field study on advanced sewage treatment with a MEB was conducted and the results obtained from study played an important role in the acquiring a certification on advanced treatment of sewage effluent by radiation, NET(New Environmental Technology), which is issued by Korea ministry of environment. The field study was carried out over four seasons in order to observe the effect of seasonal temperature changes on decomposition of chemicals contained in effluent of sewage. The major antibiotics and endocrine disruptors with initial concentration of 0.5 mg/l were decomposed completely by the irradiation dose less than 1.5 kGy, and coli form and microorganisms were also sterilized under the same irradiation dose. Toxicity arising by antibiotics on algae was reduced according to irradiation dose. In a future, achievements from the field demonstration study will be transferred to industry. Research on by-products from irradiated antibiotics and toxicity before and after irradiation of antibiotics will be continued in the field with MEB. This information will be useful for the project by radiation treatment of wastewater for reuse, particularly focused on the wastewater containing organic pollutants. (author)

A Demonstration Study on Decomposition of Anntibiotics and Endocrine Disrupters Contained in Sewage Effluent by Mobile Electron Beam Accelerator

International Nuclear Information System (INIS)

Lee, Myun Joo; Kim, Tae Hoon; Jung, In Ha

2012-01-01

This report described a work plan on advanced sewage treatments focusing on reduction of antibiotics and endocrine disruptors and sterilization by radiation in Korea. It included a demonstration study on decomposition of antibiotics and endocrine disruptor contained in sewage effluent by MEB(Mobile Electron Beam accelerator). According to the KAERI’s national research plan, basic radiation application working on sterilization, decomposition of antibiotics and endocrine disruptor contained in effluent by using radiation were conducted in KAERI’s laboratory for three years. In 2011, a field study on advanced sewage treatment with a MEB was conducted and the results obtained from study played an important role in the acquiring a certification on advanced treatment of sewage effluent by radiation, NET(New Environmental Technology), which is issued by Korea ministry of environment. The field study was carried out over four seasons in order to observe the effect of seasonal temperature changes on decomposition of chemicals contained in effluent of sewage. The major antibiotics and endocrine disruptors with initial concentration of 0.5 mg/l were decomposed completely by the irradiation dose less than 1.5 kGy, and coli form and microorganisms were also sterilized under the same irradiation dose. Toxicity arising by antibiotics on algae was reduced according to irradiation dose. In a future, achievements from the field demonstration study will be transferred to industry. Research on by-products from irradiated antibiotics and toxicity before and after irradiation of antibiotics will be continued in the field with MEB. This information will be useful for the project by radiation treatment of wastewater for reuse, particularly focused on the wastewater containing organic pollutants. (author)

Consensus models to predict endocrine disruption for all ...

Science.gov (United States)

Humans are potentially exposed to tens of thousands of man-made chemicals in the environment. It is well known that some environmental chemicals mimic natural hormones and thus have the potential to be endocrine disruptors. Most of these environmental chemicals have never been tested for their ability to disrupt the endocrine system, in particular, their ability to interact with the estrogen receptor. EPA needs tools to prioritize thousands of chemicals, for instance in the Endocrine Disruptor Screening Program (EDSP). Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) was intended to be a demonstration of the use of predictive computational models on HTS data including ToxCast and Tox21 assays to prioritize a large chemical universe of 32464 unique structures for one specific molecular target – the estrogen receptor. CERAPP combined multiple computational models for prediction of estrogen receptor activity, and used the predicted results to build a unique consensus model. Models were developed in collaboration between 17 groups in the U.S. and Europe and applied to predict the common set of chemicals. Structure-based techniques such as docking and several QSAR modeling approaches were employed, mostly using a common training set of 1677 compounds provided by U.S. EPA, to build a total of 42 classification models and 8 regression models for binding, agonist and antagonist activity. All predictions were evaluated on ToxCast data and on an exte

Androgens and polycystic ovary syndrome.

Science.gov (United States)

Nisenblat, Vicki; Norman, Robert J

2009-06-01

Polycystic ovary syndrome (PCOS) is a common complex endocrine genetic disorder, which involves overproduction of androgens, leading to heterogeneous range of symptoms and associated with increased metabolic and cardiovascular morbidity. This review focuses on androgen biosynthesis, use, metabolism in PCOS and clinical consequences of hyperandrogenism. Controversial definition of the disorder and different phenotypic subgroups present a challenge for clinical and basic research. Further investigation of different phenotypes highlights the fact that PCOS probably represents a group of disorders with different etiologies. Prenatal androgen exposure and adolescent studies suggest early in life androgen excess as initiating factor of PCOS, but insufficient evidence available to confirm this hypothesis. Various intracellular signaling pathways implicated in PCOS steroidogenesis and in androgen action have been studied, however, PCOS pathogenesis remains obscure. Growing evidence links androgens with pathophysiology of PCOS and metabolic derangements. Despite intensive investigation, etiology and underlying mechanisms of PCOS remain unclear, warranting further investigation. Better understanding of molecular and genetic basis might lead to invention of novel therapeutic approaches. Long-term interventional studies that lower androgen levels in women with hyperandrogenism might protect against metabolic and cardiovascular comorbidities are needed.

New endocrine disruptors: their importance in pediatric population Nuevos disruptores endocrinos: su importancia en la población pediátrica

OpenAIRE

Juan Manuel Alfaro Velásquez; Alejandro Román González

2005-01-01

Changes in the environment that have taken place during the last 40 years have generated frequent contacts with natural and synthetic chemical products with potential endocrine-disrupting roles; among them: the intensive use of pesticides after the introduction of DDT, the petrochemical derivatives of the plastic industry, the synthetic medicines and the growing market of clothes, cleaning products, cosmetics and motor vehicles. In every one of these groups there are signals of an endocrine-d...

Disruptores endocrinos. El caso particular de los xenobióticos estrogénicos. II Estrógenos sintéticos Endocrine disrupters. The case of oestrogenic xenobiotics II: synthetic oestrogens

Directory of Open Access Journals (Sweden)

P. Martín Olmedo

2001-11-01

Full Text Available En los últimos años se ha puesto en evidencia que muchas sustancias químicas de origen antropogénico son capaces de alterar el sistema endocrino de los seres vivos y se ha acuñado el nombre de disruptores endocrinos para definirlas. El número de disruptores endocrinos es una preocupación creciente si se añade a la inclusión de nuevos compuestos químicos, hasta ahora insospechados, la información generada sobre sus precursores, metabolitos y productos de degradación que tan solo ahora empiezan a conocerse. No se ha podido definir una estructura química única que permita clasificar a un compuesto químico como mimetizador de las hormonas sexuales femeninas, de tal manera que estructuras químicas similares a los estrógenos naturales, basados en el ciclopentanoperhidrofenantreno, comparten con los estilbenos, bisfenoles, bifenilos, alquilfenoles, dioxinas, furanos y parabenes su efecto hormonal estrogénico. El reconocimiento de la actividad estrogénica en diferentes modelos biológicos se ha utilizado para actualizar el censo de xenoestrógenos y poner de manifiesto fuentes de exposición humana hasta el momento insospechadas.In recent years, it has been demonstrated that endocrine systems of living beings can be altered by many chemical substances of anthropogenic origin, designated as endocrine disrupters. There are growing concerns about the number of these endocrine disrupters. It has not been possible to define a single chemical structure that allows the classification of a chemical compound as a mimic of female sex hormones, so that chemical structures similar to natural estrogens, based on cyclopentanoperhydrophenanthrene, share their hormonal effect with stilbenes, bisphenols, alkylphenols, dioxins, furans and parabenes. The recognition of estrogenic activity in different biological models has been used to update the list of xenoestrogens and reveal sources of human exposure that were previously unknown. New previously

Preparation and characterization of sodium dodecyl sulfate doped polypyrrole solid phase micro extraction fiber and its application to endocrine disruptor pesticide analysis.

Science.gov (United States)

Korba, Korcan; Pelit, Levent; Pelit, Füsun Okçu; Ozdokur, K Volkan; Ertaş, Hasan; Eroğlu, Ahmet E; Ertaş, F Nil

2013-06-15

A robust in house solid-phase micro extraction (SPME) surface has been developed for the headspace (HS)-SPME determination of endocrine disruptor pesticides, namely, Chlorpyrifos, Penconazole, Procymidone, Bromopropylate and Lambda-Cyhalothrin in wine sample by using sodium dodecylsulfate doped polypyrrole SPME fiber. Pyrrole monomer was electrochemically polymerized on a stainless steel wire in laboratory conditions in virtue of diminishing the cost and enhancing the analyte retention on its surface to exert better selectivity and hence the developed polymerized surface could offer to analyst to exploit it as a fiber in headspace SPME analysis. The parameters, mainly, adsorption temperature and time, desorption temperature, stirring rate and salt amount were optimized to be as 70°C and 45min, 200°C, 600rpm and 10gL(-1), respectively. Limit of detection was estimated in the range of 0.073-1.659ngmL(-1) for the pesticides studied. The developed method was applied in to red wine sample with acceptable recovery values (92-107%) which were obtained for these selected pesticides. Copyright © 2013 Elsevier B.V. All rights reserved.

Principles of Pharmacology and Toxicology Also Govern Effects of Chemicals on the Endocrine System

NARCIS (Netherlands)

Autrup, Herman; Barile, Frank A.; Blaauboer, Bas J.; Degen, Gisela H.; Dekant, Wolfgang; Dietrich, Daniel; Domingo, Jose L.; Gori, Gio Batta; Greim, Helmuth; Hengstler, Jan G.; Kacew, Sam; Marquardt, Hans; Pelkonen, Olavi; Savolainen, Kai; Vermeulen, Nico P.

The present debate on chemicals with Hormonal activity, often termed 'endocrine disruptors', is highly controversial and includes challenges of the present paradigms used in toxicology and in hazard identification and risk characterization. In our opinion, chemicals with hormonal activity can be

Principles of Pharmacology and Toxicology Also Govern Effects of Chemicals on the Endocrine System

DEFF Research Database (Denmark)

Autrup, Herman; Barile, Frank A; Blaauboer, Bas J

2015-01-01

The present debate on chemicals with Hormonal activity, often termed 'endocrine disruptors', is highly controversial and includes challenges of the present paradigms used in toxicology and in hazard identification and risk characterization. In our opinion, chemicals with hormonal activity can be ...

Early endocrine disruptors exposure acts on 3T3-L1 differentiation and endocrine activity

Directory of Open Access Journals (Sweden)

Sofiane Boudalia

2017-06-01

Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity.

Demasculinization and feminization of male gonads by atrazine: Consistent effects across vertebrate classes

Science.gov (United States)

Hayes, Tyrone B.; Anderson, Lloyd L.; Beasley, Val R.; de Solla, Shane R.; Iguchi, Taisen; Ingraham, Holly; Kestemont, Patrick; Kniewald, Jasna; Kniewald, Zlatko; Langlois, Valerie S.; Luque, Enrique H.; McCoy, Krista A.; Muñoz-de-Toro, Mónica; Oka, Tomohiro; Oliveira, Cleida A.; Orton, Frances; Ruby, Sylvia; Suzawa, Miyuki; Tavera-Mendoza, Luz E.; Trudeau, Vance L.; Victor-Costa, Anna Bolivar; Willingham, Emily

2015-01-01

Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called “Hill criteria” (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause–effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a state of the art summary of the mechanisms by which atrazine acts as an endocrine disruptor to produce these effects. Atrazine demasculinizes male gonads producing testicular lesions associated with reduced germ cell numbers in teleost fish, amphibians, reptiles, and mammals, and induces partial and/or complete feminization in fish, amphibians, and reptiles. These effects are strong (statistically significant), consistent across vertebrate classes, and specific. Reductions in androgen levels and the induction of estrogen synthesis – demonstrated in fish, amphibians, reptiles, and mammals – represent plausible and coherent mechanisms that explain these effects. Biological gradients are observed in several of the cited studies, although threshold doses and patterns vary among species. Given that the effects on the male gonads described in all of these experimental studies occurred only after atrazine exposure, temporality is also met here. Thus the case for atrazine as an endocrine disruptor that demasculinizes and feminizes male vertebrates meets all nine of the “Hill criteria”. PMID:21419222

Peroxisome proliferator-activated receptor gamma (PPARγ) in brown trout: Interference of estrogenic and androgenic inputs in primary hepatocytes.

Science.gov (United States)

Lopes, Célia; Madureira, Tânia Vieira; Ferreira, Nádia; Pinheiro, Ivone; Castro, L Filipe C; Rocha, Eduardo

2016-09-01

Peroxisome proliferator-activated receptor gamma (PPARγ) is a pivotal regulator of lipid and glucose metabolism in vertebrates. Here, we isolated and characterized for the first time the PPARγ gene from brown trout (Salmo trutta f. fario). Hormones have been reported to interfere with the regulatory function of PPARγ in various organisms, albeit with little focus on fish. Thus, primary hepatocytes isolated from juveniles of brown trout were exposed to 1, 10 and 50μM of ethinylestradiol (EE2) or testosterone (T). A significant (3 fold) decrease was obtained in response to 50μM of EE2 and to 10 and 50μM of T (13 and 14 folds), while a 3 fold increase was observed at 1μM of EE2. Therefore, trout PPARγ seems a target for natural/synthetic compounds with estrogenic or androgenic properties and so, we advocate considering PPARγ as another alert sensor gene when assessing the effects of sex-steroid endocrine disruptors. Copyright © 2016 Elsevier B.V. All rights reserved.

QSAR Methods to Screen Endocrine Disruptors

Directory of Open Access Journals (Sweden)

Nicola Porta

2016-08-01

Full Text Available The identification of endocrine disrupting chemicals (EDCs is one of the important goals of environmental chemical hazard screening. We report on in silico methods addressing toxicological studies about EDCs with a special focus on the application of QSAR models for screening purpose. Since Estrogen-like (ER activity has been extensively studied, the majority of the available models are based on ER-related endpoints. Some of these models are here reviewed and described. As example for their application, we screen an assembled dataset of candidate substitutes for some known EDCs belonging to the chemical classes of phthalates, bisphenols and parabens, selected considering their toxicological relevance and broad application, with the general aim of preliminary assessing their ED potential. The goal of the substitution processes is to advance inherently safer chemicals and products, consistent with the principles of green chemistry. Results suggest that the integration of a family of different models accounting for different endpoints can be a convenient way to describe ED as properly as possible and allow also both to increase the confidence of the predictions and to maximize the probability that most active compounds are correctly found.

Transcriptomic and phenotypic profiling in developing zebrafish exposed to thyroid hormone receptor agonists

Energy Technology Data Exchange (ETDEWEB)

Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

2018-04-01

There is a need to develop novel, high-throughput screening and prioritization methods to identify chemicals with adverse estrogen, androgen, and thyroid activity to protect human health and the environment and is of interest to the Endocrine Disruptor Screening Program. The current aim is to explore the utility of zebrafish as a testing paradigm to classify endocrine activity using phenotypically anchored transcriptome profiling. Transcriptome analysis was conducted on embryos exposed to 25 estrogen-, androgen-, or thyroid-active chemicals at a concentration that elicited adverse malformations or mortality at 120 hours post-fertilization in 80% of the animals exposed. Analysis of the top 1000 significant differentially expressed transcripts across all treatments identified a unique transcriptional and phenotypic profile for thyroid hormone receptor agonists, which can be used as a biomarker screen for potential thyroid hormone agonists.

Two Virus Based Endocrine Disruptor Assays Effective Across Vertebrate Classes.

Science.gov (United States)

The presence of hormone mimics, or endocrine disrupting compounds (EDC’s), in the environment are increasing. Sources range from agricultural run–off, pharmaceuticals in waste water, to industrial operations. Current levels of contamination are sufficient to alter sexual develo...

Endocrine disruptors in freshwater streams of Hesse, Germany: Changes in concentration levels in the time span from 2003 to 2005

Energy Technology Data Exchange (ETDEWEB)

Quednow, Kristin [J. W. Goethe University Frankfurt am Main, Institute of Atmospheric and Environmental Sciences, Department of Environmental Analytical Chemistry, Georg-Voigt-Strasse 14, 60054 Frankfurt (Germany)], E-mail: quednow@kristall.uni-frankfurt.de; Puettmann, Wilhelm [J. W. Goethe University Frankfurt am Main, Institute of Atmospheric and Environmental Sciences, Department of Environmental Analytical Chemistry, Georg-Voigt-Strasse 14, 60054 Frankfurt (Germany)

2008-03-15

Four small freshwater streams in the region known as Hessisches Ried in Germany were investigated with respect to the temporal and spatial concentration variations of the endocrine disruptors bisphenol A (BPA), 4-tert-octylphenol (4-tert-OP), and the technical isomer mixture of 4-nonylphenol (tech.-4-NP). Measured concentrations of the target compounds in the river water samples ranged from <20 ng/l to 1927 ng/l, <10 ng/l to 770 ng/l, and <10 ng/l to 420 ng/l for BPA, 4-tert-OP and tech.-4-NP, respectively. BPA levels were, with the exception of two samples, below the predicted no-effect concentration (PNEC) for water organisms. Tech.-4-NP concentrations showed a significant tendency of decreasing concentrations during the sampling period. This is mainly attributed to the implementation of the European Directive 2003/53/EG, which restricts both the marketing and use of nonylphenols. Results from the analysis of additionally collected water samples from sewage treatment plant (STP) effluents indicate that the STPs cannot be the only sources for tech.-4-NP found in the river water. - Concentrations of 4-nonylphenols in rivers of Hessisches Ried in Germany decreased in the sampling period from September 2003 to September 2005.

Endocrine disruptors in freshwater streams of Hesse, Germany: Changes in concentration levels in the time span from 2003 to 2005

International Nuclear Information System (INIS)

Quednow, Kristin; Puettmann, Wilhelm

2008-01-01

Four small freshwater streams in the region known as Hessisches Ried in Germany were investigated with respect to the temporal and spatial concentration variations of the endocrine disruptors bisphenol A (BPA), 4-tert-octylphenol (4-tert-OP), and the technical isomer mixture of 4-nonylphenol (tech.-4-NP). Measured concentrations of the target compounds in the river water samples ranged from <20 ng/l to 1927 ng/l, <10 ng/l to 770 ng/l, and <10 ng/l to 420 ng/l for BPA, 4-tert-OP and tech.-4-NP, respectively. BPA levels were, with the exception of two samples, below the predicted no-effect concentration (PNEC) for water organisms. Tech.-4-NP concentrations showed a significant tendency of decreasing concentrations during the sampling period. This is mainly attributed to the implementation of the European Directive 2003/53/EG, which restricts both the marketing and use of nonylphenols. Results from the analysis of additionally collected water samples from sewage treatment plant (STP) effluents indicate that the STPs cannot be the only sources for tech.-4-NP found in the river water. - Concentrations of 4-nonylphenols in rivers of Hessisches Ried in Germany decreased in the sampling period from September 2003 to September 2005

Consensus models to predict endocrine disruption for all human-exposure chemicals (AAAS Annual Meeting)

Science.gov (United States)

Humans are potentially exposed to tens of thousands of man-made chemicals in the environment. It is well known that some environmental chemicals mimic natural hormones and thus have the potential to be endocrine disruptors. Most of these environmental chemicals have never been te...

Tributyltin: Advancing the Science on Assessing Endocrine Disruption with an Unconventional Endocrine-Disrupting Compound.

Science.gov (United States)

Lagadic, Laurent; Katsiadaki, Ioanna; Biever, Ron; Guiney, Patrick D; Karouna-Renier, Natalie; Schwarz, Tamar; Meador, James P

Tributyltin (TBT) has been recognized as an endocrine disrupting chemical (EDC) for several decades. However, only in the last decade, was its primary endocrine mechanism of action (MeOA) elucidated-interactions with the nuclear retinoid-X receptor (RXR), peroxisome proliferator-activated receptor γ (PPARγ), and their heterodimers. This molecular initiating event (MIE) alters a range of reproductive, developmental, and metabolic pathways at the organism level. It is noteworthy that a variety of MeOAs have been proposed over the years for the observed endocrine-type effects of TBT; however, convincing data for the MIE was provided only recently and now several researchers have confirmed and refined the information on this MeOA. One of the most important lessons learned from years of research on TBT concerns apparent species sensitivity. Several aspects such as the rates of uptake and elimination, chemical potency, and metabolic capacity are all important for identifying the most sensitive species for a given chemical, including EDCs. For TBT, much of this was discovered by trial and error, hence important relationships and important sensitive taxa were not identified until several decades after its introduction to the environment. As recognized for many years, TBT-induced responses are known to occur at very low concentrations for molluscs, a fact that has more recently also been observed in fish species. This review explores the MeOA and effects of TBT in different species (aquatic molluscs and other invertebrates, fish, amphibians, birds, and mammals) according to the OECD Conceptual Framework for Endocrine Disruptor Testing and Assessment (CFEDTA). The information gathered on biological effects that are relevant for populations of aquatic animals was used to construct Species Sensitivity Distributions (SSDs) based on No Observed Effect Concentrations (NOECs) and Lowest Observed Effect Concentrations (LOECs). Fish appear at the lower end of these distributions

Tributyltin: Advancing the science on assessing endocrine disruption with an unconventional endocrine-disrupting compound

Science.gov (United States)

Lagadic, Laurent; Katsiadaki, Ioanna; Biever, Ronald C.; Guiney, Patrick; Karouna-Renier, Natalie; Schwarz, Tamar; Meador, James P.

2018-01-01

Tributyltin (TBT) has been recognized as an endocrine disrupting chemical (EDC) for several decades. However, only in the last decade, was its primary endocrine mechanism of action (MeOA) elucidated—interactions with the nuclear retinoid-X receptor (RXR), peroxisome proliferator-activated receptor γ (PPARγ), and their heterodimers. This molecular initiating event (MIE) alters a range of reproductive, developmental, and metabolic pathways at the organism level. It is noteworthy that a variety of MeOAs have been proposed over the years for the observed endocrine-type effects of TBT; however, convincing data for the MIE was provided only recently and now several researchers have confirmed and refined the information on this MeOA. One of the most important lessons learned from years of research on TBT concerns apparent species sensitivity. Several aspects such as the rates of uptake and elimination, chemical potency, and metabolic capacity are all important for identifying the most sensitive species for a given chemical, including EDCs. For TBT, much of this was discovered by trial and error, hence important relationships and important sensitive taxa were not identified until several decades after its introduction to the environment. As recognized for many years, TBT-induced responses are known to occur at very low concentrations for molluscs, a fact that has more recently also been observed in fish species. This review explores the MeOA and effects of TBT in different species (aquatic molluscs and other invertebrates, fish, amphibians, birds, and mammals) according to the OECD Conceptual Framework for Endocrine Disruptor Testing and Assessment (CFEDTA). The information gathered on biological effects that are relevant for populations of aquatic animals was used to construct Species Sensitivity Distributions (SSDs) based on No Observed Effect Concentrations (NOECs) and Lowest Observed Effect Concentrations (LOECs). Fish appear at the lower end of these distributions

Steroidogenesis in vitro : towards relevant models for endocrine disruptor screening

NARCIS (Netherlands)

Roelofs, M.J.E.

2016-01-01

Starting our search for in vitro alternative methods to screen for steroidogenesis toxicity, we focused on the effects of (suggested) endocrine disrupting compounds (EDCs) on cytochrome P450 17 (CYP17) enzyme activity. CYP17 is responsible for conversion of progestagens to dehydroepiandrosterone

Unexpected metabolic disorders induced by endocrine disruptors in Xenopus tropicalis provide new lead for understanding amphibian decline.

Science.gov (United States)

Regnault, Christophe; Usal, Marie; Veyrenc, Sylvie; Couturier, Karine; Batandier, Cécile; Bulteau, Anne-Laure; Lejon, David; Sapin, Alexandre; Combourieu, Bruno; Chetiveaux, Maud; Le May, Cédric; Lafond, Thomas; Raveton, Muriel; Reynaud, Stéphane

2018-05-08

Despite numerous studies suggesting that amphibians are highly sensitive to endocrine disruptors (EDs), both their role in the decline of populations and the underlying mechanisms remain unclear. This study showed that frogs exposed throughout their life cycle to ED concentrations low enough to be considered safe for drinking water, developed a prediabetes phenotype and, more commonly, a metabolic syndrome. Female Xenopus tropicalis exposed from tadpole stage to benzo( a )pyrene or triclosan at concentrations of 50 ng⋅L -1 displayed glucose intolerance syndrome, liver steatosis, liver mitochondrial dysfunction, liver transcriptomic signature, and pancreatic insulin hypersecretion, all typical of a prediabetes state. This metabolic syndrome led to progeny whose metamorphosis was delayed and occurred while the individuals were both smaller and lighter, all factors that have been linked to reduced adult recruitment and likelihood of reproduction. We found that F 1 animals did indeed have reduced reproductive success, demonstrating a lower fitness in ED-exposed Xenopus Moreover, after 1 year of depuration, Xenopus that had been exposed to benzo( a )pyrene still displayed hepatic disorders and a marked insulin secretory defect resulting in glucose intolerance. Our results demonstrate that amphibians are highly sensitive to EDs at concentrations well below the thresholds reported to induce stress in other vertebrates. This study introduces EDs as a possible key contributing factor to amphibian population decline through metabolism disruption. Overall, our results show that EDs cause metabolic disorders, which is in agreement with epidemiological studies suggesting that environmental EDs might be one of the principal causes of metabolic disease in humans.

Nuevos disruptores endocrinos: su importancia en la población pediátrica New endocrine disruptors: their importance in pediatric population

OpenAIRE

Juan Manuel Alfaro Velásquez; Alejandro Román González

2005-01-01

Los cambios de nuestro hábitat en los últimos 40 años han generado contactos frecuentes con sustancias químicas tanto naturales como sintéticas que funcionan como disruptores endocrinos; son ejemplos los pesticidas ampliamente usados tras la introducción del DDT, los derivados petroquímicos en la industria del plástico, las medicinas sintéticas, y el volumen creciente de artículos de vestuario, aseo, cosmética y transporte. En cada uno de los grupos anotados hay señales de actividad de algún ...

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

Science.gov (United States)

Scholz, S; Renner, P; Belanger, S E; Busquet, F; Davi, R; Demeneix, B A; Denny, J S; Léonard, M; McMaster, M E; Villeneuve, D L; Embry, M R

2013-01-01

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

Endocrine Activity of AVB, 2MR, BHA, and Their Mixtures.

Science.gov (United States)

Klopcic, Ivana; Dolenc, Marija Sollner

2017-03-01

Personal care products are used increasingly, resulting in growing concern concerning their potential disruption of normal hormonal functions. Recent results on the bioaccumulation of cosmetic ingredients in wildlife and humans point to the need for an in-depth analysis for endocrine activity, in particular with respect to their influence on the androgen (AR), glucocorticoid (GR), and thyroid hormone receptors (TRs). Furthermore, humans are commonly exposed simultaneously to complex mixtures of endocrine active compounds. We have therefore examined 3 frequently used cosmetic ingredients: 2-methylresorcinol (2MR), butylated hydroxyanisole (BHA) and avobenzone (AVB), for (anti)-androgen-, (anti)-glucocorticoid-, and (anti)-thyroid hormone-like activities. Their binary and ternary mixtures at EC50 or IC50 concentrations have also been examined for anti-androgen-, glucocorticoid-, and thyroid hormone-like activities. In the MDA-kb2 reporter cell line, compounds possessed anti-androgen-, glucocorticoid-, and anti-glucocorticoid-like activities (except AVB). A new cell line, GH3.TRE-Luc, was used to evaluate anti-thyroid and thyroid hormone-like activities. The combinations 2MR + BHA and 2MR + BHA + AVB have glucocorticoid-like activity: only 2MR + AVB has anti-androgen-like activity. On the other hand, binary and ternary mixtures of compounds showed no thyroid hormone-like activity. Thus, in addition to identifying new endocrine disrupting compounds, it is also necessary to determine the effects of their mixtures in order to assess fully their risk to human health. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Recent Advances on Endocrine Disrupting Effects of UV Filters

Directory of Open Access Journals (Sweden)

Jiaying Wang

2016-08-01

Full Text Available Ultraviolet (UV filters are used widely in cosmetics, plastics, adhesives and other industrial products to protect human skin or products against direct exposure to deleterious UV radiation. With growing usage and mis-disposition of UV filters, they currently represent a new class of contaminants of emerging concern with increasingly reported adverse effects to humans and other organisms. Exposure to UV filters induce various endocrine disrupting effects, as revealed by increasing number of toxicological studies performed in recent years. It is necessary to compile a systematic review on the current research status on endocrine disrupting effects of UV filters toward different organisms. We therefore summarized the recent advances on the evaluation of the potential endocrine disruptors and the mechanism of toxicity for many kinds of UV filters such as benzophenones, camphor derivatives and cinnamate derivatives.

Endocrine disruptors compounds, pharmaceuticals and personal care products in urban wastewater: implications for agricultural reuse and their removal by adsorption process.

Science.gov (United States)

Grassi, Mariangela; Rizzo, Luigi; Farina, Anna

2013-06-01

In the last years, a lot of emerging contaminants, such as, endocrine disruptors compounds (EDCs), pharmaceuticals, and personal care products (PPCPs) have been detected in wastewater. Because of their toxicity and possible adverse effects on the environment and humans, their release from urban wastewater treatment plants (UWWTPs) effluents should be minimized, particularly when a wastewater reuse for crops irrigation is expected. Many processes have been investigated for advanced treatment of UWWTP effluents as well as for emerging contaminant degradation; among these, adsorption process was successfully used to remove EDCs and PPCPs from wastewater. This article shortly reviews EDCs and PPCPs removal from UWWTP effluents by adsorption process using conventional and non-conventional adsorbents. The fate of EDCs and PPCPs in UWWTPs and the implications for agricultural wastewater reuse has been addressed too. In spite of the adsorption process looking to be a valuable alternative to other advanced technologies for the removal of emerging contaminants from wastewater, some gaps still remain to evaluate the actual feasibility at full scale. However, according to a few studies available in scientific literature on the use of both powdered activated carbon and granular activated carbon at full scale, adsorption process by activated carbon is a promising, potentially effective, and economically feasible solution for producing safe wastewater for agricultural reuse.

Endocrine potency of wastewater: Contents of endocrine disrupting chemicals and effects measured by in vivo and in vitro assays

DEFF Research Database (Denmark)

Kusk, Kresten Ole; Krüger, Tanja; Long, Manhai

2011-01-01

chemical analysis and a battery of bioassays. Influent samples, collected at the first STP grate, and effluent samples, collected after the sewage treatment, were extracted using solid phase extraction. Extracts were analyzed for the content of a range of industrial chemicals with endocrine disrupting...... properties: phthalate metabolites, parabens, industrial phenols, ultraviolet screens, and natural and synthetic steroid estrogens. The endocrine disrupting bioactivity and toxicity of the extracts were analyzed in cell culture assay for the potency to affect the function of the estrogen, androgen, aryl......Industrial and municipal effluents are important sources of endocrine disrupting compounds (EDCs) discharged into the aquatic environment. This study investigated the endocrine potency of wastewater and the cleaning efficiency of two typical urban Danish sewage treatment plants (STPs), using...

Reproductive toxicity of the endocrine disrupters vinclozolin and bisphenol A in the terrestrial isopod Porcellio scaber (Latreille, 1804).

NARCIS (Netherlands)

Lemos, M.F.L.; van Gestel, C.A.M.; Soares, A.M.V.M.

2010-01-01

Endocrine Disruptor Compounds (EDCs) have been largely studied concerning their effects on vertebrates. Nevertheless, invertebrates as targets for these chemicals have been neglected and few studies are available. Specifically for edaphic invertebrates, data concerning the effects of EDCs is

STRATEGIES TO REDUCE OR REPLACE THE USE OF ANIMALS IN THE ENDOCRINE SCREENING AND TESTING PROGRAM.

Science.gov (United States)

Abstract: The US Environmental Protection Agency (EPA) is developing a screening and testing program for endocrine disrupting chemicals (EDCs) to detect alterations of hypothalamic-pituitary-gonadal (HPG) function, estrogen, androgen and thyroid hormone synthesis and androgen (AR...

El tejido graso como modulador endocrino: Cambios hormonales asociados a la obesidad

OpenAIRE

BAUDRAND B,RENÉ; ARTEAGA U,EUGENIO; MORENO G,MANUEL

2010-01-01

Adipose tissue not only stores fat, but secretes factors and hormones, which modify the regulation, metabolism and secretion of several other hormones. The objective of this review is to describe the hormonal disorders associated with increased adipose tissue, which acts as a modulator or disruptor of the endocrine physiology, with special reference to cortisol, androgens, growth hormone and thyroid axis, and discuss the implications for the management and treatment of these patients.

Bisphenol A in the aquatic environment and its endocrine-disruptive effects on aquatic organisms.

Science.gov (United States)

Kang, Jeong-Hun; Asai, Daisuke; Aasi, Daisuke; Katayama, Yoshiki

2007-01-01

Bisphenol A [BPA; 2,2-bis(4-hydroxyphenyl)propane], which is mainly used in the production of epoxy resins and polycarbonate plastics, is a known endocrine disruptor and is acutely toxic to aquatic organisms. Due to intensified usage of these products, exposure of organisms to BPA via several routes, such as the environment and food, has increased. The aquatic environment is an important area for the study of BPA. This report reviews the literature concerning contamination routes and degradation of BPA in the aquatic environment and its endocrine-disruptive effects on aquatic organisms.

Decontamination of a municipal landfill leachate from endocrine disruptors using a combined sorption/bioremoval approach.

Science.gov (United States)

Loffredo, Elisabetta; Castellana, Giancarlo; Senesi, Nicola

2014-02-01

Sorption and biodegradation are the main mechanisms for the removal of endocrine disruptor compounds (EDs) from both solid and liquid matrices. There are recent evidences about the capacity of white-rot fungi to decontaminate water systems from phenolic EDs by means of their ligninolytic enzymes. Most of the available studies report the removal of EDs by biodegradation or adsorption separately. This study assessed the simultaneous removal of five EDs—the xenoestrogens bisphenol A (BPA), ethynilestradiol (EE2), and 4-n-nonylphenol (NP), and the herbicide linuron and the insecticide dimethoate—from a municipal landfill leachate (MLL) using a combined sorption/bioremoval approach. The adsorption matrices used were potato dextrose agar alone or added with each of the following adsorbent materials: ground almond shells, a coffee compost, a coconut fiber, and a river sediment. These matrices were either not inoculated or inoculated with the fungus Pleurotus ostreatus and superimposed on the MLL. The residual amount of each ED in the MLL was quantified after 4, 7, 12, and 20 days by HPLC analysis and UV detection. Preliminary experiments showed that (1) all EDs did not degrade significantly in the untreatedMLL for at least 28 days, (2) the mycelial growth of P. ostreatus was largely stimulated by components of the MLL, and (3) the enrichment of potato dextrose agar with any adsorbent material favored the fungal growth for 8 days after inoculation. A prompt relevant disappearance of EDs in the MLL occurred both without and, especially, with fungal activity, with the only exception of the very water soluble dimethoate that was poorly adsorbed and possibly degraded only during the first few days of experiments. An almost complete removal of phenolic EDs, especially EE2 and NP, occurred after 20 days or much earlier and was generally enhanced by the adsorbent materials used. Data obtained indicated that both adsorption and biodegradation mechanisms contribute

Effects of different endocrine disruptor (EDC) mixtures on gene expression in neonatal rat brain regions

DEFF Research Database (Denmark)

Lichtensteiger, Walter; Bassetti-Gaille, Catherine; Faass, Oliver

2013-01-01

Sexual brain differentiation is a potential EDC target. It depends on a combination of estrogen receptor- and androgen receptor-mediated effects in males and on estrogens in females. It is not known how these processes are affected by real-world mixtures of EDCs. We investigated the effect of three...... EDC mixtures on gene expression in developing brain. Amix (8 anti-androgenic chemicals), Emix (4 estrogenic chemicals) and Tmix (Amix + Emix + paracetamol recently identified as anti-androgenic) were administered by oral gavage to rat dams from gestational day 7 until weaning, at doses corresponding...... to 450×, 200× and 100× high end human intakes (S. Christiansen et al., 2012. International Journal of Andrology 35, 303). At postnatal day 6, during the last part of sexual brain differentiation, exon microarray analyses were performed in medial preoptic area (MPO) in the highest dose group, and real...

Environmental analysis of endocrine disrupting effects from hydrocarbon contaminants in the ecosystem. 1997 annual progress report

International Nuclear Information System (INIS)

1997-01-01

'The overall objective of the basic research grant is to characterize the potential of common hydrocarbon contaminants in ecosystems to act as endocrine disruptors. The three major lines of research include (1) a biotechnology based screening system to identify potential hormone mimics and antagonists; (2) an animal screening system to identify biomarkers of endocrine effects. and (3) a literature review to identify compounds at a variety of DOE sites that need to be examined for endocrine disrupting effects. By relating results obtained from this research project to contamination problems at various DOE sites. CBR will provide data and information on endocrine disrupting contaminants to DOE for consideration in risk analyses for determining clean-up levels and priorities needed at the sites.'

Bisphenol A affects androgen receptor function via multiple mechanisms.

Science.gov (United States)

Teng, Christina; Goodwin, Bonnie; Shockley, Keith; Xia, Menghang; Huang, Ruili; Norris, John; Merrick, B Alex; Jetten, Anton M; Austin, Christopher P; Tice, Raymond R

2013-05-25

Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100 nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2 μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2 μM), did not compete with R1881 for AR binding, when tested at 30 μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. Published by Elsevier Ireland Ltd.

Endocrine control of epigenetic mechanisms in male reproduction.

Science.gov (United States)

Ankolkar, Mandar; Balasinor, N H

2016-01-01

Endocrine control of reproduction is very well known and has been echoed by many research groups. However, recent developments point to the ability of toxic endocrine disrupting chemicals (EDC) to alter epigenetic information of the gametes which gets transferred to the developing embryo and affects the immediate reproductive outcome or even persists transgenerationally. These epigenetic aberrations contribute to the ensuing pathophysiology of reproductive disorders. Investigations of the female in cases of poor reproductive outcome have been the main strategy towards diagnosis. However, despite the male partner contributing half of his genome to the progeny, thorough investigations in the male have been ignored. Environmental pollutants are all pervading and are encountered in our day-to-day life. Many of these pollutants have potential to disrupt the endocrine system. Here, we discuss how the male gametes (spermatozoa) are susceptible to a myriad of epigenetic insults inflicted by exposure to endocrine disruptors and how important is the contribution of the epigenetic marks of the spermatozoa in healthy reproduction. We advocate that sperm epigenetics should be considered as a significant contributor to reproductive health and should be researched further and be subsequently included in routine diagnostic workup in cases of poor reproductive outcome.

Phenotypic malignant changes and untargeted lipidomic analysis of long-term exposed prostate cancer cells to endocrine disruptors

Energy Technology Data Exchange (ETDEWEB)

Bedia, Carmen, E-mail: carmen.bedia@idaea.csic.es; Dalmau, Núria, E-mail: nuria.dalmau@idaea.csic.es; Jaumot, Joaquim, E-mail: joaquim.jaumot@idaea.csic.es; Tauler, Romà, E-mail: roma.tauler@idaea.csic.es

2015-07-15

Endocrine disruptors (EDs) are a class of environmental toxic molecules able to interfere with the normal hormone metabolism. Numerous studies involve EDs exposure to initiation and development of cancers, including prostate cancer. In this work, three different EDs (aldrin, aroclor 1254 and chlorpyrifos (CPF)) were investigated as potential inducers of a malignant phenotype in DU145 prostate cancer cells after a chronic exposure. Epithelial to mesenchymal transition (EMT) induction, proliferation, migration, colony formation and release of metalloproteinase 2 (MMP-2) were analyzed in 50-day exposed cells to the selected EDs. As a result, aldrin and CPF exposure led to an EMT induction (loss of 16% and 14% of E-cadherin levels, respectively, compared to the unexposed cells). Aroclor and CPF presented an increased migration (134% and 126%, respectively), colony formation (204% and 144%, respectively) and MMP-2 release (137% in both cases) compared to the unexposed cells. An untargeted lipidomic analysis was performed to decipher the lipids involved in the observed transformations. As general results, aldrin exposure showed a global decrease in phospholipids and sphingolipids, and aroclor and CPF showed an increase of certain phospholipids, glycosphingolipids as well as a remarkable increase of some cardiolipin species. Furthermore, the three exposures resulted in an increase of some triglyceride species. In conclusion, some significant changes in lipids were identified and thus we postulate that some lipid compounds and lipid metabolic pathways could be involved in the acquisition of the malignant phenotype in exposed prostate cancer cells to the selected EDs. - Highlights: • Aldrin, aroclor and chlorpyrifos induced an aggressive phenotype in DU145 cells. • An untargeted lipidomic analysis has been performed on chronic exposed cells. • Lipidomic results showed changes in specific lipid species under chronic exposure. • These lipids may have a role in the

Phenotypic malignant changes and untargeted lipidomic analysis of long-term exposed prostate cancer cells to endocrine disruptors

International Nuclear Information System (INIS)

Bedia, Carmen; Dalmau, Núria; Jaumot, Joaquim; Tauler, Romà

2015-01-01

Endocrine disruptors (EDs) are a class of environmental toxic molecules able to interfere with the normal hormone metabolism. Numerous studies involve EDs exposure to initiation and development of cancers, including prostate cancer. In this work, three different EDs (aldrin, aroclor 1254 and chlorpyrifos (CPF)) were investigated as potential inducers of a malignant phenotype in DU145 prostate cancer cells after a chronic exposure. Epithelial to mesenchymal transition (EMT) induction, proliferation, migration, colony formation and release of metalloproteinase 2 (MMP-2) were analyzed in 50-day exposed cells to the selected EDs. As a result, aldrin and CPF exposure led to an EMT induction (loss of 16% and 14% of E-cadherin levels, respectively, compared to the unexposed cells). Aroclor and CPF presented an increased migration (134% and 126%, respectively), colony formation (204% and 144%, respectively) and MMP-2 release (137% in both cases) compared to the unexposed cells. An untargeted lipidomic analysis was performed to decipher the lipids involved in the observed transformations. As general results, aldrin exposure showed a global decrease in phospholipids and sphingolipids, and aroclor and CPF showed an increase of certain phospholipids, glycosphingolipids as well as a remarkable increase of some cardiolipin species. Furthermore, the three exposures resulted in an increase of some triglyceride species. In conclusion, some significant changes in lipids were identified and thus we postulate that some lipid compounds and lipid metabolic pathways could be involved in the acquisition of the malignant phenotype in exposed prostate cancer cells to the selected EDs. - Highlights: • Aldrin, aroclor and chlorpyrifos induced an aggressive phenotype in DU145 cells. • An untargeted lipidomic analysis has been performed on chronic exposed cells. • Lipidomic results showed changes in specific lipid species under chronic exposure. • These lipids may have a role in the

Endocrine Disrupting Contaminants—Beyond the Dogma

Science.gov (United States)

Guillette, Louis J.

2006-01-01

Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. For example, the DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] metabolite, p,p′-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] is known to disrupt prostaglandin synthesis in the uterus of birds, providing part of the explanation for DDT-induced egg shell thinning. Few studies have examined prostaglandin synthesis as a target for endocrine disruption, yet these hormones are active in reproduction, immune responses, and cardiovascular physiology. Future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continue to emphasize a narrower approach based on regulatory needs. Without this broader approach, research into endocrine disruption will become dominated by a narrow dogma, focusing on a few end points and mechanisms. PMID:16818240

MicroRNAs related to androgen metabolism and polycystic ovary syndrome

DEFF Research Database (Denmark)

Sørensen, Anja Elaine; Udesen, Pernille Bækgaard; Wissing, Marie Louise

2016-01-01

Polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women. PCOS is associated with altered features of androgen metabolism, increased insulin resistance and impaired fertility. Furthermore, PCOS, being a syndrome diagnosis, is heterogeneous and characterized by polycystic ovaries...

The indication of endocrine therapy from the radiological view with mammary carcinoma

International Nuclear Information System (INIS)

Nadji-Esfahani, A.

1982-01-01

Important for the determining of the indication of endocrine treatment with mammary carcinoma is the pre-determination of receptors. A safe method for the choice of patients, for whom endocrine therapy would be appropriate, is not yet available. Patients who have no estrogen receptors, have as good as no chance, to be picked for endocrine therapy. The highest remission rates (around 60%) with endocrine therapy are attained when estrogen and progesterone receptors are both present, which, however, is usually only so in about one-third of the cases. Estrogen receptors are present in about 60 to 70% of the cases. With pre-menopausal women the following would be considered as endocrine procedures after switching off the ovaries: Androgens with abdominal, lung and pleura metastases; anti-estrogens (at best Tamoxifen) with abdominal and visceral metastasis; adrenalectomy with abdominal and bone metastases; and hypophyseal switching-off mostly with skeletal pains. In post-menopause estrogens are the first choice. In combination with progestogen they are indicated for abdominal and lung metastases and for carcinomatic pleura discharges. With abdominal and visceral metastasis Tamoxifen can be considered as first choice. The indications for hypophyseal switching-off, adrenalectomy and androgens are the same as for pre-menopausal women. (TRV) [de

Endocrine disrupting activities and immunomodulatory effects in lymphoblastoid cell lines of diclofenac, 4-hydroxydiclofenac and paracetamol.

Science.gov (United States)

Klopčič, Ivana; Markovič, Tijana; Mlinarič-Raščan, Irena; Dolenc, Marija Sollner

2018-05-16

A critical literature review reveals that knowledge of side effects of pharmaceuticals diclofenac and paracetamol is extremely important because of their widespread use and occurrence in the environment. In order to delineate whether these compounds have endocrine activity and influence on the immune system, we assessed the potential endocrine disrupting and immunomodulatory activities of: diclofenac (DIC), its metabolite 4-hydroxydiclofenac (4-HD) and paracetamol (PAR). Herein, we report on their impact on estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR) and thyroid hormone receptor (TR). The endocrine disrupting effects were assessed in vitro in MDA-kb2 and GH3.TRE-Luc cell lines and by the XenoScreen YES/YAS assay. Moreover, binding affinity to nuclear receptors (GR and AR) was also measured. Immunomodulatory properties of the compounds were evaluated in lymphoblastoid cell lines. All the tested compounds showed endocrine disrupting and immunomodulatory activities. The results revealed that both DIC and its metabolite 4-HD exhibited significant estrogenic, anti-androgenic (in YAS assay), (anti)-androgenic, (anti)-glucocorticoid and anti-thyroid hormonal activities (in luciferase reporter gene assays). DIC showed direct binding to the GR, while its metabolite 4-HD to the GR and AR. Only metabolite 4-HD showed estrogenic, androgenic (in YAS assay) and thyroid-hormonal activities. PAR had anti-androgenic activity and anti-thyroid hormonal activity. PAR displayed GR agonist activity with competition to its receptor and agonistic activity to AR. All of the compounds significantly modulated pro-inflammatory and immunoregulatory cytokine production in lymphoblastoid cell lines and were thus proven immunomodulatory. The study is useful in determining toxicological effects and contributes to the knowledge of possible side effects of diclofenac, its metabolite and paracetamol. Copyright © 2018 Elsevier B.V. All rights reserved.

Low-dose effects of hormones and endocrine disruptors.

Science.gov (United States)

Vandenberg, Laura N

2014-01-01

Endogenous hormones have effects on tissue morphology, cell physiology, and behaviors at low doses. In fact, hormones are known to circulate in the part-per-trillion and part-per-billion concentrations, making them highly effective and potent signaling molecules. Many endocrine-disrupting chemicals (EDCs) mimic hormones, yet there is strong debate over whether these chemicals can also have effects at low doses. In the 1990s, scientists proposed the "low-dose hypothesis," which postulated that EDCs affect humans and animals at environmentally relevant doses. This chapter focuses on data that support and refute the low-dose hypothesis. A case study examining the highly controversial example of bisphenol A and its low-dose effects on the prostate is examined through the lens of endocrinology. Finally, the chapter concludes with a discussion of factors that can influence the ability of a study to detect and interpret low-dose effects appropriately. © 2014 Elsevier Inc. All rights reserved.

Endocrine disrupting chemicals: harmful substances and how to test them Produtos químicos como desreguladores endócrinos: substâncias danosas e como devem ser testadas

Directory of Open Access Journals (Sweden)

Nicolás Olea-Serrano

2002-04-01

Full Text Available This paper presents an analysis of the opinions of different groups from: scientists, international regulatory bodies, non-governmental organizations and industry; with an interest in the problem of identifying chemical substances with endocrine disrupting activity. There is also discussion of the consequences that exposure to endocrine disruptors may have for human health, considering concrete issues related to: the estimation of risk; the tests that must be used to detect endocrine disruption; the difficulties to establish an association between dose, time of exposure, individual susceptibility, and effect; and the attempts to create a census of endocrine disruptors. Finally, it is proposed that not all hormonal mimics should be included under the single generic denomination of endocrine disruptors.Este artigo apresenta uma análise das opiniões de diferentes grupos, inclusive de cientistas, agências regulatórias internacionais, organizações não-governamentais e indústrias, interessados na questão da identificação de substâncias químicas com atividade desreguladora endócrina. Os autores discutem também o impacto da exposição aos desreguladores endócrinos sobre a saúde humana, considerando as seguintes questões: estimativa de risco; testes utilizados para detectar distúrbios endócrinos; dificuldades na identificação de uma associação entre dose, tempo de exposição, suscetibilidade individual e efeito e tentativas no sentido de mapear os desreguladores endócrinos. Finalmente, os autores argumentam que nem todos os agonistas hormonais devem ser incluídos sob a denominação genérica de desreguladores endócrinos.

Immune System: An Emerging Player in Mediating Effects of Endocrine Disruptors on Metabolic Health.

Science.gov (United States)

Bansal, Amita; Henao-Mejia, Jorge; Simmons, Rebecca A

2018-01-01

The incidence of metabolic disorders like type 2 diabetes and obesity continues to increase. In addition to the well-known contributors to these disorders, such as food intake and sedentary lifestyle, recent research in the exposure science discipline provides evidence that exposure to endocrine-disrupting chemicals like bisphenol A and phthalates via multiple routes (e.g., food, drink, skin contact) also contribute to the increased risk of metabolic disorders. Endocrine-disrupting chemicals (EDCs) can disrupt any aspect of hormone action. It is becoming increasingly clear that EDCs not only affect endocrine function but also adversely affect immune system function. In this review, we focus on human, animal, and in vitro studies that demonstrate EDC exposure induces dysfunction of the immune system, which, in turn, has detrimental effects on metabolic health. These findings highlight how the immune system is emerging as a novel player by which EDCs may mediate their effects on metabolic health. We also discuss studies highlighting mechanisms by which EDCs affect the immune system. Finally, we consider that a better understanding of the immunomodulatory roles of EDCs will provide clues to enhance metabolic function and contribute toward the long-term goal of reducing the burden of environmentally induced diabetes and obesity. Copyright © 2018 Endocrine Society.

Evaluation of two membrane-based microextraction techniques for the determination of endocrine disruptors in aqueous samples by HPLC with diode array detection.

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Luiz Oenning, Anderson; Lopes, Daniela; Neves Dias, Adriana; Merib, Josias; Carasek, Eduardo

2017-11-01

In this study, the viability of two membrane-based microextraction techniques for the determination of endocrine disruptors by high-performance liquid chromatography with diode array detection was evaluated: hollow fiber microporous membrane liquid-liquid extraction and hollow-fiber-supported dispersive liquid-liquid microextraction. The extraction efficiencies obtained for methylparaben, ethylparaben, bisphenol A, benzophenone, and 2-ethylhexyl-4-methoxycinnamate from aqueous matrices obtained using both approaches were compared and showed that hollow fiber microporous membrane liquid-liquid extraction exhibited higher extraction efficiency for most of the compounds studied. Therefore, a detailed optimization of the extraction procedure was carried out with this technique. The optimization of the extraction conditions and liquid desorption were performed by univariate analysis. The optimal conditions for the method were supported liquid membrane with 1-octanol for 10 s, sample pH 7, addition of 15% w/v of NaCl, extraction time of 30 min, and liquid desorption in 150 μL of acetonitrile/methanol (50:50 v/v) for 5 min. The linear correlation coefficients were higher than 0.9936. The limits of detection were 0.5-4.6 μg/L and the limits of quantification were 2-16 μg/L. The analyte relative recoveries were 67-116%, and the relative standard deviations were less than 15.5%. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Detection of endocrine active substances in the aquatic environment in southern Taiwan using bioassays and LC-MS/MS.

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Chen, Kuang-Yu; Chou, Pei-Hsin

2016-06-01

Endocrine active substances, including naturally occurring hormones and various synthetic chemicals have received much concern owing to their endocrine disrupting potencies. It is essential to monitor their environmental occurrence since these compounds may pose potential threats to biota and human health. In this study, yeast-based reporter assays were carried out to investigate the presence of (anti-)androgenic, (anti-)estrogenic, and (anti-)thyroid compounds in the aquatic environment in southern Taiwan. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was also used to measure the environmental concentrations of selected endocrine active substances for assessing potential ecological risks and characterizing contributions to the endocrine disrupting activities. Bioassay results showed that anti-androgenic (ND-7489 μg L(-1) flutamide equivalent), estrogenic (ND-347 ng L(-1) 17β-estradiol equivalent), and anti-thyroid activities were detected in the dissolved and particulate phases of river water samples, while anti-estrogenic activities (ND-10 μg L(-1) 4-hydroxytamoxifen equivalent) were less often found. LC-MS/MS analysis revealed that anti-androgenic and estrogenic contaminants, such as bisphenol A, triclosan, and estrone were frequently detected in Taiwanese rivers. In addition, their risk quotient values were often higher than 1, suggesting that they may pose an ecological risk to the aquatic biota. Further identification of unknown anti-androgenic and estrogenic contaminants in Taiwanese rivers may be necessary to protect Taiwan's aquatic environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coumestrol and its metabolite in mares' plasma after ingestion of phytoestrogen-rich plants: potent endocrine disruptors inducing infertility.

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Ferreira-Dias, G; Botelho, M; Zagrajczuk, A; Rebordão, M R; Galvão, A M; Bravo, P Pinto; Piotrowska-Tomala, K; Szóstek, A Z; Wiczkowski, W; Piskula, M; Fradinho, M J; Skarzynski, D J

2013-10-01

Phytoestrogens exist in plants that are present in forages fed to horses. They may compete with 17-β estradiol and influence the estrous cycle. Therefore, the objective was to determine whether coumestrol from clover-mixed pastures is present in mare's plasma after their ingestion (experiment I), and when this phytoestrogen was present in mare's plasma after ingestion (experiment II). The effect of a long-term ingestion of phytoestrogens on estrous cycle disruption was assessed (experiment III; clinical case). Experiment I was carried out in nonpregnant anestrous and cyclic Lusitano mares (n = 14) kept on clover and grass-mixed pastures, and supplemented with concentrate and hay or cereal straw. Blood and feedstuff were obtained from November to March. In experiment II, stabled cyclic Lusitano mares (n = 6) were fed for 14 days with increasing amounts of alfalfa pellets (250 g to 1 kg/day). Sequential blood samples were obtained for 8 hours after feed intake on Day 0 (control) and on Days 13 and 14 (1 kg/day alfalfa pellets). Experiment III mares were fed with a mixture of alfalfa and clover haylage for 5 months (group 1; n = 4) or for 9 months (group 2; n = 12). Estrous cycle was determined on the basis of plasma estradiol (E2), progesterone (P4), and ultrasound (experiment III). Concentrations of phytoestrogen coumestrol and its metabolite methoxycoumestrol were determined by high-performance liquid chromatography coupled with mass spectrometry. Phytoestrogens decreased in pasture from November until March (P haylage) than in group 1, after haylage withdrawal (P < 0.001). These data show that in the mare, coumestrol and its metabolite increase in blood after ingestion of estrogenic plants and can influence reproduction in mares as potent endocrine disruptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Endocrine disruptive effects of chemicals eluted from nitrile-butadiene rubber gloves using reporter gene assay systems.

Science.gov (United States)

Satoh, Kanako; Nonaka, Ryouichi; Ohyama, Ken-ichi; Nagai, Fumiko; Ogata, Akio; Iida, Mitsuru

2008-03-01

Disposable gloves made of nitrile-butadiene rubber (NBR) are used for contact with foodstuffs rather than polyvinyl chloride gloves containing di(2-ethylhexyl)phthalate (DEHP), because endocrine-disruptive effects are suspected for phthalate diesters including DEHP. However, 4,4'-butylidenebis(6-t-butyl-m-cresol) (BBBC), 2,4-di-t-butylphenol, and 2,2,4-trimetyl-1,3-pentanediol diisobutyrate can be eluted from NBR gloves, and possibly also detected in food. In this study, we examined the endocrine-disrupting effects of these chemicals via androgen receptor (AR) and estrogen receptor (ER)-mediated pathways using stably transfected reporter gene cell lines expressing AR (AR-EcoScreen system) and ER (MVLN cells), respectively. We also examined the binding activities of these chemicals to AR and ER. The IC50 value of BBBC for antagonistic androgen was in the range of 10(-6)M. The strength of inhibition was about 5 times that of a known androgen antagonist, 1,1'-(2,2-dichloroethylidene)bis[4-chlorobenzene] (p,p'-DDE), and similar to that of bisphenol A. The IC50 value of BBBC for antagonistic estrogen was in the range of 10(-6)M. These results suggest that BBBC and its structural homologue, 4,4'-thiobis(6-t-butyl-m-cresol) are androgen and estrogen antagonists. It is therefore necessary to study these chemicals in vivo, and clarify their effect on the endocrine system.

Plastics derived endocrine disruptors (BPA, DEHP and DBP induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations.

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Mohan Manikkam

Full Text Available Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset disease in subsequent generations (F1-F3 following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA, bis(2-ethylhexylphthalate (DEHP and dibutyl phthalate (DBP at two different doses promoted epigenetic transgenerational inheritance of adult onset disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the "plastics" or "lower dose plastics" mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis disease, obesity, and ovarian disease (primary ovarian insufficiency and polycystic ovaries were increased in the F3 generation animals. Kidney and prostate disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational disease and/or ancestral environmental exposures.

The low dose gamma ionising radiation impact upon cooperativity of androgen-specific proteins.

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Filchenkov, Gennady N; Popoff, Eugene H; Naumov, Alexander D

2014-01-01

The paper deals with effects of the ionising radiation (γ-IR, 0.5 Gy) upon serum testosterone (T), characteristics of testosterone-binding globulin (TeBG) and androgen receptor (AR) in parallel with observation of androgen (A) responsive enzyme activity - hexokinase (HK). The interdependence or relationships of T-levels with parameters of the proteins that provide androgenic regulation are consequently analyzed in post-IR dynamics. The IR-stress adjustment data reveal expediency of TeBG- and AR-cooperativity measurements for more precise assessments of endocrine A-control at appropriate emergencies. Copyright © 2013 Elsevier Ltd. All rights reserved.

The use of metabolising systems for in vitro testing of endocrine disruptors

NARCIS (Netherlands)

Jacobs, M.N.; Janssens, W.; Bernauer, U.; Brandon, E.; Coecke, S.; Combes, R.; Edwards, P.; Freidig, A.; Freyberger, A.; Kolanczyk, R.; Mc Ardie, C.; Mekenyan, O.; Schmieder, P.; Schrader, T.; Takeyoshi, M.; Burg, B. van der

2008-01-01

Legislation and prospective legislative proposals in for instance the USA, Europe, and Japan require, or may require that chemicals are tested for their ability to disrupt the hormonal systems of mammals. Chemicals found to test positive are considered to be endocrine active substances (EAS) and may

The effect of perinatal exposure to ethinyl oestradiol or a mixture of endocrine disrupting pesticides on kisspeptin neurons in the rat hypothalamus

DEFF Research Database (Denmark)

Overgaard, Agnete; Holst, Klaus; Mandrup, Karen

2013-01-01

Early life exposure to endocrine disruptors is considered to disturb normal development of hormone sensitive parameters and contribute to advanced puberty and reduced fecundity in humans. Kisspeptin is a positive regulator of the hypothalamic–pituitary–gonadal axis, and plays a key role in the in......Early life exposure to endocrine disruptors is considered to disturb normal development of hormone sensitive parameters and contribute to advanced puberty and reduced fecundity in humans. Kisspeptin is a positive regulator of the hypothalamic–pituitary–gonadal axis, and plays a key role.......We find that perinatal EE2 exposure did not affect Kiss1 mRNA expression in this study designed to model human exposure to estrogenic compounds, and we find only minor effects on puberty onset. Further, the Kiss1 system does not exhibit persistent changes and puberty onset is not affected after perinatal...... exposure to a pesticide mixture in this experimental setting. However, we find that the pesticide mancozeb tends to increase Kiss1 expression in the ARC, presumably through neurotoxic mechanisms rather than via classical endocrine disruption, calling for increased awareness that Kiss1 expression can...

Evidence of endocrine alteration in the red mullet, Mullus barbatus from the NW Mediterranean

International Nuclear Information System (INIS)

Martin-Skilton, Rebeca; Lavado, Ramon; Thibaut, Remi; Minier, Christophe; Porte, Cinta

2006-01-01

Red mullet (Mullus barbatus) were collected from different sampling sites (NW Mediterranean) in spring and autumn, with the aim of assessing potential alterations of the endocrine system. Alkylphenols were measured in fish bile as an indicator of estrogenic exposure. Key enzymatic activities involved in both synthesis (ovarian 17β-hydroxysteroid dehydrogenases and P450 aromatase) and metabolism of steroids were assessed together with histological alterations of the gonads. During the spring sampling, delayed gamete maturation, intersexuality, fibrosis, and depressed ovarian P450 aromatase activity were observed in organisms from the most polluted sites. During the autumn sampling, those effects were less evident, indicating that fish might be more susceptible to endocrine disrupting chemicals during the reproductive period. Nonetheless, enhanced glucuronidation of testosterone and estradiol was observed. Overall, this work provides first evidences of significant alterations in the endocrine system of red mullet from highly impacted areas in the NW Mediterranean. - Red mullet may be more susceptible to endocrine disruptors during the reproductive period

Evidence of endocrine alteration in the red mullet, Mullus barbatus from the NW Mediterranean

Energy Technology Data Exchange (ETDEWEB)

Martin-Skilton, Rebeca [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Lavado, Ramon [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Thibaut, Remi [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain); Minier, Christophe [Laboratoire d' Ecotoxicologie, Universite du Havre, 25 rue Philippe Lebon, B.P. 540, F-76058 Le Havre (France); Porte, Cinta [Department of Environmental Chemistry, IIQAB-CSIC, Jordi Girona 18, 08034 Barcelona (Spain)]. E-mail: cpvqam@cid.csic.es

2006-05-15

Red mullet (Mullus barbatus) were collected from different sampling sites (NW Mediterranean) in spring and autumn, with the aim of assessing potential alterations of the endocrine system. Alkylphenols were measured in fish bile as an indicator of estrogenic exposure. Key enzymatic activities involved in both synthesis (ovarian 17{beta}-hydroxysteroid dehydrogenases and P450 aromatase) and metabolism of steroids were assessed together with histological alterations of the gonads. During the spring sampling, delayed gamete maturation, intersexuality, fibrosis, and depressed ovarian P450 aromatase activity were observed in organisms from the most polluted sites. During the autumn sampling, those effects were less evident, indicating that fish might be more susceptible to endocrine disrupting chemicals during the reproductive period. Nonetheless, enhanced glucuronidation of testosterone and estradiol was observed. Overall, this work provides first evidences of significant alterations in the endocrine system of red mullet from highly impacted areas in the NW Mediterranean. - Red mullet may be more susceptible to endocrine disruptors during the reproductive period.

[Endocrine disruptors : Evidence from epidemiological studies necessitates a critical review of model systems].

Science.gov (United States)

Hoffmann, M; Gebauer, S; Nüchter, M; Baber, R; Ried, J; von Bergen, M; Kiess, W

2017-06-01

Endocrine disruptive chemicals (EDCs) cause adverse health effects through interaction with endocrine systems. They are classified by chemical structure, effects on specific endocrine systems, bioaccumulation, persistence in the environment, or clinically observable effects. For research of the complex mechanisms of action in the human body, only in vitro model systems have so far been available, that have insufficient high-throughput capacity, which makes risk evaluation more difficult. In addition, in industrial nations, living people are often exposed to mixtures of substances, with various effects. The clinical importance of epigenetic changes caused by the action of EDCs during vulnerable phases of development is currently unclear. Epidemiological studies are criticized because reproducibility is not always guaranteed. Nevertheless, they remain the method of choice for the development and analysis of suitable model systems. Positive associations, in spite of sometimes conflicting results, are key in the selection of factors that can then be analysed in model systems in an unbiased way. This article depicts the mainly positive epidemiological findings for EDC-caused effects in the fields of growth and metabolism, neurocognitive development and sexual development and reproduction. As a result, there is a need for closer linkage between epidemiological studies and mechanistic research into model systems, especially focusing on the interaction of different EDCs and the consequences of prenatal and early life exposure.

Flame retardants, surfactants and organotins in sediment and mysid shrimp of the Scheldt estuary (The Netherlands)

International Nuclear Information System (INIS)

Verslycke, Tim A.; Vethaak, A. Dick; Arijs, Katrien; Janssen, Colin R.

2005-01-01

Sediment and mysids from the Scheldt estuary, one of the largest and most polluted estuaries in Western Europe, were analyzed for a number of contaminants that have been shown to possess endocrine-disrupting activity, i.e. organotins, polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), tetrabromobisphenol A (TBBPA), nonylphenol ethoxylates (NPE) and transformation products, nonylphenol (NP) and nonylphenol ether carboxylates (NPEC). In addition, in vitro estrogenic and androgenic potencies of water and sediment extracts were determined. Total organotin concentrations ranged from 84 to 348 ng/g dw in sediment and 1110 to 1370 ng/g dw in mysid. Total PBDE (excluding BDE-209) concentrations ranged from 14 to 22 ng/g dw in sediment and from 1765 to 2962 ng/g lipid in mysid. High concentrations of BDE-209 (240-1650 ng/g dw) were detected in sediment and mysid (269-600 ng/g lipid). Total HBCD concentrations in sediment and mysid were 14-71 ng/g dw and 562-727 ng/g lipid, respectively. Total NPE concentrations in sediment were 1422 ng/g dw, 1222 ng/g dw for NP and 80 ng/g dw for NPEC and ranged from 430 to 1119 ng/g dw for total NPE and from 206 to 435 ng/g dw for NP in mysid. Significant estrogenic potency, as analyzed using the yeast estrogen assay, was detected in sediment and water samples from the Scheldt estuary, but no androgenic activity was found. This study is the first to report high levels of endocrine disruptors in estuarine mysids. - Field populations of mysid shrimp (Neomysis integer) of the Scheldt estuary (The Netherlands) are exposed to high concentrations of endocrine disruptors

Overview of the Pathophysiological Implications of Organotins on the Endocrine System.

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Marques, Vinicius Bermond; Faria, Rodrigo Alves; Dos Santos, Leonardo

2018-01-01

Organotins (OTs) are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic-pituitary axis), altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus) or peripheral (e.g., adipose tissue) mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed.

An Update on Plant Derived Anti-Androgens

Science.gov (United States)

Grant, Paul; Ramasamy, Shamin

2012-01-01

Anti-androgens are an assorted group of drugs and compounds that reduce the levels or activity of androgen hormones within the human body. Disease states in which this is relevant include polycystic ovarian syndrome, hirsutism, acne, benign prostatic hyperplasia, and endocrine related cancers such as carcinoma of the prostate. We provide an overview and discussion of the use of anti-androgen medications in clinical practice and explore the increasing recognition of the benefits of plant-derived anti-androgens, for example, spearmint tea in the management of PCOS, for which some evidence about efficacy is beginning to emerge. Other agents covered include red reishi, which has been shown to reduce levels 5-alpha reductase, the enzyme that facilitates conversion of testosterone to dihydrotestosterone (DHT); licorice, which has phytoestrogen effects and reduces testosterone levels; Chinese peony, which promotes the aromatization of testosterone into estrogen; green tea, which contains epigallocatechins and also inhibits 5-alpha reductase, thereby reducing the conversion of normal testosterone into the more potent DHT; black cohosh, which has been shown to kill both androgenresponsive and non-responsive human prostate cancer cells; chaste tree, which has a reduces prolactin from the anterior pituitary; and saw palmetto extract, which is used as an anti-androgen although it shown no difference in comparison to placebo in clinical trials. PMID:23843810

The OBELIX project: early life exposure to endocrine disruptors and obesity.

Science.gov (United States)

Legler, Juliette; Hamers, Timo; van Eck van der Sluijs-van de Bor, Margot; Schoeters, Greet; van der Ven, Leo; Eggesbo, Merete; Koppe, Janna; Feinberg, Max; Trnovec, Tomas

2011-12-01

The hypothesis of whether early life exposure (both pre- and early postnatal) to endocrine-disrupting chemicals (EDCs) may be a risk factor for obesity and related metabolic diseases later in life will be tested in the European research project OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life). OBELIX is a 4-y project that started in May 2009 and which has the following 5 main objectives: 1) to assess early life exposure in humans to major classes of EDCs identified as potential inducers of obesity (ie, dioxin-like compounds, non-dioxin-like polychlorinated biphenyls, organochlorine pesticides, brominated flame retardants, phthalates, and perfluorinated compounds) by using mother-child cohorts from 4 European regions with different food-contaminant exposure patterns; 2) to relate early life exposure to EDCs with clinical markers, novel biomarkers, and health-effect data related to obesity; 3) to perform hazard characterization of early life exposure to EDCs for the development of obesity later in life by using a mouse model; 4) to determine mechanisms of action of obesogenic EDCs on developmental programming with in vivo and in vitro genomics and epigenetic analyses; and 5) to perform risk assessments of prenatal exposure to obesogenic EDCs in food by integrating maternal exposure through food-contaminant exposure and health-effect data in children and hazard data in animal studies.

The occurrence of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs in surface water in South Wales, UK.

Science.gov (United States)

Kasprzyk-Hordern, Barbara; Dinsdale, Richard M; Guwy, Alan J

2008-07-01

The presence and fate of 56 pharmaceuticals, personal care products, endocrine disruptors and illicit drugs (PPCPs) were investigated in the South Wales region of the UK. Two contrasting rivers: River Taff and River Ely were chosen for this investigation and were monitored for a period of 10 months. The impact of the factors affecting the levels of concentration of PPCPs and illicit drugs in surface water such as surrounding area, proximity to wastewater effluent and weather conditions, mainly rainfall was also investigated. Most PPCPs were frequently found in river water at concentrations reaching single microgL(-1) and their levels depended mainly on the extent of water dilution resulting from rainfall. Discharge of treated wastewater effluent into the river course was found to be the main cause of water contamination with PPCPs. The most frequently detected PPCPs represent the group of pharmaceuticals dispensed at the highest levels in the Welsh community. These were antibacterial drugs (trimethoprim, erythromycin-H(2)O and amoxicillin), anti-inflammatories/analgesics (paracetamol, tramadol, codeine, naproxen, ibuprofen and diclofenac) and antiepileptic drugs (carbamazepine and gabapentin). Only four PPCPs out of 56 (simvastatin, pravastatin, digoxin and digoxigenin) were not quantified over the course of the study. Several PPCPs were found to be both ubiquitous and persistent in the aqueous environment (e.g. erythromycin-H(2)O, codeine, carbamazepine, gabapentin and valsartan). The calculated average daily loads of PPCPs indicated that in total almost 6 kg of studied PPCPs are discharged daily into the studied rivers. The illicit drugs studied were found in rivers at low levels of ng L(-1). Average daily loads of amphetamine, cocaine and its main metabolite benzoylecgonine were as follows: 8, 1.2 and 39 gday(-1), respectively. Their frequent occurrence in surface water is primarily associated with their high illegal usage and is strongly associated with the

Effects of combined exposure to anti-androgens on development and sexual dimorphic behaviour in rats

DEFF Research Database (Denmark)

Christiansen, Sofie

Summary Background: Androgens are key regulators of male sexual differentiation during the in utero and early postnatal development. Exposure to endocrine disrupting chemicals (EDCs) that counteract androgen action at some stage in these periods can permanently demasculinise male foetuses and lead......?  Is sexually dimorphic behaviour in rats affected at lower dose levels of anti-androgens and thereby a more sensitive endpoint than morphological effects on the male external reproductive organs? The thesis is based on the results of in vivo studies where mated female Wistar rats were exposed to anti......-androgens either alone or in mixtures during pregnancy and lactation. The endpoints examined for anti-androgenic effects in the offspring were: Anogenital distance (AGD), nipple retention (NR), and external (morphological) malformations in pups and sexually mature male rats. Furthermore, the effects of the anti...

Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005-2014.

Science.gov (United States)

Varshavsky, Julia R; Morello-Frosch, Rachel; Woodruff, Tracey J; Zota, Ami R

2018-06-01

Anti-androgenic phthalates are reproductive toxicants that may have additive effects on male development. Diet is the primary exposure source for most phthalates, which contaminate the food supply through food contact materials and industrialized production. To compare dietary sources of cumulative phthalates exposure between "food at home" (e.g. food consumed from a grocery store) and "food away from home" (e.g. food consumed from fast food/restaurants and cafeterias) in the U.S. general population. We estimated cumulative phthalates exposure by calculating daily intake from metabolite concentrations in urinary spot samples for 10,253 participants (≥6 years old) using National Health and Nutrition Examination Survey (NHANES, 2005-2014) data. We constructed a biologically relevant metric of phthalates daily intake (∑androgen-disruptor, μg/kg/day) by converting phthalates into anti-androgen equivalent terms prior to their summation. Particular foods and the percent of total energy intake (TEI) consumed from multiple dining out sources were ascertained from 24-h recall surveys. Associations with ∑androgen-disruptor levels were estimated for children, adolescents, and adults using multivariable linear regression. We observed a consistent positive association between dining out and Σandrogen-disruptor levels across the study population (p-trend consumers of foods outside the home had 55% (95% CI: 35%, 78%) higher Σandrogen-disruptor levels compared to those who only consumed food at home. The contribution of specific dining out sources to Σandrogen-disruptor levels varied by age group. For example, cafeteria food was associated with 15% (95% CI: 4.0%, 28%) and 64% (95% CI: 40%, 92%) higher Σandrogen-disruptor levels in children and adults, respectively. Particular foods, especially sandwiches (i.e. cheeseburgers), were associated with increased Σandrogen-disruptor levels only if they were purchased away from home (p food supply in addition to the

The removal of pharmaceuticals, personal care products, endocrine disruptors and illicit drugs during wastewater treatment and its impact on the quality of receiving waters.

Science.gov (United States)

Kasprzyk-Hordern, Barbara; Dinsdale, Richard M; Guwy, Alan J

2009-02-01

A 5-month monitoring program was undertaken in South Wales in the UK to determine the fate of 55 pharmaceuticals, personal care products, endocrine disruptors and illicit drugs (PPCPs) in two contrasting wastewater plants utilising two different wastewater treatment technologies: activated sludge and trickling filter beds. The impact of treated wastewater effluent on the quality of receiving waters was also assessed. PPCPs were found to be present at high loads reaching 10kgday(-1) in the raw sewage. Concentrations of PPCPs in raw sewage were found to correlate with their usage/consumption patterns in Wales and their metabolism. The efficiency of the removal of PPCPs was found to be strongly dependent on the technology implemented in the wastewater treatment plant (WWTP). In general, the WWTP utilising trickling filter beds resulted in, on average, less than 70% removal of all 55 PPCPs studied, while the WWTP utilising activated sludge treatment gave a much higher removal efficiency of over 85%. The monitoring programme revealed that treated wastewater effluents were the main contributors to PPCPs concentrations (up to 3kg of PPCPsday(-1)) in the rivers studied. Bearing in mind that in the cases examined here the WWTP effluents were also major contributors to rivers' flows (dilution factor for the studied rivers did not exceed 23 times) the effect of WWTP effluent on the quality of river water is significant and cannot be underestimated.

Long non-coding RNAs as regulators of the endocrine system.

Science.gov (United States)

Knoll, Marko; Lodish, Harvey F; Sun, Lei

2015-03-01

Long non-coding RNAs (lncRNAs) are a large and diverse group of RNAs that are often lineage-specific and that regulate multiple biological functions. Many are nuclear and are essential parts of ribonucleoprotein complexes that modify chromatin segments and establish active or repressive chromatin states; others are cytosolic and regulate the stability of mRNA or act as microRNA sponges. This Review summarizes the current knowledge of lncRNAs as regulators of the endocrine system, with a focus on the identification and mode of action of several endocrine-important lncRNAs. We highlight lncRNAs that have a role in the development and function of pancreatic β cells, white and brown adipose tissue, and other endocrine organs, and discuss the involvement of these molecules in endocrine dysfunction (for example, diabetes mellitus). We also address the associations of lncRNAs with nuclear receptors involved in major hormonal signalling pathways, such as estrogen and androgen receptors, and the relevance of these associations in certain endocrine cancers.

Inhibition of Chondrocyte Hypertrophy of Osteoarthritis by Disruptor Peptide

Science.gov (United States)

2017-07-01

with PTHR and inhibits the pathogenic beta-catenin- mediated PTHR signaling switch. In Aim 2, we will define the role of disruptor peptide in...confirmed that disruptor peptide conjugated to penetratin can enter cells. Importantly, disruptor peptide can reverse the beta-catenin- mediated PTH... mediated PTHR signaling switch in chondrocytes. Mouse primary chondrocytes express both β-catenin and PTHR. Our data showed that Pen-dis- pep

A MATHEMATICAL MODEL FOR THE KINETICS OF THE MALE REPRODUCTIVE ENDOCRINE SYSTEM

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In this presentation a model for the hormonal regulation of the reproductive endocrine system in the adult male rat will be discussed. The model includes a description of the kinetics of the androgenic hormones testosterone and dihydrotestosterone, as well as the receptor-mediate...

The Current Role of Venous Sampling in the Localization of Endocrine Disease

International Nuclear Information System (INIS)

Lau, Jeshen H. G.; Drake, William; Matson, Matthew

2007-01-01

Endocrine venous sampling plays a specific role in the diagnosis of endocrine disorders. In this article, we cover inferior petrosal sinus sampling, selective parathyroid venous sampling, hepatic venous sampling with arterial stimulation, adrenal venous sampling, and ovarian venous sampling. We review their indications and the scientific evidence justifying these indications in the diagnosis and management of Cushing's syndrome, hyperparathyroidism, pancreatic endocrine tumors, Conn's syndrome, primary hyperaldosteronism, pheochromocytomas, and androgen-secreting ovarian tumors. For each sampling technique, we compare its diagnostic accuracy with that of other imaging techniques and, where possible, look at how it impacts patient management. Finally, we incorporate venous sampling into diagnostic algorithms used at our institution

Endocrine Disruptors

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... Smoke Cockroaches Dust Mites Pets & Animals Pollen Aloe Vera Arsenic Bisphenol A (BPA) Cell Phones Climate Change ... effects from Safety Data Sheets for this chemical. E.hormone: Hormones and the Environment - A gateway to ...

Overview of the Pathophysiological Implications of Organotins on the Endocrine System

Directory of Open Access Journals (Sweden)

Vinicius Bermond Marques

2018-03-01

Full Text Available Organotins (OTs are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic–pituitary axis, altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus or peripheral (e.g., adipose tissue mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed.

Overview of the Pathophysiological Implications of Organotins on the Endocrine System

Science.gov (United States)

Marques, Vinicius Bermond; Faria, Rodrigo Alves; Dos Santos, Leonardo

2018-01-01

Organotins (OTs) are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic–pituitary axis), altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus) or peripheral (e.g., adipose tissue) mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed. PMID:29615977

Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism.

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Carmina, E; Rosato, F; Jannì, A; Rizzo, M; Longo, R A

2006-01-01

We undertook this study to estimate the prevalence of the various androgen excess disorders using the new criteria suggested for the diagnosis of polycystic ovary syndrome (PCOS). The study was performed at two endocrine departments at the University of Palermo (Palermo, Italy). The records of all patients referred between 1980 and 2004 for evaluation of clinical hyperandrogenism were reevaluated. All past diagnoses were reviewed using the actual diagnostic criteria. To be included in this study, the records of the patients had to present the following available data: clinical evaluation of hyperandrogenism, body weight and height, testosterone (T), free T, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, progesterone, and pelvic sonography. A total of 1226 consecutive patients were seen during the study period, but only the scores of 950 patients satisfied all criteria and were reassessed for the diagnosis. The prevalence of androgen excess disorders was: PCOS, 72.1% (classic anovulatory patients, 56.6%; mild ovulatory patients, 15.5%), idiopathic hyperandrogenism, 15.8%; idiopathic hirsutism, 7.6%; 21-hydroxylase-deficient nonclassic adrenal hyperplasia, 4.3%; and androgen-secreting tumors, 0.2%. Compared with other androgen excess disorders, patients with PCOS had increased body weight whereas nonclassic adrenal hyperplasia patients were younger and more hirsute and had higher serum levels of T, free T, and 17-hydroxyprogesterone. Classic PCOS is the most common androgen excess disorder. However, mild androgen excess disorders (ovulatory PCOS and idiopathic hyperandrogenism) are also common and, in an endocrine setting, include about 30% of patients with clinical hyperandrogenism.

Are endocrine disruptors among the causes of the deterioration of aquatic biodiversity?

Science.gov (United States)

Zhou, Jin; Cai, Zhong-Hua; Zhu, Xiao-Shan

2010-07-01

Exposure to environmental pollutants such as endocrine-disrupting compounds (EDCs) is now taken into account to explain partially the biodiversity decline of aquatic ecosystems. Much research has demonstrated that EDCs can adversely affect the endocrine system, reproductive health, and immune function in aquatic species. These toxicological effects include 1) interference with normal hormonal synthesis, release, and transport, 2) impairment of growth, development, and gonadal maturation, and 3) increased sensitivity to environmental stressors. Recent studies also have confirmed that EDCs have carcinogenic and mutagenic potential. In essence, these changes in physiological and biochemical parameters reflect, to some extent, some phenotypic characteristics of the deterioration of aquatic biodiversity. At present, evidence at the molecular level shows that exposure to EDCs can trigger genotoxicity, such as DNA damage, and can reduce genetic diversity. Field studies have also provided more direct evidence that EDCs contribute to the population decrease and biodiversity decline. Evolutionary toxicology and multigenerational toxicity tests have further demonstrated that EDCs can damage an organism's offspring and eventually likely lead to loss of evolutionary potential. Taken together, these results provide some basis for understanding the relationship between variety deterioration and EDC exposure. It is conceivable that there is a causal association between EDC exposure and variety deterioration of aquatic organisms. (c) 2010 SETAC.

Effects of Xenoestrogen and Androgen Mixtures on Ovarian Transcriptome of the Fathead Minnow

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Endocrine disrupting chemicals (EDCs), such as the estrogens ethinylestradiol (EE2) and bisphenol A (BPA), and androgens like 17â-trenbolone (TRB) can occur as mixtures in aquatic environments. To date, however, most studies with EDCs in fish have focused on their effects as indi...

Phytoplankton blooms: an overlooked marine source of natural endocrine disrupting chemicals.

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Gong, Yinhan; Wang, Xiaochong; Indran, Inthrani Raja; Zhang, Shi-Jun; Lv, Zhengbing; Li, Jun; Holmes, Michael; Tang, Ying Zhong; Yong, E L

2014-09-01

We had previously reported high androgenic and estrogenic activities in seawaters in confined clusters close to Singapore. Further investigations revealed a hitherto unsuspected link between estrogenic/androgenic activity and net phytoplankton count. The primary objective of this study was to investigate the cause of a correlation between net phytoplankton and endocrine activity, and corroborate this observation, and rule out other possible confounding factors. Our secondary objective was to study if these estrogenic secretions can impact human health. Five species of phytoplankton, Gymnodinium catenatum, Prorocentrum minimum, Alexandrium leei, Chattonella marina, and Fibrocapsa japonica, were isolated from Singapore waters and mass cultured and the cells and culture media screened for estrogenic and androgenic activity using human cell-based bioassays. The raphidophytes C. marina and F. japonica displayed significant estrogenic activity whilst the dinoflagellates G. catenatum and P. minimum displayed significant androgenic activity in both the cell extracts and the cell culture media extract. Our data shows that selected phytoplankton isolates are potent secretors of estrogenic and androgenic substances, which are potential endocrine disrupting chemicals (EDCs). As the harmful nature of EDCs is largely due to their bioaccumulation in the aquatic food chain our findings imply that the impact of these phytoplankton secretions needs to be investigated especially for seafoods, which are only a single trophic level away from phytoplankton. Alternatively, should these phytoplankton-origin EDCs not accumulate through marine food chains to significantly impact humans or marine mammals, our results indicate that functional assays could greatly over-estimate the risk from naturally occurring EDCs produced by marine phytoplankton. It remains to be determined if these EDCs affect zooplankton and other organisms that directly feed on marine phytoplankton, or if the secreted

Cardiometabolic Features of Polycystic Ovary Syndrome: Role of Androgens.

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Yanes Cardozo, Licy L; Romero, Damian G; Reckelhoff, Jane F

2017-09-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects reproductive-age women. Hyperandrogenemia is present in a significant fraction (~80%) of women with PCOS. Increased prevalence of cardiometabolic risk factors is frequently observed in PCOS women. The present review aims to highlight the key role of androgens in mediating the negative cardiometabolic profile observed in PCOS women. Copyright © 2017 the American Physiological Society.

Non-neural androgen receptors affect sexual differentiation of brain and behaviour.

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Monks, D A; Swift-Gallant, A

2018-02-01

Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. © 2017 British Society for Neuroendocrinology.

Differential gene expression patterns in developing sexually dimorphic rat brain regions exposed to antiandrogenic, estrogenic, or complex endocrine disruptor mixtures: glutamatergic synapses as target.

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Lichtensteiger, Walter; Bassetti-Gaille, Catherine; Faass, Oliver; Axelstad, Marta; Boberg, Julie; Christiansen, Sofie; Rehrauer, Hubert; Georgijevic, Jelena Kühn; Hass, Ulla; Kortenkamp, Andreas; Schlumpf, Margret

2015-04-01

The study addressed the question whether gene expression patterns induced by different mixtures of endocrine disrupting chemicals (EDCs) administered in a higher dose range, corresponding to 450×, 200×, and 100× high-end human exposure levels, could be characterized in developing brain with respect to endocrine activity of mixture components, and which developmental processes were preferentially targeted. Three EDC mixtures, A-Mix (anti-androgenic mixture) with 8 antiandrogenic chemicals (di-n-butylphthalate, diethylhexylphthalate, vinclozolin, prochloraz, procymidone, linuron, epoxiconazole, and DDE), E-Mix (estrogenic mixture) with 4 estrogenic chemicals (bisphenol A, 4-methylbenzylidene camphor, 2-ethylhexyl 4-methoxycinnamate, and butylparaben), a complex mixture, AEP-Mix, containing the components of A-Mix and E-Mix plus paracetamol, and paracetamol alone, were administered by oral gavage to rat dams from gestation day 7 until weaning. General developmental endpoints were not affected by EDC mixtures or paracetamol. Gene expression was analyzed on postnatal day 6, during sexual brain differentiation, by exon microarray in medial preoptic area in the high-dose group, and by real-time RT-PCR in medial preoptic area and ventromedial hypothalamus in all dose groups. Expression patterns were mixture, sex, and region specific. Effects of the analgesic drug paracetamol, which exhibits antiandrogenic activity in peripheral systems, differed from those of A-Mix. All mixtures had a strong, mixture-specific impact on genes encoding for components of excitatory glutamatergic synapses and genes controlling migration and pathfinding of glutamatergic and GABAergic neurons, as well as genes linked with increased risk of autism spectrum disorders. Because development of glutamatergic synapses is regulated by sex steroids also in hippocampus, this may represent a general target of ECD mixtures.

Zebrafish (Danio rerio) androgen receptor: sequence homology and up-regulation by the fungicide vinclozolin.

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Smolinsky, Amanda N; Doughman, Jennifer M; Kratzke, Liên-Thành C; Lassiter, Christopher S

2010-03-01

Steroid hormones regulate gene expression in organisms by binding to receptor proteins. These hormones include the androgens, which signal through androgen receptors (ARs). Endocrine disrupters (EDCs) are chemicals in the environment that adversely affect organisms by binding to nuclear receptors, including ARs. Vinclozolin, a fungicide used on fruit and vegetable crops, is a known anti-androgen, a type of EDC that blocks signals from testosterone and its derivatives. In order to better understand the effects of EDCs, further research on androgen receptors and other hormone signaling pathways is necessary. In this study, we demonstrate the evolutionary conservation between the genomic structure of the human and zebrafish ar genes and find that ar mRNA expression increases in zebrafish embryos exposed to vinclozolin, which may be evolutionarily conserved as well. At 48 and 72 h post-fertilization, vinclozolin-treated embryos express ar mRNA 8-fold higher than the control level. These findings suggest that zebrafish embryos attempt to compensate for the presence of an anti-androgen by increasing the number of androgen receptors available.

Comparison of Individual and Combined Effects of Four Endocrine Disruptors on Estrogen Receptor Beta Transcription in Cerebellar Cell Culture: The Modulatory Role of Estradiol and Triiodo-Thyronine

Science.gov (United States)

Jocsak, Gergely; Kiss, David Sandor; Toth, Istvan; Goszleth, Greta; Bartha, Tibor; Frenyo, Laszlo V.; Horvath, Tamas L.; Zsarnovszky, Attila

2016-01-01

Background: Humans and animals are continuously exposed to a number of environmental substances that act as endocrine disruptors (EDs). While a growing body of evidence is available to prove their adverse health effects, very little is known about the consequences of simultaneous exposure to a combination of such chemicals; Methods: Here, we used an in vitro model to demonstrate how exposure to bisphenol A, zearalenone, arsenic, and 4-methylbenzylidene camphor, alone or in combination, affect estrogen receptor β (ERβ) mRNA expression in primary cerebellar cell cultures. Additionally, we also show the modulatory role of intrinsic biological factors, such as estradiol (E2), triiodo-thyronine (T3), and glial cells, as potential effect modulators; Results: Results show a wide diversity in ED effects on ERβ mRNA expression, and that the magnitude of these ED effects highly depends on the presence or absence of E2, T3, and glial cells; Conclusion: The observed potency of the EDs to influence ERβ mRNA expression, and the modulatory role of E2, T3, and the glia suggests that environmental ED effects may be masked as long as the hormonal milieu is physiological, but may tend to turn additive or superadditive in case of hormone deficiency. PMID:27338438

Effects of Tribulus terrestris on endocrine sensitive organs in male and female Wistar rats.

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Martino-Andrade, Anderson J; Morais, Rosana N; Spercoski, Katherinne M; Rossi, Stefani C; Vechi, Marina F; Golin, Munisa; Lombardi, Natália F; Greca, Cláudio S; Dalsenter, Paulo R

2010-01-08

Investigate the possible effects of Tribulus terrestris (TT) on endocrine sensitive organs in intact and castrated male rats as well as in a post-menopausal rat model using ovariectomized females. Three different dose levels of TT (11, 42 and 110 mg/kg/day) were administered to castrated males for 7 days and to intact males and castrated females for 28 days. In addition to TT treatment, all experiments also included a group of rats treated with dehydroepiandrosterone (DHEA). In experiments using castrated males and females we also used testosterone and 17 alpha-ethynylestradiol, respectively, as positive controls for androgenicity and estrogenicity. Neither DHEA nor TT was able to stimulate androgen sensitive tissues like the prostate and seminal vesicle in both intact and castrated male rats. In addition, administration of TT to intact male rats for 28 days did not change serum testosterone levels as well as did not produce any quantitative change in the fecal excretion of androgenic metabolites. However, a slight increase in the number of homogenization-resistant spermatids was observed in rats treated with 11 mg/kg/day of TT extract. In ovariectomized females, TT did not produce any stimulatory effects in uterine and vaginal epithelia. Tribulus terrestris was not able to stimulate endocrine sensitive tissues such as the prostate, seminal vesicle, uterus and vagina in Wistar rats, indicating lack of androgenic and estrogenic activity in vivo. We also showed a positive effect of TT administration on rat sperm production, associated with unchanged levels of circulating androgens. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Monitoring and risk assessment for endocrine disruptors in the aquatic environment: a biomarker approach

Energy Technology Data Exchange (ETDEWEB)

Bjerregaard, P.; Korsgaard, B.; Christiansen, L.B.; Pedersen, K.L.; Christensen, L.J.; Pedersen, S.N.; Horn, P. [Odense Univ. (Denmark). Biologisk Inst.

1998-12-31

Evidence that a number of chemicals affect wildlife populations or individuals via interaction with endocrine systems has been increasing in recent years. Not all of the mechanisms of action are fully understood, but endocrine disrupting chemicals may work at various biochemical levels, e.g. affecting the synthesis of hormones, interfering with hormone transporting proteins in the blood, affecting the metabolisation of hormones or by direct effects on cellular hormone receptors. In dogwhelks Nucella lapillus tributyltin inhibits the aromatase that converts testosterone to oestrogen thereby masculinising the females (Oehlmann et al. 1996). Metabolites of polychlorinated biphenyls interfere with thyroxin transporting proteins in the blood of seals. Chemicals that induce MFO-activity may indirectly lead to altered hormone levels by increasing the metabolisation of hormones. Alkylphenols react directly with the oestrogen receptor which in turn may lead to feminisation of male organisms exposed. (orig.)

Current Limitations and Recommendations to Improve Testing for the Environmental Assessment of Endocrine Active Substances

DEFF Research Database (Denmark)

Coady, Katherine K; Biever, Ronald C; Denslow, Nancy D

2017-01-01

In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across geographies, but all basically...... evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or the environment. Current test systems include in silico, in vitro and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect...... methods currently do not exist, and addressing key endocrine pathways of possible concern in addition to those associated with estrogen, androgen and thyroid signaling. This article is protected by copyright. All rights reserved....

ANDROGENS REGULATE T47D CELLS MOTILITY AND INVASION THROUGH ACTIN CYTOSKELETON REMODELLING

Directory of Open Access Journals (Sweden)

Maria Magdalena Montt-Guevara

2016-09-01

Full Text Available The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgens receptor (AR is expressed in approximately 70% to 90% of invasive breast carcinomas, which has prognostic relevance in basal-like cancers and in triple negative breast cancers. Recent studies have associated the actin-binding proteins of the Ezrin-Radixin-Moesin (ERM family with metastasis in endocrine-sensitive cancers. We studied on T47D breast cancer cells whether androgens with different characteristics, such as testosterone (T, dihydrotestosterone (DHT and dehydroepiandrosterone (DHEA may regulate breast cancer cell motility and invasion through the control of actin remodelling. We demonstrate that androgens promote migration and invasion in T47D via Moesin activation. We show that T and DHEA exert their actions via the AR and estrogen receptor (ER, while the non aromatizable androgen – DHT only recruits AR. We further report that androgen induced significant changes in actin organization with pseudopodia along with membrane ruffles formation, and this process is mediated by Moesin. Our work identifies novel mechanisms of action of androgens on breast cancer cells. Through the modulation of Moesin, androgens alter the architecture of cytoskeleton in T47D breast cancer cell and promote cell migration and invasion. These results could help to understand the biological actions of androgens on breast cancer, and eventually to develop new strategies for treatment of breast cancer.

A critical review of histopathological findings associated with endocrine and non-endocrine hepatic toxicity in fish models.

Science.gov (United States)

Wolf, Jeffrey C; Wheeler, James R

2018-04-01

Although frequently examined as a target organ for non-endocrine toxicity, histopathological evaluation of the liver is becoming a routine component of endocrine disruption studies that utilize various fish species as test subjects. However, the interpretation of microscopic liver findings can be challenging, especially when attempting to distinguish adverse changes associated with endocrine disrupting substances from those caused by systemic or direct hepatic toxicity. The purpose of this project was to conduct a critical assessment of the available peer-reviewed and grey literature concerning the histopathologic effects of reproductive endocrine active substances (EAS) and non-endocrine acting substances in the livers of fish models, and to determine if liver histopathology can be used to reliably distinguish endocrine from non-endocrine etiologies. The results of this review suggest that few compound-specific histopathologic liver effects have been identified, among which are estrogen agonist-induced increases in hepatocyte basophilia and proteinaceous intravascular fluid in adult male teleosts, and potentially, decreased hepatocyte basophilia in female fish exposed to substances that possess androgenic, anti-estrogenic, or aromatase inhibitory activity. This review also used published standardized methodology to assess the credibility of the histopathology data in each of the 117 articles that reported liver effects of treatment, and consequently it was determined that in only 37% of those papers were the data considered either highly credible or credible. The outcome of this work highlights the value of histopathologic liver evaluation as an investigative tool for EAS studies, and provides information that may have implications for EAS hazard assessment. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Microsomal cytochrome P450-3A4 (CYP3A4) nanobiosensor for the determination of 2,4-dichlorophenol-An endocrine disruptor compound

International Nuclear Information System (INIS)

Hendricks, Nicolette R.; Waryo, Tesfaye T.; Arotiba, Omotayo; Jahed, Nazeem; Baker, Priscilla G.L.; Iwuoha, Emmanuel I.

2009-01-01

Cytochrome P450-3A4 (CYP3A4) is a monooxygenase enzyme that plays a major role in the detoxification of bioactive compounds and hydrophobic xenobiotics (e.g. medicines, drugs, environmental pollutants, food supplements and steroids). Physiologically the monooxygenation reactions of this class II, microsomal, b-type heme enzyme, usually requires cytochrome P450 reductase, NADPH. A novel CYP3A4 biosensor system that essentially simplified the enzymatic redox processes by allowing electron transfer between the electrode and the enzyme redox centre to occur, without any need for the physiological redox partners, was developed for the detection of 2,4-dichlorophenol (2,4-DCP), a priority environmental pollutant and an endocrine disruptor. The biosensor, GC/Naf-Co(Sep) 3+ /CYP3A4/Naf, was constructed by encapsulating CYP3A4 in a Nafion-cobalt (III) sepulchrate (Naf-Co(Sep) 3+ ) composite film on a glassy carbon (GC) electrode. The responses of the biosensor to 2,4-dichlorophenol, erythromycin (CYP3A4 native substrate) and ketoconazole (CYP 3A4 natural inhibitor) were studied by cyclic and square wave voltammetric techniques. The detection limit (DL) of the biosensor for 2,4-dichlorophenol was 0.043 μg L -1 , which is by an order of magnitude lower than the EU limit (0.3 μg L -1 ) for any pesticide compound in ground water. The biosensor's DL is lower than the U.S. Environmental Protection Agency's drinking water equivalent level (DWEL) value for 2,4-DCP, which is 2 μg L -1

A Two-Tiered-Testing Decision Tree for Assays in the USEPA-EDSP Screening Battery: Using 15 years of Experience to Improve Screening and Testing for Endocrine Active Chemicals##

Science.gov (United States)

This product is a brief description of the oral presentation given by Dr LE Gray Jr at the meeting for the T4 workshop report-Lessons learned, challenges, ansd opportunities: The U.S. Endocrine Disruptor Scrrening Program published in the journal ALTEX, edited by the Swiss Societ...

Species-specific considerations in using the fish embryo test as an alternative to identify endocrine disruption.

Science.gov (United States)

Schiller, Viktoria; Zhang, Xiaowei; Hecker, Markus; Schäfers, Christoph; Fischer, Rainer; Fenske, Martina

2014-10-01

A number of regulations have been implemented that aim to control the release of potentially adverse endocrine disrupters into the aquatic environment based on evidence from laboratory studies. Currently, such studies rely on testing approaches with adult fish because reliable alternatives have not been validated so far. Fish embryo tests have been proposed as such an alternative, and here we compared two species (medaka and zebrafish) to determine their suitability for the assessment of substances with estrogenic and anti-androgenic activity. Changes in gene expression (in here the phrase gene expression is used synonymously to gene transcription, although it is acknowledged that gene expression is additionally regulated, e.g., by translation and protein stability) patterns between the two species were compared in short term embryo exposure tests (medaka: 7-day post fertilization [dpf]; zebrafish: 48 and 96h post fertilization [hpf]) by using relative quantitative real-time RT-PCR. The tested genes were related to the hypothalamic-gonadal-axis and early steroidogenesis. Test chemicals included 17α-ethinylestradiol and flutamide as estrogenic and anti-androgenic reference compounds, respectively, as well as five additional substances with endocrine activities, namely bisphenol A, genistein, prochloraz, linuron and propanil. Estrogenic responses were comparable in 7-dpf medaka and 48/96-hpf zebrafish embryos and included transcriptional upregulation of aromatase b, vitellogenin 1 as well as steroidogenic genes, suggesting that both species reliably detected exposure to estrogenic compounds. However, anti-androgenic responses differed between the two species, with each species providing specific information concerning the mechanism of anti-androgenic disruption in fish embryos. Although small but significant changes in the expression of selected genes was observed in 48-hpf zebrafish embryos, exposure prolonged to 96hpf was necessary to obtain a response indicative

Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances

Science.gov (United States)

Coady, Katherine K.; Biever, Ronald C.; Denslow, Nancy D.; Gross, Melanie; Guiney, Patrick D.; Holbech, Henrik; Karouna-Renier, Natalie K.; Katsiadaki, Ioanna; Krueger, Hank; Levine, Steven L.; Maack, Gerd; Williams, Mike; Wolf, Jeffrey C.; Ankley, Gerald T.

2017-01-01

In the present study, existing regulatory frameworks and test systems for assessing potential endocrine active chemicals are described, and associated challenges are discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across geographies, but all basically evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or to the environment. Current test systems include in silico, in vitro, and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormone signaling pathways; however, there are some limitations of current test systems for evaluating endocrine hazard and risk. These limitations include a lack of certainty regarding: 1) adequately sensitive species and life stages; 2) mechanistic endpoints that are diagnostic for endocrine pathways of concern; and 3) the linkage between mechanistic responses and apical, adverse outcomes. Furthermore, some existing test methods are resource intensive with regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to and guidance for existing test methods and to reduce uncertainty. For example, in vitro high-throughput screening could be used to prioritize chemicals for testing and provide insights as to the most appropriate assays for characterizing hazard and risk. Other recommendations include adding endpoints for elucidating connections between mechanistic effects and adverse outcomes, identifying potentially sensitive taxa for which test methods currently do not exist, and addressing key endocrine pathways of possible concern in addition to those associated with estrogen, androgen, and thyroid

Distribution of Non-Persistent Endocrine Disruptors in Two Different Regions of the Human Brain

NARCIS (Netherlands)

van der Meer, Thomas P; Artacho-Cordón, Francisco; Swaab, Dick F; Struik, Dicky; Makris, Konstantinos C; Wolffenbuttel, Bruce H R; Frederiksen, Hanne; van Vliet-Ostaptchouk, Jana V

2017-01-01

Non-persistent endocrine disrupting chemicals (npEDCs) can affect multiple organs and systems in the body. Whether npEDCs can accumulate in the human brain is largely unknown. The major aim of this pilot study was to examine the presence of environmental phenols and parabens in two distinct brain

Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, Focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

Science.gov (United States)

The focus of this meeting is the SAP's review and comment on the Agency's proposed high-throughput computational model of androgen receptor pathway activity as an alternative to the current Tier 1 androgen receptor assay (OCSPP 890.1150: Androgen Receptor Binding Rat Prostate Cyt...

Binding of bisphenol A, bisphenol AF, and bisphenol S on the androgen receptor: Coregulator recruitment and stimulation of potential interaction sites.

Science.gov (United States)

Perera, Lalith; Li, Yin; Coons, Laurel A; Houtman, Rene; van Beuningen, Rinie; Goodwin, Bonnie; Auerbach, Scott S; Teng, Christina T

2017-10-01

Bisphenol A (BPA), bisphenol AF (BPAF), and bisphenol S (BPS) are well known endocrine disruptors. Previous in vitro studies showed that these compounds antagonize androgen receptor (AR) transcriptional activity; however, the mechanisms of action are unclear. In the present study, we investigated interactions of coregulator peptides with BPA, BPAF, or BPS at the AR complexes using Micro Array for Real-time Coregulator Nuclear Receptor Interaction (MARCoNI) assays and assessed the binding of these compounds on AR by molecular dynamics (MD) simulations. The set of coregulator peptides that are recruited by BPA-bound AR, either positively/or negatively, are different from those recruited by the agonist R1881-bound AR. Therefore, the data indicates that BPA shows no similarities to R1881 and suggests that it may recruit other coregulators to the AR complex. BPAF-bound AR recruits about 70-80% of the same coregulator peptides as BPA-bound AR. Meanwhile, BPS-bound AR interacts with only few peptides compared to BPA or BPAF-bound AR. MD results show that multiple binding sites with varying binding affinities are available on AR for BPA, BPAF, and BPS, indicating the availability of modified binding surfaces on AR for coregulator interactions. These findings help explain some of the distinct AR-related toxicities observed with bisphenol chemicals and raise concern for the use of substitutes for BPA in commercial products. Published by Elsevier Ltd.

Development of partial life-cycle experiments to assess the effects of endocrine disruptors on the freshwater gastropod Lymnaea stagnalis: a case-study with vinclozolin.

Science.gov (United States)

Ducrot, Virginie; Teixeira-Alves, Mickaël; Lopes, Christelle; Delignette-Muller, Marie-Laure; Charles, Sandrine; Lagadic, Laurent

2010-10-01

Long-term effects of endocrine disruptors (EDs) on aquatic invertebrates remain difficult to assess, mainly due to the lack of appropriate sensitive toxicity test methods and relevant data analysis procedures. This study aimed at identifying windows of sensitivity to EDs along the life-cycle of the freshwater snail Lymnaea stagnalis, a candidate species for the development of forthcoming test guidelines. Juveniles, sub-adults, young adults and adults were exposed for 21 days to the fungicide vinclozolin (VZ). Survival, growth, onset of reproduction, fertility and fecundity were monitored weekly. Data were analyzed using standard statistical analysis procedures and mixed-effect models. No deleterious effect on survival and growth occurred in snails exposed to VZ at environmentally relevant concentrations. A significant impairment of the male function occurred in young adults, leading to infertility at concentrations exceeding 0.025 μg/L. Furthermore, fecundity was impaired in adults exposed to concentrations exceeding 25 μg/L. Biological responses depended on VZ concentration, exposure duration and on their interaction, leading to complex response patterns. The use of a standard statistical approach to analyze those data led to underestimation of VZ effects on reproduction, whereas effects could reliably be analyzed by mixed-effect models. L. stagnalis may be among the most sensitive invertebrate species to VZ, a 21-day reproduction test allowing the detection of deleterious effects at environmentally relevant concentrations of the fungicide. These results thus reinforce the relevance of L. stagnalis as a good candidate species for the development of guidelines devoted to the risk assessment of EDs.

Adverse outcome pathways (AOPs) to enhance EDC ...

Science.gov (United States)

Screening and testing for endocrine active chemicals was mandated under 1996 amendments to the Safe Drinking Water Act and Food Quality Protection Act. Efficiencies can be gained in the endocrine disruptor screening program by using available biological and toxicological knowledge to facilitate greater use of high throughput screening data and other data sources to inform endocrine disruptor assessments. Likewise, existing knowledge, when properly organized, can help aid interpretation of test results. The adverse outcome pathway (AOP) framework, which organizes information concerning measureable changes that link initial biological interactions with a chemical to adverse effects that are meaningful to risk assessment and management, can aid this process. This presentation outlines the ways in which the AOP framework has already been employed to support EDSP and how it may further enhance endocrine disruptor assessments in the future. Screening and testing for endocrine active chemicals was mandated under 1996 amendments to the Safe Drinking Water Act and Food Quality Protection Act. Efficiencies can be gained in the endocrine disruptor screening program by using available biological and toxicological knowledge to facilitate greater use of high throughput screening data and other data sources to inform endocrine disruptor assessments. Likewise, existing knowledge, when properly organized, can help aid interpretation of test results. The adverse outcome pathway

EDC IMPACT: Reduced sperm counts in rats exposed to human relevant mixtures of endocrine disrupters

Directory of Open Access Journals (Sweden)

M Axelstad

2018-01-01

Full Text Available Human semen quality is declining in many parts of the world, but the causes are ill defined. In rodents, impaired sperm production can be seen with early life exposure to certain endocrine-disrupting chemicals, but the effects of combined exposures are not properly investigated. In this study, we examined the effects of early exposure to the painkiller paracetamol and mixtures of human relevant endocrine-disrupting chemicals in rats. One mixture contained four estrogenic compounds; another contained eight anti-androgenic environmental chemicals and a third mixture contained estrogens, anti-androgens and paracetamol. All exposures were administered by oral gavage to time-mated Wistar dams rats (n = 16–20 throughout gestation and lactation. In the postnatal period, testicular histology was affected by the total mixture, and at the end of weaning, male testis weights were significantly increased by paracetamol and the high doses of the total and the anti-androgenic mixture, compared to controls. In all dose groups, epididymal sperm counts were reduced several months after end of exposure, i.e. at 10  months of age. Interestingly, the same pattern of effects was seen for paracetamol as for mixtures with diverse modes of action. Reduced sperm count was seen at a dose level reflecting human therapeutic exposure to paracetamol. Environmental chemical mixtures affected sperm count at the lowest mixture dose indicating an insufficient margin of safety for the most exposed humans. This causes concern for exposure of pregnant women to paracetamol as well as environmental endocrine disrupters.

Reversibility of endocrine disruption in zebrafish (Danio rerio) - comparison of different effect levels

DEFF Research Database (Denmark)

Baumann, Lisa; Holbech, Henrik; Schiller, V.S.

: the androgen trenbolone binds directly and very effectively to the androgen receptor. Ethinylestradiol, a synthetic derivative of estradiol, causes feminization in wildlife and humans. The fungicide prochloraz acts as an aromatase inhibitor by direct interference with the aromatization of androgens......Endocrine disrupting chemicals (EDCs) exert effects at very low concentrations and can cause serious problems for the hormonal balance of various organisms. Exposure of wildlife to EDCs is not necessarily continuous, but may often occur in pulses. Consequently for the evaluation of the long......-term effects on populations, it is essential to know whether such EDC-related effects are reversible. Three different substances selected for different modes of action were tested for their long-term impact on sex ratio, gonadal development, vitellogenin (VTG) induction and aromatase activity in zebrafish...

Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

Directory of Open Access Journals (Sweden)

Satwant Kaur

Full Text Available Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT, under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment.

Microsomal cytochrome P450-3A4 (CYP3A4) nanobiosensor for the determination of 2,4-dichlorophenol-An endocrine disruptor compound

Energy Technology Data Exchange (ETDEWEB)

Hendricks, Nicolette R.; Waryo, Tesfaye T.; Arotiba, Omotayo; Jahed, Nazeem; Baker, Priscilla G.L. [SensorLab, Department of Chemistry, University of Western Cape, Moderddam Road, Bellville, Cape Town 7535 (South Africa); Iwuoha, Emmanuel I. [SensorLab, Department of Chemistry, University of Western Cape, Moderddam Road, Bellville, Cape Town 7535 (South Africa)], E-mail: eiwuoha@uwc.ac.za

2009-02-28

Cytochrome P450-3A4 (CYP3A4) is a monooxygenase enzyme that plays a major role in the detoxification of bioactive compounds and hydrophobic xenobiotics (e.g. medicines, drugs, environmental pollutants, food supplements and steroids). Physiologically the monooxygenation reactions of this class II, microsomal, b-type heme enzyme, usually requires cytochrome P450 reductase, NADPH. A novel CYP3A4 biosensor system that essentially simplified the enzymatic redox processes by allowing electron transfer between the electrode and the enzyme redox centre to occur, without any need for the physiological redox partners, was developed for the detection of 2,4-dichlorophenol (2,4-DCP), a priority environmental pollutant and an endocrine disruptor. The biosensor, GC/Naf-Co(Sep){sup 3+}/CYP3A4/Naf, was constructed by encapsulating CYP3A4 in a Nafion-cobalt (III) sepulchrate (Naf-Co(Sep){sup 3+}) composite film on a glassy carbon (GC) electrode. The responses of the biosensor to 2,4-dichlorophenol, erythromycin (CYP3A4 native substrate) and ketoconazole (CYP 3A4 natural inhibitor) were studied by cyclic and square wave voltammetric techniques. The detection limit (DL) of the biosensor for 2,4-dichlorophenol was 0.043 {mu}g L{sup -1}, which is by an order of magnitude lower than the EU limit (0.3 {mu}g L{sup -1}) for any pesticide compound in ground water. The biosensor's DL is lower than the U.S. Environmental Protection Agency's drinking water equivalent level (DWEL) value for 2,4-DCP, which is 2 {mu}g L{sup -1}.

In vitro bioassay investigations of the endocrine disrupting potential of steviol glycosides and their metabolite steviol, components of the natural sweetener Stevia.

Science.gov (United States)

Shannon, Maeve; Rehfeld, Anders; Frizzell, Caroline; Livingstone, Christina; McGonagle, Caoimhe; Skakkebaek, Niels E; Wielogórska, Ewa; Connolly, Lisa

2016-05-15

The food industry is moving towards the use of natural sweeteners such as those produced by Stevia rebaudiana due to the number of health and safety concerns surrounding artificial sweeteners. Despite the fact that these sweeteners are natural; they cannot be assumed safe. Steviol glycosides have a steroidal structure and therefore may have the potential to act as an endocrine disruptor in the body. Reporter gene assays (RGAs), H295R steroidogenesis assay and Ca(2+) fluorimetry based assays using human sperm cells have been used to assess the endocrine disrupting potential of two steviol glycosides: stevioside and rebaudioside A, and their metabolite steviol. A decrease in transcriptional activity of the progestagen receptor was seen following treatment with 25,000 ng/ml steviol in the presence of progesterone (157 ng/ml) resulting in a 31% decrease in progestagen response (p=<0.01). At the level of steroidogenesis, the metabolite steviol (500-25,000 ng/ml) increased progesterone production significantly by 2.3 fold when exposed to 10,000 ng/ml (p=<0.05) and 5 fold when exposed to 25,000 ng/ml (p=<0.001). Additionally, steviol was found to induce an agonistic response on CatSper, a progesterone receptor of sperm, causing a rapid influx of Ca(2+). The response was fully inhibited using a specific CatSper inhibitor. These findings highlight the potential for steviol to act as a potential endocrine disruptor. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Endocrine therapy for recurrence after definitive radiotherapy in patients with prostate cancer

International Nuclear Information System (INIS)

Furuya, Yuzo; Akakura, Koichiro; Ichikawa, Tomohiko; Igarashi, Tatsuo; Ito, Haruo; Tanaka, Masashi; Murakami, Shino

2001-01-01

Long-term results were analyzed to evaluate the role of endocrine therapy in the management of local and distant recurrence of prostate cancer following external radiation therapy. Between 1976 and 1994, 92 patients with untreated prostate cancer underwent external beam radiation therapy alone. Endocrine therapy had been started when relapse was evident. Failure was seen in 35 of 92 patients: 10 local, 19 distant and six biochemical failures. Endocrine treatment was performed in 28 patients with nine local and 19 distant failures. The cancer-specific survival rate from the endocrine treatment was 54.5% at 5 years. Prostate-specific antigen level in 20 of 20 patients (100%) decreased to below the normal limit 3 months after the start of endocrine therapy. In univariate analysis, T classification was the most significant variable for cancer-specific survival from the initial treatment. A favorable outcome was achieved by endocrine therapy in patients who had relapsed after external beam radiation monotherapy. Even the recurrent tumor had a sensitivity to androgen. Patients with locally advanced disease (T2b and T3) had poorer prognosis than those with minimally extended disease (T1b and T2a). (author)

Effect of organochlorine pesticides on human androgen receptor activation in vitro

International Nuclear Information System (INIS)

Lemaire, Geraldine; Terouanne, Beatrice; Mauvais, Pascale; Michel, Serge; Rahmani, Roger

2004-01-01

Many persistent organochlorine pesticides (OCs) have been implicated in adverse effects, that is, reproductive and developmental effects, in man and in wildlife alike. It has been hypothesized that these so-called xeno-hormones could be responsible for the increased incidence in various male sexual differentiation disorders such as hypospadias, cryptorchidism, low sperm counts and quality. In this report, OCs, called endocrine disrupters, were tested for their interaction with the androgen receptor. The stable prostatic cell line PALM, which contains a human androgen receptor (hAR) expression vector and the reporter MMTV-luciferase, was used to characterize the response of hAR to OC and was compared with synthetic androgen compound R1881. We found that all the OC pesticides tested were able to shift the agonist [ 3 H]-R1881 from its binding site to the AR in competitive binding assays. In addition, these compounds antagonize - in a dose-dependent manner - the AR-mediated transcription by synthetic AR ligand R1881. None of the pesticides reacted as agonists. These results demonstrate that OC endocrine activities in vivo probably result from direct and specific binding to the AR ligand-binding domain. Although the antagonistic potential of OC pesticides is lower than that of hydroxyflutamide, they are capable of disrupting the male hormone signaling pathway. Because these chemicals are extremely persistent and tend to bioaccumulate, these results support the hypothesis that the recent increase in the incidence of male sexual disorders could be due to long exposure to ubiquitous OC pesticides found in the environment

Current perspectives on the androgen 5 alpha-dihydrotestosterone (DHT) and 5 alpha-reductases in teleost fishes and amphibians.

Science.gov (United States)

Martyniuk, Christopher J; Bissegger, Sonja; Langlois, Valérie S

2013-12-01

) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms. Copyright © 2013 Elsevier Inc. All rights reserved.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

Science.gov (United States)

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats

DEFF Research Database (Denmark)

Mandrup, Karen Riiber; Johansson, Hanna Katarina Lilith; Boberg, Julie

2015-01-01

Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures...

The effects of actomyosin disruptors on the mechanical integrity of the avian crystalline lens.

Science.gov (United States)

Won, Gah-Jone; Fudge, Douglas S; Choh, Vivian

2015-01-01

Actin and myosin within the crystalline lens maintain the structural integrity of lens fiber cells and form a hexagonal lattice cradling the posterior surface of the lens. The actomyosin network was pharmacologically disrupted to examine the effects on lenticular biomechanics and optical quality. One lens of 7-day-old White Leghorn chickens was treated with 10 µM of a disruptor and the other with 0.01% dimethyl sulfoxide (vehicle). Actin, myosin, and myosin light chain kinase (MLCK) disruptors were used. The stiffness and the optical quality of the control and treated lenses were measured. Western blotting and confocal imaging were used to confirm that treatment led to a disruption of the actomyosin network. The times for the lenses to recover stiffness to match the control values were also measured. Disruptor-treated lenses were significantly less stiff than their controls (p≤0.0274 for all disruptors). The disruptors led to changes in the relative protein amounts as well as the distributions of proteins within the lattice. However, the disruptors did not affect the clarity of the lenses (p≥0.4696 for all disruptors), nor did they affect spherical aberration (p = 0.02245). The effects of all three disruptors were reversible, with lenses recovering from treatment with actin, myosin, and MLCK disruptors after 4 h, 1 h, and 8 min, respectively. Cytoskeletal protein disruptors led to a decreased stiffness of the lens, and the effects were reversible. Optical quality was mostly unaffected, but the long-term consequences remain unclear. Our results raise the possibility that the mechanical properties of the avian lens may be actively regulated in vivo via adjustments to the actomyosin lattice.

Overview of a workshop on screening methods for detecting potential (anti-) estrogenic/androgenic chemicals in wildlife

Science.gov (United States)

Ankley, Gerald T.; Mihaich, Ellen; Stahl, Ralph G.; Tillitt, Donald E.; Colborn, Theo; McMaster, Suzzanne; Miller, Ron; Bantle, John; Campbell, Pamela; Denslow, Nancy; Dickerson, Richard L.; Folmar, Leroy C.; Fry, Michael; Giesy, John P.; Gray, L. Earl; Guiney, Patrick; Hutchinson, Thomas; Kennedy, Sean W.; Kramer, Vincent; LeBlanc, Gerald A.; Mayes, Monte; Nimrod, Alison; Patino, Reynaldo; Peterson, Richard; Purdy, Richard; Ringer, Robert; Thomas, Peter C.; Touart, Les; Van Der Kraak, Glen; Zacharewski, Tim

1998-01-01

The U.S. Congress has passed legislation requiring the U.S. Environmental Protection Agency (U.S. EPA) to develop, validate, and implement screening tests for identifying potential endocrine-disrupting chemicals within 3 years. To aid in the identification of methods suitable for this purpose, the U.S. EPA, the Chemical Manufacturers Association, and the World Wildlife Fund sponsored several workshops, including the present one, which dealt with wildlife species. This workshop was convened with 30 international scientists representing multiple disciplines in March 1997 in Kansas City, Missouri, USA. Participants at the meeting identified methods in terms of their ability to indicate (anti-) estrogenic/androgenic effects, particularly in the context of developmental and reproductive processes. Data derived from structure-activity relationship models and in vitro test systems, although useful in certain contexts, cannot at present replace in vivo tests as the sole basis for screening. A consensus was reached that existing mammalian test methods (e.g., with rats or mice) generally are suitable as screens for assessing potential (anti-) estrogenic/ androgenic effects in mammalian wildlife. However, due to factors such as among-class variation in receptor structure and endocrine function, it is uncertain if these mammalian assays would be of broad utility as screens for other classes of vertebrate wildlife. Existing full and partial life-cycle tests with some avian and fish species could successfully identify chemicals causing endocrine disruption; however, these long-term tests are not suitable for routine screening. However, a number of short-term tests with species from these two classes exist that could serve as effective screening tools for chemicals inducing (anti-) estrogenic/androgenic effects. Existing methods suitable for identifying chemicals with these mechanisms of action in reptiles and amphibians are limited, but in the future, tests with species from

EDCs DataBank: 3D-Structure database of endocrine disrupting chemicals.

Science.gov (United States)

Montes-Grajales, Diana; Olivero-Verbel, Jesus

2015-01-02

Endocrine disrupting chemicals (EDCs) are a group of compounds that affect the endocrine system, frequently found in everyday products and epidemiologically associated with several diseases. The purpose of this work was to develop EDCs DataBank, the only database of EDCs with three-dimensional structures. This database was built on MySQL using the EU list of potential endocrine disruptors and TEDX list. It contains the three-dimensional structures available on PubChem, as well as a wide variety of information from different databases and text mining tools, useful for almost any kind of research regarding EDCs. The web platform was developed employing HTML, CSS and PHP languages, with dynamic contents in a graphic environment, facilitating information analysis. Currently EDCs DataBank has 615 molecules, including pesticides, natural and industrial products, cosmetics, drugs and food additives, among other low molecular weight xenobiotics. Therefore, this database can be used to study the toxicological effects of these molecules, or to develop pharmaceuticals targeting hormone receptors, through docking studies, high-throughput virtual screening and ligand-protein interaction analysis. EDCs DataBank is totally user-friendly and the 3D-structures of the molecules can be downloaded in several formats. This database is freely available at http://edcs.unicartagena.edu.co. Copyright © 2014. Published by Elsevier Ireland Ltd.

Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads

International Nuclear Information System (INIS)

Martinovic-Weigelt, Dalma; Wang Ronglin; Villeneuve, Daniel L.; Bencic, David C.; Lazorchak, Jim; Ankley, Gerald T.

2011-01-01

The studies presented in this manuscript focus on characterization of transcriptomic responses to anti-androgens in zebrafish (Danio rerio). Research on the effects of anti-androgens in fish has been characterized by a heavy reliance on apical endpoints, and molecular mechanisms of action (MOA) of anti-androgens remain poorly elucidated. In the present study, we examined effects of a short term exposure (24-96 h) to the androgen receptor antagonists flutamide (FLU) and vinclozolin (VZ) on gene expression in gonads of sexually mature zebrafish, using commercially available zebrafish oligonucleotide microarrays (4 x 44 K platform). We found that VZ and FLU potentially impact reproductive processes via multiple pathways related to steroidogenesis, spermatogenesis, and fertilization. Observed changes in gene expression often were shared by VZ and FLU, as demonstrated by overlap in differentially-expressed genes and enrichment of several common key pathways including: (1) integrin and actin signaling, (2) nuclear receptor 5A1 signaling, (3) fibroblast growth factor receptor signaling, (4) polyamine synthesis, and (5) androgen synthesis. This information should prove useful to elucidating specific mechanisms of reproductive effects of anti-androgens in fish, as well as developing biomarkers for this important class of endocrine-active chemicals.

Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads

Energy Technology Data Exchange (ETDEWEB)

Martinovic-Weigelt, Dalma, E-mail: dalma@stthomas.edu [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States); University of St. Thomas, 2115 Summit Ave, Saint Paul, MN 55105 (United States); Wang Ronglin [US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, 26W. Martin Luther King Dr., Cincinnati, OH 45268 (United States); Villeneuve, Daniel L. [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States); Bencic, David C.; Lazorchak, Jim [US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, 26W. Martin Luther King Dr., Cincinnati, OH 45268 (United States); Ankley, Gerald T. [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States)

2011-01-25

The studies presented in this manuscript focus on characterization of transcriptomic responses to anti-androgens in zebrafish (Danio rerio). Research on the effects of anti-androgens in fish has been characterized by a heavy reliance on apical endpoints, and molecular mechanisms of action (MOA) of anti-androgens remain poorly elucidated. In the present study, we examined effects of a short term exposure (24-96 h) to the androgen receptor antagonists flutamide (FLU) and vinclozolin (VZ) on gene expression in gonads of sexually mature zebrafish, using commercially available zebrafish oligonucleotide microarrays (4 x 44 K platform). We found that VZ and FLU potentially impact reproductive processes via multiple pathways related to steroidogenesis, spermatogenesis, and fertilization. Observed changes in gene expression often were shared by VZ and FLU, as demonstrated by overlap in differentially-expressed genes and enrichment of several common key pathways including: (1) integrin and actin signaling, (2) nuclear receptor 5A1 signaling, (3) fibroblast growth factor receptor signaling, (4) polyamine synthesis, and (5) androgen synthesis. This information should prove useful to elucidating specific mechanisms of reproductive effects of anti-androgens in fish, as well as developing biomarkers for this important class of endocrine-active chemicals.

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters.

Science.gov (United States)

Isling, Louise Krag; Boberg, Julie; Jacobsen, Pernille Rosenskjold; Mandrup, Karen Riiber; Axelstad, Marta; Christiansen, Sofie; Vinggaard, Anne Marie; Taxvig, Camilla; Kortenkamp, Andreas; Hass, Ulla

2014-01-01

This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.

Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents.

Science.gov (United States)

Bomba, Monica; Gambera, Alessandro; Bonini, Luisa; Peroni, Maria; Neri, Francesca; Scagliola, Pasquale; Nacinovich, Renata

2007-04-01

To determine trigger factors and neuropsychologic correlates of functional hypothalamic amenorrhea (FHA) in adolescence and to evaluate the correlations with the endocrine-metabolic profile. Cross-sectional comparison of adolescents with FHA and eumenorrheic controls Academic medical institution Twenty adolescent girls with FHA (aged <18 years) and 20 normal cycling girls All subjects underwent endocrine-gynecologic (hormone) and neuropsychiatric (tests and interview) investigations. A separate semistructured interview was also used to investigate parents. Gonadotropins, leptin, prolactin, androgens, estrogens, cortisol, carrier proteins (SHBG, insulin-like growth factor-binding protein 1), and metabolic parameters (insulin, insulin-like growth factor 1, thyroid hormones) were assayed in FHA and control subjects. All girls were evaluated using a test for depression, a test for disordered eating, and a psychodynamic semistructured interview. Adolescents with FHA showed a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders. The endocrine-metabolic profile was strictly correlated to the severity of the psychopathology. Functional hypothalamic amenorrhea in adolescence is due to a particular neuropsychologic vulnerability to stress, probably related to familial relationship styles, expressed by a proportional endocrine impairment.

In utero and lactational exposure to low-dose genistein-vinclozolin mixture affects the development and growth factor mRNA expression of the submandibular salivary gland in immature female rats.

Science.gov (United States)

Kouidhi, Wided; Desmetz, Catherine; Nahdi, Afef; Bergès, Raymond; Cravedi, Jean-Pierre; Auger, Jacques; El May, Michèle; Canivenc-Lavier, Marie Chantal

2012-06-01

It has been suggested that hormonally controlled submandibular salivary gland (SSG) development and secretions may be affected by endocrine disruptor compounds. We investigated the effects of oral gestation-lactation exposure to 1 mg/kg body weight daily dose of the estrogenic soy-isoflavone genistein and/or the anti-androgenic food contaminant vinclozolin in female rats. The SSGs of female offspring were collected at postnatal day 35 to study gland morphogenesis and mRNA expression of sex-hormone receptors and endocrine growth factors as sex-dependent biomarkers. Because of high expression in neonatal SSG, mRNA expression of transforming growth factor α was also studied. Exposure to genistein, vinclozolin, or a genistein+vinclozolin mixture resulted in significantly lower numbers of striated ducts linked to an increase in their area and lower acinar proliferation (Ki-67-positive nuclei). Exposure to the mixture had the highest significant effects, which were particularly associated with repression of epidermal growth factor, nerve growth factor, and transforming growth factor α expression. In conclusion, early exposure to low doses of genistein and vinclozolin can affect glandular structure and endocrine gene mRNA expression in prepubertal SSG in female rats, and the effects are potentialized by the genistein+vinclozolin mixture. Our study provides the first evidence that SSG are targeted by both estrogenic and anti-androgenic disrupting compounds and are more sensitive to mixtures.

Analytical Methodologies for the Determination of Endocrine Disrupting Compounds in Biological and Environmental Samples

Directory of Open Access Journals (Sweden)

Zoraida Sosa-Ferrera

2013-01-01

Full Text Available Endocrine-disruptor compounds (EDCs can mimic natural hormones and produce adverse effects in the endocrine functions by interacting with estrogen receptors. EDCs include both natural and synthetic chemicals, such as hormones, personal care products, surfactants, and flame retardants, among others. EDCs are characterised by their ubiquitous presence at trace-level concentrations and their wide diversity. Since the discovery of the adverse effects of these pollutants on wildlife and human health, analytical methods have been developed for their qualitative and quantitative determination. In particular, mass-based analytical methods show excellent sensitivity and precision for their quantification. This paper reviews recently published analytical methodologies for the sample preparation and for the determination of these compounds in different environmental and biological matrices by liquid chromatography coupled with mass spectrometry. The various sample preparation techniques are compared and discussed. In addition, recent developments and advances in this field are presented.

78 FR 35909 - Endocrine Disruptor Screening Program; Final Policies and Procedures for Screening Safe Drinking...

Science.gov (United States)

2013-06-14

... for Responsible Medicine (PCRM), ACC, BCS, and CLA and the Endocrine Policy Forum (EPF)) indicated... chemicals and drinking water contaminants. G. Other Topics 1. Cost sharing. ACC, CLA, EPF, and CPDA stated... should strictly disallow CBI claims. The ACC, CLA, and EPF commented that FFDCA authorized, and EPA...

Elucidating the mechanism of action of tributyltin (TBT) in zebrafish.

Science.gov (United States)

McGinnis, Courtney L; Crivello, Joseph F

2011-05-01

Tributyltin (TBT), an antifouling agent, has been implicated in the masculinization of fish species worldwide, but the masculinizing mechanism is not fully understood. We have examined the actions of TBT as an endocrine disruptor in zebrafish (Danio rerio). In HeLa cells transiently co-transfected with plasmid constructs containing the zebrafish estrogen receptors (zfERα, zfERβ(1) and zfERβ(2)) and the zebrafish estrogen response element (zfERE-tk-luc), ethinyl estradiol (EE2) induced luciferase activity 4 to 6-fold and was inhibited by TBT. In HeLa cells transiently co-transfected with the zebrafish androgen receptor (zfAR) and the murine androgen receptor response element (ARE-slp-luc), testosterone induced luciferase activity was not inhibited by TBT. In HeLa cells co-transfected with zfERα, zfERβ(1) and zfERβ(2) and a plasmid containing zebrafish aromatase (zfCyp19b-luc), TBT inhibited luciferase activity. In zebrafish exposed to 1mg/kg and 5mg/kg TBT in vivo, there was a increase in liver sulfotransferase and a decrease acyl-CoA testosterone acyltransferase activity. Real-time PCR analysis of sexual differentiation markers in fish exposed to TBT in vivo revealed a tissue-specific response. In brain there was increased production of Sox9, Dax1, and SF1 mRNA, an androgenizing effect, while in the liver there was increased production of Dax1, Cyp19a and zfERβ(1) mRNA but decreased production of Sox9 mRNA, a feminizing effect. In the gonads there was increased production of zfERα and zfCyp19a mRNA, again a feminizing effect. TBT has an overall masculinizing effect but the masculinizing effect is tempered by a feminizing effect on gene transcription in certain tissues. These results are discussed in the context of TBT as an endocrine disruptor in zebrafish. Copyright © 2011 Elsevier B.V. All rights reserved.

Distribution of Non-Persistent Endocrine Disruptors in Two Different Regions of the Human Brain

DEFF Research Database (Denmark)

van der Meer, Thomas P; Artacho-Cordón, Francisco; Swaab, Dick F

2017-01-01

Non-persistent endocrine disrupting chemicals (npEDCs) can affect multiple organs and systems in the body. Whether npEDCs can accumulate in the human brain is largely unknown. The major aim of this pilot study was to examine the presence of environmental phenols and parabens in two distinct brain...... and BMI triclosan, triclocarban and methyl-, ethyl-, n-propyl-, and benzyl paraben) were detected, while five npEDCs (bisphenol A...

77 FR 15101 - Results From Inert Ingredient Test Orders Issued Under EPA's Endocrine Disruptor Screening...

Science.gov (United States)

2012-03-14

... the selection criteria for endocrine testing under the Safe Drinking Water Act (SDWA). EPA has no...) because the chemicals meet the selection criteria. EPA has no plans to issue further test orders for the... Screening Program (EDSP) and the Federal Food, Drug, and Cosmetic Act (FFDCA). In response to the test...

Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

Energy Technology Data Exchange (ETDEWEB)

Muñoz, Alexandra; Chervona, Yana [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States); Hall, Megan [Department of Epidemiology, Mailman School of Public Health, Columbia University, New York (United States); Kluz, Thomas [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States); Gamble, Mary V., E-mail: mvg7@columbia.edu [Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York (United States); Costa, Max, E-mail: Max.Costa@nyumc.org [New York University School of Medicine, Nelson Institute of Environmental Medicine, Tuxedo, NY (United States)

2015-05-01

Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common

Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

International Nuclear Information System (INIS)

Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

2015-01-01

Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common

The influence of endocrine disruptors on growth and development of children.

Science.gov (United States)

DiVall, Sara A

2013-02-01

This review describes the most recent data about the effects of endocrine disrupting compounds (EDCs) on infant and early childhood growth and reproductive tract development as well as controversies in the field. EDCs are present in pregnant women, young children and adolescents. Whether the level of exposure contributes to disease is an ongoing debate. Epidemiological studies suggest associations between prenatal EDC exposure and disease outcome, but animal studies using controlled EDC exposure have varying results with underlying mechanisms largely unknown. Human exposure to EDCs is widespread; bisphenol A, phthalates and persistent organic pollutants are detectable in all age groups and geographical locations in the USA. Epidemiological and animal studies suggest that phthalates and bisphenol A have adverse effects on birth weight, promote development of childhood obesity and adversely affect male reproductive tract development. Differences in the interpretation of available studies underlie the disparate conclusions of scientific and regulatory body's panels on potential toxicological effects of EDCs at current levels of human exposure.

Juvenile exposure to vinclozolin shifts sex ratios and impairs reproductive capacity of zebrafish.

Science.gov (United States)

Lor, Yer; Revak, Andrew; Weigand, Jenna; Hicks, Elisabeth; Howard, David R; King-Heiden, Tisha C

2015-12-01

Exposure to endocrine disruptors during critical periods of development can impact the sustainability of wild fish populations. Anti-androgenic compounds have received less attention, but are capable of modulating gonad differentiation and maturation, and impairing reproduction in fish. The fungicide vinclozolin (VZ) has been shown to impair reproduction in adult fish, but less is known about its effects following exposure earlier in development. Here we show that waterborne exposure to 400μg VZ/L during critical periods of sex differentiation (21-35 days post fertilization) permanently shifts sex ratios towards females, and alters the maturation of the gonad. Both fecundity and fertility were reduced, even when oogenesis and spermatogenesis recover and sperm motility is not altered. These results demonstrate the need to better understand the impacts of early exposure to anti-androgenic compounds on fish. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional behavior and reproduction in androgenic sex reversed zebrafish (Danio rerio).

Science.gov (United States)

Larsen, Mia G; Baatrup, Erik

2010-08-01

Endocrine-disrupting chemicals released into natural watercourses may cause biased sex ratios by sex reversal in fish populations. The present study investigated the androgenic sex reversal of zebrafish (Danio rerio) exposed to the androgenic compound 17beta-trenbolone (TB) and whether sex-changed females would revert to the female phenotype after cessation of TB exposure. 17beta-Trenbolone is a metabolite of trenbolone acetate, an anabolic steroid used as a growth promoter in beef cattle. 17beta-Trenbolone in runoff from cattle feedlots may reach concentrations that affect fish sexual development. Zebrafish were exposed to a concentration of 20 ng/L TB in a flow-through system for five months from egg until sexual maturity. This resulted in an all-male population. It was further found that all these phenotypic males displayed normal male courtship behavior and were able to reproduce successfully, implying that the sex reversal was complete and functional. None of the phenotypic males developed into females after six months in clean water, demonstrating that androgenic sex reversal of zebrafish is irreversible. Copyright 2010 SETAC

Reprint of "Current perspectives on the androgen 5 alpha-dihydrotestosterone (DHT) and 5 alpha-reductases in teleost fishes and amphibians".

Science.gov (United States)

Martyniuk, Christopher J; Bissegger, Sonja; Langlois, Valérie S

2014-07-01

) examine the full range of biological responses to endogenous DHT, and its interactions with other signaling pathways; and (3) investigate how DHT production varies with reproductive stage. Lastly, we suggest that the Srd5a enzymes can be targets of endocrine disruptors in fish and frogs, which may result in disruptions in the estrogen:androgen balance in aquatic organisms. Copyright © 2013 Elsevier Inc. All rights reserved.

Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

Science.gov (United States)

Valera Yepes, Rocío; Virgili Casas, Maria; Povedano Panades, Monica; Guerrero Gual, Mireia; Villabona Artero, Carles

2015-05-01

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Developmental programming by androgen affects the circadian timing system in female mice.

Science.gov (United States)

Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T

2015-04-01

Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. © 2015 by the Society for the Study of Reproduction, Inc.

Classifying chemical mode of action using gene networks and machine learning: a case study with the herbicide linuron.

Science.gov (United States)

Ornostay, Anna; Cowie, Andrew M; Hindle, Matthew; Baker, Christopher J O; Martyniuk, Christopher J

2013-12-01

The herbicide linuron (LIN) is an endocrine disruptor with an anti-androgenic mode of action. The objectives of this study were to (1) improve knowledge of androgen and anti-androgen signaling in the teleostean ovary and to (2) assess the ability of gene networks and machine learning to classify LIN as an anti-androgen using transcriptomic data. Ovarian explants from vitellogenic fathead minnows (FHMs) were exposed to three concentrations of either 5α-dihydrotestosterone (DHT), flutamide (FLUT), or LIN for 12h. Ovaries exposed to DHT showed a significant increase in 17β-estradiol (E2) production while FLUT and LIN had no effect on E2. To improve understanding of androgen receptor signaling in the ovary, a reciprocal gene expression network was constructed for DHT and FLUT using pathway analysis and these data suggested that steroid metabolism, translation, and DNA replication are processes regulated through AR signaling in the ovary. Sub-network enrichment analysis revealed that FLUT and LIN shared more regulated gene networks in common compared to DHT. Using transcriptomic datasets from different fish species, machine learning algorithms classified LIN successfully with other anti-androgens. This study advances knowledge regarding molecular signaling cascades in the ovary that are responsive to androgens and anti-androgens and provides proof of concept that gene network analysis and machine learning can classify priority chemicals using experimental transcriptomic data collected from different fish species. © 2013.

Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads.

Science.gov (United States)

Martinović-Weigelt, Dalma; Wang, Rong-Lin; Villeneuve, Daniel L; Bencic, David C; Lazorchak, Jim; Ankley, Gerald T

2011-01-25

The studies presented in this manuscript focus on characterization of transcriptomic responses to anti-androgens in zebrafish (Danio rerio). Research on the effects of anti-androgens in fish has been characterized by a heavy reliance on apical endpoints, and molecular mechanisms of action (MOA) of anti-androgens remain poorly elucidated. In the present study, we examined effects of a short term exposure (24-96h) to the androgen receptor antagonists flutamide (FLU) and vinclozolin (VZ) on gene expression in gonads of sexually mature zebrafish, using commercially available zebrafish oligonucleotide microarrays (4×44K platform). We found that VZ and FLU potentially impact reproductive processes via multiple pathways related to steroidogenesis, spermatogenesis, and fertilization. Observed changes in gene expression often were shared by VZ and FLU, as demonstrated by overlap in differentially-expressed genes and enrichment of several common key pathways including: (1) integrin and actin signaling, (2) nuclear receptor 5A1 signaling, (3) fibroblast growth factor receptor signaling, (4) polyamine synthesis, and (5) androgen synthesis. This information should prove useful to elucidating specific mechanisms of reproductive effects of anti-androgens in fish, as well as developing biomarkers for this important class of endocrine-active chemicals. 2010 Elsevier B.V. All rights reserved.

First year growth in relation to prenatal exposure to endocrine disruptors - a Dutch prospective cohort study

NARCIS (Netherlands)

de Cock, M.; de Boer, M.R.; Lamoree, M.H.; Legler, J.; van de Bor, M.

2014-01-01

Growth in the first year of life may already be predictive of obesity later in childhood. The objective was to assess the association between prenatal exposure to various endocrine disrupting chemicals (EDCs) and child growth during the first year. Dichloro-diphenyldichloroethylene (DDE),

Neurobehavioral endocrine regulation of small mammal populations

International Nuclear Information System (INIS)

Christian, J.J.

1978-01-01

A brief review is given of the hypothesis that density-dependent behavioral-endocrine negative feedbacks can regulate and often limit the growth of populations of many species of small mammals. Recent laboratory studies are summarized that show how stress, particularly psychogenic, which results in increased adrenocortical secretion also alters gonadotropin secretion and inhibits reproduction. Chronic stress due to crowding, immobilization, et al. inhibits the release of LH and FSH, particularly by abolishing the pulsatile release of LH, and also causes a rise in prolactin (at least acutely). Stimulation of the hypothalamo-pituitary-adrenocortical system is accompanied by an inversely proportional inhibition of growth hormone secretion. Decreasing photoperiod enhances the sensitivity of the hypothalamus to inhibition of gonadotropin secretion by androgens and estrogens. Other endocrine responses to increased density or subordinate social rank also are summarized. How these facts fit into the negative feedback scheme is discussed, including the greatly prolonged effects of diminished lactation. The changed quality of the animals associated with changes in density discussed by Lidicker also can be explained by the above responses to density. Data on changes in growth and reproductive function which are consistent with the behavioral-endocrine feedback hypothesis are presented for several populations of small mammals, including some previously unpublished data for Microtus pennsylvanicus

Changes in male reproductive health and effects of endocrine disruptors in Scandinavian countries

Directory of Open Access Journals (Sweden)

Toppari Jorma

2002-01-01

Full Text Available Male reproductive health has deteriorated in many ways during the last decades. The incidence of testicular cancer has rapidly increased in Europe and European-derived populations. Sperm concentrations have declined and sperm motility and morphology have worsened in many areas. Both adverse trends have been shown to be associated with year of birth. Older birth cohorts have better reproductive health than the younger generations. Incidences of cryptorchidism and hypospadias have also increased according to several studies. The reasons for secular trends are unknown, but the rapid pace of the change points to environmental causes. Endocrine disrupting chemicals have been hypothesized to influence male reproductive health.

Glifosato como desregulador endócrino químico / Glyphosate as an endocrine chemical disruptor

Directory of Open Access Journals (Sweden)

Renata Marino Romano

2009-08-01

Full Text Available ResumoDesreguladores endócrinos são moléculas exógenas ambientais que podem afetar a síntese, secreção, transporte, metabolismo, ligação, ação e catabolismo de hormônios naturais do organismo, podendo exercer seu efeito mesmo quando em mínimas quantidades. O glifosato é um herbicida utilizado no combate às plantas daninhas prejudiciais a diversas culturas, bastante efetivo, não seletivo e pós-emergente que inibe o crescimento da planta através da interferência com a produção de aminoácidos aromáticos essenciais pela inibição da fotossíntese. Em baixas concentrações não tóxicas ele causa efeito de desregulação sobre a enzima aromatase em células de placenta humana in vitro, reduzindo a atividade da enzima aromatase e reduzindo a expressão da proteína StAR (proteína de regulação rápida da esteroidogênese. Acontaminação do solo e da água tanto fluvial como subterrânea, pelo intenso uso do glifosato, pode levar a distúrbios reprodutivos, além da possibilidade da persistência de resíduos destas substâncias no sangue, na carne, no leite, na urina e nas fezes dos animais levando à recontaminação do solo e podendo chegar ao consumo humano. O objetivo desta revisão é apresentar informações atuais sobre a toxicologia do glifosato e a sua importância sobre a saúde humana, suscitando o debate nessa área, uma vez que a legislação brasileira ainda não contempla o controle desse tipo de efeito tóxico.AbstractEndocrine disruptors (EDs are exogenous molecular factors that may affect the synthesis, secretion, transport, metabolism, binding, action, and catabolism of the body’s natural hormones. They are able to produce their effect even when they are present in minimum quantities. Glyphosate is an herbicide used to combat weeds that are harmful to different plants. It is very effective, non-selective and post-emergent, inhibiting the plant growth by interfering with the production of essential

November 6, 2017, Virtual Meeting on the Charge Questions for the Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) Meeting on Endocrine Disruption

Science.gov (United States)

This virtual FIFRA SAP meeting will be discus questions on Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

Androgen insensitivity syndrome: gonadal androgen receptor activity

International Nuclear Information System (INIS)

Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

1984-01-01

To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE LEVELS BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF MALE RAT PUBERTY

Science.gov (United States)

Prochloraz (PCZ) is an imidazole fungicide that has several endocrine modes of action. In vitro, PCZ inhibits steroidogenesis and acts as an androgen receptor (AR) antagonist. We hypothesized that pubertal exposure to prochloraz would delay preputial separation and growth of an...

Computational Assessment of Pharmacokinetics and Biological Effects of Some Anabolic and Androgen Steroids.

Science.gov (United States)

Roman, Marin; Roman, Diana Larisa; Ostafe, Vasile; Ciorsac, Alecu; Isvoran, Adriana

2018-02-05

The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism. Investigated steroids usually reveal a high gastrointestinal absorption and a good oral bioavailability, may inhibit someof the human cytochromes involved in the metabolism of xenobiotics (CYP2C9 being the most affected) and reflect a good capacity for skin penetration. There are predicted numerous side effects of investigated steroids in humans: genotoxic carcinogenicity, hepatotoxicity, cardiovascular, hematotoxic and genitourinary effects, dermal irritations, endocrine disruption and reproductive dysfunction. These results are important to be known as an occupational exposure to anabolic and androgenic steroids at workplaces may occur and because there also is a deliberate human exposure to steroids for their performance enhancement and anti-aging properties.

Inhibition of the Functional Interplay between Endoplasmic Reticulum (ER) Oxidoreduclin-1α (Ero1α) and Protein-disulfide Isomerase (PDI) by the Endocrine Disruptor Bisphenol A*

Science.gov (United States)

Okumura, Masaki; Kadokura, Hiroshi; Hashimoto, Shoko; Yutani, Katsuhide; Kanemura, Shingo; Hikima, Takaaki; Hidaka, Yuji; Ito, Len; Shiba, Kohei; Masui, Shoji; Imai, Daiki; Imaoka, Susumu; Yamaguchi, Hiroshi; Inaba, Kenji

2014-01-01

Bisphenol A (BPA) is an endocrine disruptor that may have adverse effects on human health. We recently isolated protein-disulfide isomerase (PDI) as a BPA-binding protein from rat brain homogenates and found that BPA markedly inhibited PDI activity. To elucidate mechanisms of this inhibition, detailed structural, biophysical, and functional analyses of PDI were performed in the presence of BPA. BPA binding to PDI induced significant rearrangement of the N-terminal thioredoxin domain of PDI, resulting in more compact overall structure. This conformational change led to closure of the substrate-binding pocket in b′ domain, preventing PDI from binding to unfolded proteins. The b′ domain also plays an essential role in the interplay between PDI and ER oxidoreduclin 1α (Ero1α), a flavoenzyme responsible for reoxidation of PDI. We show that BPA inhibited Ero1α-catalyzed PDI oxidation presumably by inhibiting the interaction between the b′ domain of PDI and Ero1α; the phenol groups of BPA probably compete with a highly conserved tryptophan residue, located in the protruding β-hairpin of Ero1α, for binding to PDI. Consistently, BPA slowed down the reoxidation of PDI and caused the reduction of PDI in HeLa cells, indicating that BPA has a great impact on the redox homeostasis of PDI within cells. However, BPA had no effect on the interaction between PDI and peroxiredoxin-4 (Prx4), another PDI family oxidase, suggesting that the interaction between Prx4 and PDI is different from that of Ero1α and PDI. These results indicate that BPA, a widely distributed and potentially harmful chemical, inhibits Ero1-PDI-mediated disulfide bond formation. PMID:25122773

The endocrine pharmacology of testosterone therapy in men

Science.gov (United States)

Oettel, Michael

The review starts off by outlining the history of the discovery of the male sex hormone testosterone and the historical background to the various, often dubious, approaches to the treatment of age-related endocrine disorders in older men. A discussion of congenital androgen deficiency in young men is followed by methods of diagnosing hypogonadism in older men. Among therapeutic options, the alternatives to direct testosterone replacement are discussed, although none of them have proved to be particularly successful in clinical practice. For testosterone replacement itself, various routes of administration and pharmaceutical formulations are now available, facilitating good monitoring and individualized therapy.

AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome.

Science.gov (United States)

O'Reilly, Michael W; Kempegowda, Punith; Walsh, Mark; Taylor, Angela E; Manolopoulos, Konstantinos N; Allwood, J William; Semple, Robert K; Hebenstreit, Daniel; Dunn, Warwick B; Tomlinson, Jeremy W; Arlt, Wiebke

2017-09-01

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index-matched healthy controls, complemented by in vitro experiments. PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis. These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS. Copyright © 2017 Endocrine Society

First characterization of the endocrine-disrupting potential of indoor gaseous and particulate contamination: comparison with urban outdoor air (France).

Science.gov (United States)

Oziol, Lucie; Alliot, Fabrice; Botton, Jérémie; Bimbot, Maya; Huteau, Viviane; Levi, Yves; Chevreuil, Marc

2017-01-01

The composition of endocrine-disrupting compounds (EDCs) in the ambient air of indoor environments has already been described, but little is known about the inherent endocrine-disrupting potential of indoor air contamination. We therefore aimed to study the distribution of bioactive EDCs in the gaseous and particulate phases of indoor air using a cellular bioassay approach that integrates the interaction effects between chemicals. Organic air extracts, both gaseous and particulate, were taken from three indoor locations (office, apartment, and children's day care) in France and sampled in two different seasons in order to study their interference with the signaling of estrogen, androgen, and thyroid receptors. The experiments were also conducted on aerial extracts from an outdoor site (urban center). We found that gaseous and/or particulate extracts from all locations displayed estrogenicity, anti-androgenicity, and thyroidicity. Overall, indoor air extracts had a higher endocrine-disrupting potential compared to outdoor ones, especially during winter and in the day care. The biological activities were predominant for the gaseous extracts and tended to increase for the particulate extracts in cool conditions. In conclusion, our data confirmed the presence of bioactive EDCs in a gaseous state and highlighted their indoor origin and concentration, especially in the cold season.

TBECH, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane, alters androgen receptor regulation in response to mutations associated with prostate cancer

Energy Technology Data Exchange (ETDEWEB)

Kharlyngdoh, Joubert Banjop; Asnake, Solomon; Pradhan, Ajay; Olsson, Per-Erik, E-mail: per-erik.olsson@oru.se

2016-09-15

Point mutations in the AR ligand-binding domain (LBD) can result in altered AR structures leading to changes of ligand specificity and functions. AR mutations associated to prostate cancer (PCa) have been shown to result in receptor activation by non-androgenic substances and anti-androgenic drugs. Two AR mutations known to alter the function of anti-androgens are the AR{sub T877A} mutation, which is frequently detected mutation in PCa tumors and the AR{sub W741C} that is rare and has been derived in vitro following exposure of cells to the anti-androgen bicalutamide. AR activation by non-androgenic environmental substances has been suggested to affect PCa progression. In the present study we investigated the effect of AR mutations (AR{sub W741C} and AR{sub T877A}) on the transcriptional activation following exposure of cells to an androgenic brominated flame retardant, 1,2-dibromo-4-(1,2 dibromoethyl) cyclohexane (TBECH, also named DBE-DBCH). The AR mutations resulted in higher interaction energies and increased transcriptional activation in response to TBECH diastereomer exposures. The AR{sub T877A} mutation rendered AR highly responsive to low levels of DHT and TBECH and led to increased AR nuclear translocation. Gene expression analysis showed a stronger induction of AR target genes in LNCaP cells (AR{sub T877A}) compared to T-47D cells (AR{sub WT}) following TBECH exposure. Furthermore, AR knockdown experiments confirmed the AR dependency of these responses. The higher sensitivity of AR{sub T877A} and AR{sub W741C} to low levels of TBECH suggests that cells with these AR mutations are more susceptible to androgenic endocrine disrupters. - Highlights: • TBECH, is an endocrine disrupting compound that differ in activity depending on AR structure and sequence. • TBECH interaction with the human AR-LBD containing the mutations W741C and T877A is increased compared to the wild type receptor • The mutations, W741C and T877A, are more potent than the wild type

Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies.

Science.gov (United States)

Xita, Nectaria; Tsatsoulis, Agathocles

2006-05-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programing of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.

Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea.

Science.gov (United States)

Miller, K K; Lawson, E A; Mathur, V; Wexler, T L; Meenaghan, E; Misra, M; Herzog, D B; Klibanski, A

2007-04-01

Anorexia nervosa and normal-weight hypothalamic amenorrhea are characterized by hypogonadism and hypercortisolemia. However, it is not known whether these endocrine abnormalities result in reductions in adrenal and/ or ovarian androgens or androgen precursors in such women, nor is it known whether relative androgen deficiency contributes to abnormalities in bone density and body composition in this population. Our objective was to determine whether endogenous androgen and dehydroepiandrosterone sulfate (DHEAS) levels: 1) are reduced in women with anorexia nervosa and normal-weight hypothalamic amenorrhea, 2) are reduced further by oral contraceptives in women with anorexia nervosa, and 3) are predictors of weight, body composition, or bone density in such women. We conducted a cross-sectional study at a general clinical research center. A total of 217 women were studied: 137 women with anorexia nervosa not receiving oral contraceptives, 32 women with anorexia nervosa receiving oral contraceptives, 21 normal-weight women with hypothalamic amenorrhea, and 27 healthy eumenorrheic controls. Testosterone, free testosterone, DHEAS, bone density, fat-free mass, and fat mass were assessed. Endogenous total and free testosterone, but not DHEAS, were lower in women with anorexia nervosa than in controls. More marked reductions in both free testosterone and DHEAS were observed in women with anorexia nervosa receiving oral contraceptives. In contrast, normal-weight women with hypothalamic amenorrhea had normal androgen and DHEAS levels. Lower free testosterone, total testosterone, and DHEAS levels predicted lower bone density at most skeletal sites measured, and free testosterone was positively associated with fat-free mass. Androgen levels are low, appear to be even further reduced by oral contraceptive use, and are predictors of bone density and fat-free mass in women with anorexia nervosa. Interventional studies are needed to confirm these findings and determine whether

Endocrine-disrupting chemicals-Mechanisms of action on male reproductive system.

Science.gov (United States)

Sidorkiewicz, Iwona; Zaręba, Kamil; Wołczyński, Sławomir; Czerniecki, Jan

2017-07-01

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that can cause disturbances in the endocrine system and have multiple harmful effects on health by targeting different organs and systems in the human body. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination. Accumulating evidence suggest that human exposure to EDCs is related to the impairment of male reproductive function and can interrupt other hormonally regulated metabolic processes, particularly if exposure occurs during early development. Investigation of studies absent in previous reviews and meta-analysis of adverse effects of EDCs on functioning of the male reproductive system is the core of this work. Four main modes of action of EDCs on male fertility have been summarized in this review. First, studies describing estrogen- pathway disturbing chemicals are investigated. Second, androgen-signaling pathway alterations and influence on androgen sensitive tissues are examined. Third, evaluation of steroidogenesis dysfunction is discussed by focusing on the steroid hormone biosynthesis pathway, which is targeted by EDCs. Last, the reportedly destructive role of reactive oxygen species (ROS) on sperm function is discussed. Spermatogenesis is a remarkably complex process, hence multiple studies point out various dysfunctions depending on the development state at which the exposure occurred. Collected data show the need to account for critical windows of exposure such as fetal, perinatal and pubertal periods as well as effects of mixtures of several compounds in future research.

In vitro effects of selected brominated flame retardants on the adreno cortical enzyme (CYP17). A novel endocrine mechanism of action?

Energy Technology Data Exchange (ETDEWEB)

Fernandez Canton, R.; Sanderson, T.; Nijmeijer, S.; Berg, M. van den [Utrecht Univ. (NL). Inst. for Risk Assessment Sciences (IRAS); Berkman, Aa. [Stockholm Univ. (Sweden). Dept. of Environmental Chemistry and Analytical Chemistry

2004-09-15

Fire incidents have decreased over the last 20 years partly due to regulations requiring addition of flame retardants (FRs) to materials. These compounds can be divided into different chemical classes: inorganic, nitrogen, phosphorus and halogen containing flame retardants (usually brominated or chlorinated). Not surprisingly, the use of brominated flame retardants (BFRs) in a variety of commercial and household products has increased over the years due to their low cost and high effectiveness. Consequence of the high production of BFRs is that these compounds are now readily detectable in air, water, birds, fish, marine mammals, and in human adipose tissue and blood. The five major BFRs are hexabromocyclododecane (HBCD), tetrabromobisphenol-A (TBBPA) and three commercial mixtures of polybrominated diphenyl ethers (PBDEs) (penta, octa, deca), which are extensively used as FRs at high production volume levels. In addition, concentrations of PBDEs concentration have been rapidly increasing during the last 10 years in human breast milk from European and American women and a number of endocrine (in vitro) effects have been reported. Consequently, the concern about BFRs and their metabolites with respect to their potential as endocrine disruptors (EDs) has been growing. Studies in our laboratory are focused on potential interactions of a wide range of BFRs with sex hormone synthesis and metabolism. Previous results from our research group, showed inhibitory and inductive effects on aromatase (CYP19) (the key enzyme that converts androgens to estrogens) by certain BFRs, in particular the hydroxylated PBDEs and several bromophenols. In the present study, the effects of ten of these BFRs on CYP17 activity were investigated. This enzyme also catalyzes an important step in the sex steroidogenesis and is responsible for the biosynthesis of dehydroepiandrosterone (DHEA). DHEA, produced in the adrenal gland, is the most abundant sex steroid hormone in human blood and has been

Multiple endocrine disrupting effects in rats perinatally exposed to butylparaben

DEFF Research Database (Denmark)

Boberg, Julie; Petersen, Marta Axelstad; Svingen, Terje

2016-01-01

) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group......Parabens comprise a group of preservatives commonly added to cosmetics, lotions and other consumer products. Butylparaben has estrogenic and anti-androgenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine...

78 FR 35922 - Endocrine Disruptor Screening Program; Final Second List of Chemicals and Substances for Tier 1...

Science.gov (United States)

2013-06-14

... health or the environment due to disruption of the endocrine system. The determination that a chemical... chemicals (e.g., triclosan, alkylphenols and alkylphenol polyethoxylates, bisphenol A, musk fragrances, and..., methanol, and perchlorate) can occur naturally in the environment, this is not the only known pathway of...

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome.

Science.gov (United States)

Caldwell, Aimee S L; Edwards, Melissa C; Desai, Reena; Jimenez, Mark; Gilchrist, Robert B; Handelsman, David J; Walters, Kirsty A

2017-04-18

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.

Prevalence of functional disorders of androgen excess in unselected premenopausal women: a study in blood donors.

Science.gov (United States)

Sanchón, Raúl; Gambineri, Alessandra; Alpañés, Macarena; Martínez-García, M Ángeles; Pasquali, Renato; Escobar-Morreale, Héctor F

2012-04-01

The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. On the contrary, the prevalences of other disorders of androgen excess such as idiopathic hyperandrogenism and idiopathic hirsutism remain unknown. We aimed to obtain an unbiased estimate of the prevalence in premenopausal women of (i) signs of androgen excess and (ii) PCOS, idiopathic hyperandrogenism and idiopathic hirsutism. A multicenter prevalence survey included 592 consecutive premenopausal women (393 from Madrid, Spain and 199 from Bologna, Italy) reporting spontaneously for blood donation. Immediately before donation, we conducted clinical and biochemical phenotyping for androgen excess disorders. We determined the prevalence of (i) hirsutism, acne and alopecia as clinical signs of androgen excess and (ii) functional disorders of androgen excess, including PCOS, defined by the National Institute of Child Health and Human Development/National Institute of Health criteria, idiopathic hyperandrogenism and idiopathic hirsutism. Regarding clinical signs of hyperandrogenism, hirsutism and acne were equally frequent [12.2% prevalence; 95% confidence interval (CI): 9.5-14.8%], whereas alopecia was uncommon (1.7% prevalence, 95% CI: 0.7-2.7%). Regarding functional disorders of androgen excess, PCOS and idiopathic hirsutism were equally frequent (5.4% prevalence, 95% CI: 3.6-7.2) followed by idiopathic hyperandrogenism (3.9% prevalence, 95% CI: 2.3-5.4). Clinical signs of hyperandrogenism and functional disorders of androgen excess show a high prevalence in premenopausal women. The prevalences of idiopathic hyperandrogenism and idiopathic hirsutism are similar to that of PCOS, highlighting the need for further research on the pathophysiology, consequences for health and clinical implications of these functional forms of androgen excess.

Endocrine effects of chemicals: aspects of hazard identification and human health risk assessment.

Science.gov (United States)

Dekant, Wolfgang; Colnot, Thomas

2013-12-16

Hazard and risk assessment of chemicals with endocrine activity is hotly debated due to claimed non-monotonous dose-response curves in the low-dose region. In hazard identification a clear definition of "endocrine disruptors" (EDs) is required; this should be based on the WHO/IPCS definition of EDs and on adverse effects demonstrated in intact animals or humans. Therefore, endocrine effects are a mode of action potentially resulting in adverse effects; any classification should not be based on a mode of action, but on adverse effects. In addition, when relying on adverse effects, most effects reported in the low-dose region will not qualify for hazard identification since most have little relation to an adverse effect. Non-monotonous dose-response curves that had been postulated from limited, exploratory studies could also not be reproduced in targeted studies with elaborate quality assurance. Therefore, regulatory agencies or advisory bodies continue to apply the safety-factor method or the concept of "margin-of-exposure" based on no observed adverse effect levels (NOAELs) in the risk assessment of chemicals with weak hormonal activity. Consistent with this approach, tolerable levels regarding human exposure have been defined for such chemicals. To conclusively support non-monotonous dose-response curves, targeted experiments with a sufficient number of animals, determination of adverse endpoints, adequate statistics and quality control would be required. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

Science.gov (United States)

Ueki, H

1987-11-01

We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

Corticosteroid production in H295R cells during exposure to 3 endocrine disrupters analyzed with LC-MS/MS

DEFF Research Database (Denmark)

Winther, Christina S; Nielsen, Frederik K; Hansen, Martin

2013-01-01

295R cell line. The method was applied by studying the effects of 2 model endocrine disrupters, ketoconazole and prochloraz, the pharmaceutical budesonide, and the inducer forskolin on the steroid production in this cell line. Dose-response curves were obtained for the correlation between hormone...... concentrations and the concentration of the individual disruptors. Exposing cells to ketoconazole resulted in a decrease in cortisol and corticosterone concentrations in a dose-dependent manner with EC₅₀ values of 0.24 and 0.40 μmol/L, respectively. The same applied for cells exposed to prochloraz with EC₅₀...

Challenges in clinical and laboratory diagnosis of androgen insensitivity syndrome: a case report

Directory of Open Access Journals (Sweden)

Silva Daniela M

2011-09-01

endocrine and genetic testing to reach a conclusive diagnosis before gender is assigned and surgical interventions are carried out. Our results show that extreme care must be taken in selecting the genetic tools that are utilized for the diagnosis for androgen insensitivity syndrome.

Inhibition of the functional interplay between endoplasmic reticulum (ER) oxidoreduclin-1α (Ero1α) and protein-disulfide isomerase (PDI) by the endocrine disruptor bisphenol A.

Science.gov (United States)

Okumura, Masaki; Kadokura, Hiroshi; Hashimoto, Shoko; Yutani, Katsuhide; Kanemura, Shingo; Hikima, Takaaki; Hidaka, Yuji; Ito, Len; Shiba, Kohei; Masui, Shoji; Imai, Daiki; Imaoka, Susumu; Yamaguchi, Hiroshi; Inaba, Kenji

2014-09-26

Bisphenol A (BPA) is an endocrine disruptor that may have adverse effects on human health. We recently isolated protein-disulfide isomerase (PDI) as a BPA-binding protein from rat brain homogenates and found that BPA markedly inhibited PDI activity. To elucidate mechanisms of this inhibition, detailed structural, biophysical, and functional analyses of PDI were performed in the presence of BPA. BPA binding to PDI induced significant rearrangement of the N-terminal thioredoxin domain of PDI, resulting in more compact overall structure. This conformational change led to closure of the substrate-binding pocket in b' domain, preventing PDI from binding to unfolded proteins. The b' domain also plays an essential role in the interplay between PDI and ER oxidoreduclin 1α (Ero1α), a flavoenzyme responsible for reoxidation of PDI. We show that BPA inhibited Ero1α-catalyzed PDI oxidation presumably by inhibiting the interaction between the b' domain of PDI and Ero1α; the phenol groups of BPA probably compete with a highly conserved tryptophan residue, located in the protruding β-hairpin of Ero1α, for binding to PDI. Consistently, BPA slowed down the reoxidation of PDI and caused the reduction of PDI in HeLa cells, indicating that BPA has a great impact on the redox homeostasis of PDI within cells. However, BPA had no effect on the interaction between PDI and peroxiredoxin-4 (Prx4), another PDI family oxidase, suggesting that the interaction between Prx4 and PDI is different from that of Ero1α and PDI. These results indicate that BPA, a widely distributed and potentially harmful chemical, inhibits Ero1-PDI-mediated disulfide bond formation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Biodegradation of endocrine disruptors in urban wastewater using Pleurotus ostreatus bioreactor.

Science.gov (United States)

Křesinová, Zdena; Linhartová, Lucie; Filipová, Alena; Ezechiáš, Martin; Mašín, Pavel; Cajthaml, Tomáš

2018-07-25

The white rot fungus Pleurotus ostreatus HK 35, which is also an edible industrial mushroom commonly cultivated in farms, was tested in the degradation of typical representatives of endocrine disrupters (EDCs; bisphenol A, estrone, 17β-estradiol, estriol, 17α-ethinylestradiol, triclosan and 4-n-nonylphenol); its degradation efficiency under model laboratory conditions was greater than 90% within 12 days and better than that of another published strain P. ostreatus 3004. A spent mushroom substrate from a local farm was tested for its applicability in various batch and trickle-bed reactors in degrading EDCs in model fortified and real communal wastewater. The reactors were tested under various regimes including a pilot-scale trickle-bed reactor, which was finally tested at a wastewater treatment plant. The result revealed that the spent substrate is an efficient biodegradation agent, where the fungus was usually able to remove about 95% of EDCs together with suppression of the estrogenic activity of the sample. The results showed the fungus was able to operate in the presence of bacterial microflora in wastewater without any substantial negative effects on the degradation abilities. Finally, a pilot-scale trickle-bed reactor was installed in a wastewater treatment plant and successfully operated for 10days, where the bioreactor was able to remove more than 76% of EDCs present in the wastewater. Copyright © 2017 Elsevier B.V. All rights reserved.

In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

Directory of Open Access Journals (Sweden)

Alison K. Heather

2013-02-01

Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

Premature reproductive aging in female rats after developmental exposure to mixtures of endocrine disrupters

DEFF Research Database (Denmark)

Jacobsen, Pernille Rosenskjold; Petersen, Marta Axelstad; Christiansen, Sofie

2013-01-01

of 13 estrogenic and anti-androgenic chemicals, including phthalates, pesticides, UV-filters, bisphenol A, butylparaben and paracetamol, and the mixture ratio was chosen to reflect high-end human intakes. Groups received combined exposures of 0,100, 150, 200 or 450 times high-end human intake levels......Long-lasting and delayed reproductive effects of developmental exposure to mixtures of environmental chemicals were investigated in female rats. Wistar rats were dosed during gestation and lactation to mixtures of endocrine disrupters, and effects in offspring were studied. The mixtures consisted....... Additionally, groups received mixtures including only the anti-androgens or estrogens at 200 or 450 times human intake. Female offspring exposed to the high dose mixture of all 13 chemicals showed earlier reproductive aging measured as early onset of irregular estrous cycle as compared to controls...

Androgens and estrogens in skeletal sexual dimorphism

Science.gov (United States)

Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

2014-01-01

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis. PMID:24385015

Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

Science.gov (United States)

Omwancha, Josephat; Brown, Terry R

2006-10-01

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

Diet-dependence of metabolic perturbations mediated by the endocrine disruptor tolylfluanid

Directory of Open Access Journals (Sweden)

Shane M Regnier

2018-01-01

Full Text Available Emerging evidence implicates environmental endocrine-disrupting chemicals (EDCs in the pathogenesis of metabolic diseases such as obesity and diabetes; however, the interactions between EDCs and traditional risk factors in disease pathogenesis remain incompletely characterized. The present study interrogates the interaction of the EDC tolylfluanid (TF and traditional dietary stressors in the promotion of metabolic dysfunction. Eight-week-old male C57BL/6 mice were fed a high-fat, high-sucrose diet (HFHSD or a high-sucrose diet (HSD, with or without TF supplementation at 100 μg/g, for 12 weeks. Food intake, body weight and visceral adiposity were quantified. Glucose homeostasis was interrogated by intraperitoneal glucose and insulin tolerance tests at 9 and 10 weeks of exposure, respectively. After 12 weeks of dietary exposure, metabolic cage analyses were performed to interrogate nutrient handling and energy expenditure. In the background of an HFHSD, TF promoted glucose intolerance; however, weight gain and insulin sensitivity were unchanged, and visceral adiposity was reduced. In the background of an HSD, TF increased visceral adiposity; however, glucose tolerance and insulin sensitivity were unchanged, while weight gain was reduced. Thus, these analyses reveal that the metabolic perturbations induced by dietary exposure to TF, including the directionality of alterations in body weight gain, visceral adiposity and glucose homeostasis, are influenced by dietary macronutrient composition, suggesting that populations may exhibit distinct metabolic risks based on their unique dietary characteristics.

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Science.gov (United States)

Caldwell, Aimee S. L.; Edwards, Melissa C.; Desai, Reena; Jimenez, Mark; Gilchrist, Robert B.; Walters, Kirsty A.

2017-01-01

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS. PMID:28320971

Endocrine disruptors in soil: Effects of bisphenol A on gene expression of the earthworm Eisenia fetida.

Science.gov (United States)

Novo, M; Verdú, I; Trigo, D; Martínez-Guitarte, J L

2018-04-15

Xenobiotics such as bisphenol A (BPA), are present in biosolids, which are applied as organic fertilizers in agricultural fields. Their effects on soil life have been poorly assessed, and this is particularly important in the case of earthworms, which represent the main animal biomass in this medium. In the present work we study the impacts of BPA on gene expression of Eisenia fetida, a widely used ecotoxicological model. Chronic soil tests and acute contact tests were performed, and gene expression was analyzed in total tissue and in masculine reproductive organs of the earthworms. The genes studied in this research played a role in endocrine pathways, detoxification mechanisms, stress response, epigenetics, and genotoxicity. Most of the genes were identified for the first time, providing potentially useful biomarkers for future assessments. For chronic exposures, no changes were detected in whole-body tissue; however, masculine reproductive organs showed changes in the expression of genes related to endocrine function (EcR, MAPR, AdipoR), epigenetic mechanisms (DNMTs), genotoxicity (PARP1), and stress responses (HSC70 4). For acute exposures, the expression of one epigenetic-related gene was altered for both whole-body tissues and male reproductive organs (Piwi2). Further changes were detected for whole-body tissues involved in detoxification (Metallothionein), stress (HSC70 4), and genotoxicity (PARP1) mechanisms. Acute exposure effects were also tested in whole-body tissues of juveniles, showing changes in the expression of Metallothionein and Piwi2. The molecular changes found in the analyzed earthworms indicate that exposure to BPA may have negative implications in their populations. Particularly interesting are the alterations related to epigenetic mechanisms, which suggest that future generations may be impacted. This study is the first to evaluate the molecular effects of BPA on soil organisms, and further assays will be necessary to better characterize

A selective androgen receptor modulator for hormonal male contraception.

Science.gov (United States)

Chen, Jiyun; Hwang, Dong Jin; Bohl, Casey E; Miller, Duane D; Dalton, James T

2005-02-01

The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

An Isomer-Specific Approach to Endocrine-Disrupting Nonylphenol in Infant Food.

Science.gov (United States)

Günther, Klaus; Räcker, Torsten; Böhme, Roswitha

2017-02-15

Nonylphenols (NPs) are persistent endocrine disruptors that are priority hazardous substances of the European Union Water Framework Directive. Their presence in the environment has caused growing concern regarding their impact on human health. Recent studies have shown that nonylphenol is ubiquitous in commercially available foodstuffs and is also present in human blood. The isomer distribution of 4-nonylphenol was analyzed by gas chromatography - mass spectrometry in 44 samples of infant food. Our study shows that the distribution of nonylphenol isomers is dependent on the foodstuff analyzed. Although some isomer groups prevail, different distributions are frequent. Variations are even found in the same food group. Nonylphenol is a complex mixture of isomers, and the estrogenic potentials of each of these isomers are very different. Consequently, to determine the potential toxicological impact of NP in food, an isomer-specific approach is necessary.

Multivariate calibration-assisted high-performance liquid chromatography with dual UV and fluorimetric detection for the analysis of natural and synthetic sex hormones in environmental waters and sediments

International Nuclear Information System (INIS)

Pérez, Rocío L.; Escandar, Graciela M.

2016-01-01

A green method is reported based on non-sophisticated instrumental for the quantification of seven natural and synthetic estrogens, three progestagens and one androgen in the presence of real interferences. The method takes advantage of: (1) chromatography, allowing total or partial resolution of a large number of compounds, (2) dual detection, permitting selection of the most appropriate signal for each analyte and, (3) second-order calibration, enabling mathematical resolution of incompletely resolved chromatographic bands and analyte determination in the presence of interferents. Consumption of organic solvents for cleaning, extraction and separation are markedly decreased because of the coupling with MCR-ALS (multivariate curve resolution/alternating least-squares) which allows the successful resolution in the presence of other co-eluting matrix constituents. Rigorous IUPAC detection limits were obtained: 6–24 ng L"−"1 in water, and 0.1–0.9 ng g"−"1 in sediments. Relative prediction errors were 2–10% (water) and 1–8% (sediments). - Highlights: • A green and simple chromatographic method for endocrine disruptors is proposed. • Diode array and fluorescence detectors are simultaneously used. • Eleven sex hormones are determined in water and sediment samples. • Outstanding selectivity is attained with MCR-ALS second-order algorithm. - Liquid chromatography coupled to chemometrics allows one to selectively and sensitively quantitate eleven endocrine disruptors in challenging scenarios using a green analytical approach.

Principles of Pharmacology and Toxicology Also Govern Effects of Chemicals on the Endocrine System.

Science.gov (United States)

Autrup, Herman; Barile, Frank A; Blaauboer, Bas J; Degen, Gisela H; Dekant, Wolfgang; Dietrich, Daniel; Domingo, Jose L; Gori, Gio Batta; Greim, Helmuth; Hengstler, Jan G; Kacew, Sam; Marquardt, Hans; Pelkonen, Olavi; Savolainen, Kai; Vermeulen, Nico P

2015-07-01

The present debate on chemicals with Hormonal activity, often termed 'endocrine disruptors', is highly controversial and includes challenges of the present paradigms used in toxicology and in hazard identification and risk characterization. In our opinion, chemicals with hormonal activity can be subjected to the well-evaluated health risk characterization approach used for many years including adverse outcome pathways. Many of the points arguing for a specific approach for risk characterization of chemicals with hormonal activity are based on highly speculative conclusions. These conclusions are not well supported when evaluating the available information. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Transcriptomics and in vivo tests reveal novel mechanisms underlying endocrine disruption in an ecological sentinel, Nucella lapillus.

Science.gov (United States)

Pascoal, Sonia; Carvalho, Gary; Vasieva, Olga; Hughes, Roger; Cossins, Andrew; Fang, Yongxiang; Ashelford, Kevin; Olohan, Lisa; Barroso, Carlos; Mendo, Sonia; Creer, Simon

2013-03-01

Anthropogenic endocrine disruptors now contaminate all environments globally, with concomitant deleterious effects across diverse taxa. While most studies on endocrine disruption (ED) have focused on vertebrates, the superimposition of male sexual characteristics in the female dogwhelk, Nucella lapillus (imposex), caused by organotins, provides one of the most clearcut ecological examples of anthropogenically induced ED in aquatic ecosystems. To identify the underpinning mechanisms of imposex for this 'nonmodel' species, we combined Roche 454 pyrosequencing with custom oligoarray fabrication inexpensively to both generate gene models and identify those responding to chronic tributyltin (TBT) treatment. The results supported the involvement of steroid, neuroendocrine peptide hormone dysfunction and retinoid mechanisms, but suggested additionally the involvement of putative peroxisome proliferator-activated receptor (PPAR) pathways. Application of rosiglitazone, a well-known vertebrate PPARγ ligand, to dogwhelks induced imposex in the absence of TBT. Thus, while TBT-induced imposex is linked to the induction of many genes and has a complex phenotype, it is likely also to be driven by PPAR-responsive pathways, hitherto not described in invertebrates. Our findings provide further evidence for a common signalling pathway between invertebrate and vertebrate species that has previously been overlooked in the study of endocrine disruption. © 2012 Blackwell Publishing Ltd.

CE with a boron-doped diamond electrode for trace detection of endocrine disruptors in water samples.

Science.gov (United States)

Browne, Damien J; Zhou, Lin; Luong, John H T; Glennon, Jeremy D

2013-07-01

Off-line SPE and CE coupled with electrochemical detection have been used for the determination of bisphenol A (BPA), bisphenol F, 4-ethylphenol, and bisphenol A diglycidyl ether in bottled drinking water. The use of boron-doped diamond electrode as an electrochemical detector in amperometric mode that provides a favorable analytical performance for detecting these endocrine-disrupting compounds, such as lower noise levels, higher peak resolution with enhanced sensitivity, and improved resistance against electrode passivation. The oxidative electrochemical detection of the endocrine-disrupting compounds was accomplished by boron-doped diamond electrode poised at +1.4 V versus Ag/AgCl without electrode pretreatment. An off-line SPE procedure (Bond Elut® C18 SPE cartridge) was utilized to extract and preconcentrate the compounds prior to separation and detection. The minimum concentration detectable for all four compounds ranged from 0.01 to 0.06 μM, having S/N equal to three. After exposing the plastic bottle water container under sunlight for 7 days, the estimated concentration of BPA in the bottled drinking water was estimated to be 0.03 μM. This proposed approach has great potential for rapid and effective determination of BPA content present in water packaging of plastic bottles that have been exposed to sunlight for an extended period of time. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of androgen receptor antagonists: In vitro investigation and classification methodology for flavonoid.

Science.gov (United States)

Wu, Yang; Doering, Jon A; Ma, Zhiyuan; Tang, Song; Liu, Hongling; Zhang, Xiaowei; Wang, Xiaoxiang; Yu, Hongxia

2016-09-01

A tremendous gap exists between the number of potential endocrine disrupting chemicals (EDCs) possibly in the environment and the limitation of traditional regulatory testing. In this study, the anti-androgenic potencies of 21 flavonoids were analyzed in vitro, and another 32 flavonoids from the literature were selected as additional chemicals. Molecular dynamic simulations were employed to obtain four different separation approaches based on the different behaviors of ligands and receptors during the process of interaction. Specifically, ligand-receptor complex which highlighted the discriminating features of ligand escape or retention via "mousetrap" mechanism, hydrogen bonds formed during simulation times, ligand stability and the stability of the helix-12 of the receptor were investigated. Together, a methodology was generated that 87.5% of flavonoids could be discriminated as active versus inactive antagonists, and over 90% inactive antagonists could be filtered out before QSAR study. This methodology could be used as a "proof of concept" to identify inactive anti-androgenic flavonoids, as well could be beneficial for rapid risk assessment and regulation of multiple new chemicals for androgenicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Endocrine disruptors and the breast: early life effects and later life disease.

Science.gov (United States)

Macon, Madisa B; Fenton, Suzanne E

2013-03-01

Breast cancer risk has both heritable and environment/lifestyle components. The heritable component is a small contribution (5-27 %), leaving the majority of risk to environment (e.g., applied chemicals, food residues, occupational hazards, pharmaceuticals, stress) and lifestyle (e.g., physical activity, cosmetics, water source, alcohol, smoking). However, these factors are not well-defined, primarily due to the enormous number of factors to be considered. In both humans and rodent models, environmental factors that act as endocrine disrupting compounds (EDCs) have been shown to disrupt normal mammary development and lead to adverse lifelong consequences, especially when exposures occur during early life. EDCs can act directly or indirectly on mammary tissue to increase sensitivity to chemical carcinogens or enhance development of hyperplasia, beaded ducts, or tumors. Protective effects have also been reported. The mechanisms for these changes are not well understood. Environmental agents may also act as carcinogens in adult rodent models, directly causing or promoting tumor development, typically in more than one organ. Many of the environmental agents that act as EDCs and are known to affect the breast are discussed. Understanding the mechanism(s) of action for these compounds will be critical to prevent their effects on the breast in the future.

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

Science.gov (United States)

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

A study of the prostate, androgens and sexual activity of male rats

Directory of Open Access Journals (Sweden)

Garcia Luis I

2007-03-01

Full Text Available Abstract Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i testosterone in serum by solid phase RIA, (ii androgen receptors at the ventral prostate with Western Blots, and (iii androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four

Occurrence of testicular microlithiasis in androgen insensitive hypogonadal mice

Directory of Open Access Journals (Sweden)

De Gendt Karl

2009-08-01

Full Text Available Abstract Background Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM. Methods This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs on the Sertoli cells (SCARKO, mice with a ubiquitous loss of androgen ARs (ARKO, hypogonadal (hpg mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO and ARKO (hpg.ARKO mice. Results Microscopic TM was seen in 94% of hpg.ARKO mice (n = 16 and the mean number of microliths per testis was 81 +/- 54. Occasional small microliths were seen in 36% (n = 11 of hpg testes (mean 2 +/- 0.5 per testis and 30% (n = 10 of hpg.SCARKO testes (mean 8 +/- 6 per testis. No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice. Conclusion We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression.

Androgens and estrogens in skeletal sexual dimorphism

Directory of Open Access Journals (Sweden)

Michaël Laurent

2014-04-01

Full Text Available Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T to estradiol (E2 by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis.

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Directory of Open Access Journals (Sweden)

Lin Hui-Ping

2011-08-01

Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

Inhibition of connexin43 gap junction channels by the endocrine disruptor ioxynil

International Nuclear Information System (INIS)

Leithe, Edward; Kjenseth, Ane; Bruun, Jarle; Sirnes, Solveig; Rivedal, Edgar

2010-01-01

Gap junctions are intercellular plasma membrane domains containing channels that mediate transport of ions, metabolites and small signaling molecules between adjacent cells. Gap junctions play important roles in a variety of cellular processes, including regulation of cell growth and differentiation, maintenance of tissue homeostasis and embryogenesis. The constituents of gap junction channels are a family of trans-membrane proteins called connexins, of which the best-studied is connexin43. Connexin43 functions as a tumor suppressor protein in various tissue types and is frequently dysregulated in human cancers. The pesticide ioxynil has previously been shown to act as an endocrine disrupting chemical and has multiple effects on the thyroid axis. Furthermore, both ioxynil and its derivative ioxynil octanoate have been reported to induce tumors in animal bioassays. However, the molecular mechanisms underlying the possible tumorigenic effects of these compounds are unknown. In the present study we show that ioxynil and ioxynil octanoate are strong inhibitors of connexin43 gap junction channels. Both compounds induced rapid loss of connexin43 gap junctions at the plasma membrane and increased connexin43 degradation. Ioxynil octanoate, but not ioxynil, was found to be a strong activator of ERK1/2. The compounds also had different effects on the phosphorylation status of connexin43. Taken together, the data show that ioxynil and ioxynil octanoate are potent inhibitors of intercellular communication via gap junctions.

Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Science.gov (United States)

Harada, Shusaku; Hiromori, Youhei; Nakamura, Shota; Kawahara, Kazuki; Fukakusa, Shunsuke; Maruno, Takahiro; Noda, Masanori; Uchiyama, Susumu; Fukui, Kiichi; Nishikawa, Jun-Ichi; Nagase, Hisamitsu; Kobayashi, Yuji; Yoshida, Takuya; Ohkubo, Tadayasu; Nakanishi, Tsuyoshi

2015-02-01

Organotin compounds such as triphenyltin (TPT) and tributyltin (TBT) act as endocrine disruptors through the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. We recently found that TPT is a particularly strong agonist of PPARγ. To elucidate the mechanism underlying organotin-dependent PPARγ activation, we here analyzed the interactions of PPARγ ligand-binding domain (LBD) with TPT and TBT by using X-ray crystallography and mass spectroscopy in conjunction with cell-based activity assays. Crystal structures of PPARγ-LBD/TBT and PPARγ-LBD/TPT complexes were determined at 1.95 Å and 1.89 Å, respectively. Specific binding of organotins is achieved through non-covalent ionic interactions between the sulfur atom of Cys285 and the tin atom. Comparisons of the determined structures suggest that the strong activity of TPT arises through interactions with helix 12 of LBD primarily via π-π interactions. Our findings elucidate the structural basis of PPARγ activation by TPT.

Combined exposure to endocrine disrupting pesticides impairs parturition and causes pup mortality in rats

DEFF Research Database (Denmark)

Hansen, Pernille Reimer; Christiansen, Sofie; Boberg, Julie

from gestational day 7 to postnatal day (PND)13 with either vehicle (control) or a mixture of the five pesticides at 25%, 50%, 75% or 100% of their individual NOAELs for causing major effects on pregnancy length and pup survival in our earlier studies. The pregnancy length was dose....... Although laboratory animal studies have shown that some endocrine disrupting pesticides can affect reproduction and sexual differentiation, individual pesticides may appear to be present in human tissues at too low levels to cause concern for adverse reproductive effects. However, recent studies in our...... laboratory have shown that combined exposure to endocrine disrupters can cause adverse effects on male sexual development, even though the doses of the single compounds are below their individual NOAELs for anti-androgenic effects. Here, we present results from range finding studies with combined exposure...

The six most widely used selective serotonin reuptake inhibitors decrease androgens and increase estrogens in the H295R cell line

DEFF Research Database (Denmark)

Hansen, Cecilie Hurup; Larsen, Lizette Weber; Sørensen, Amalie Møller

2017-01-01

Selective serotonin reuptake inhibitors (SSRIs) used as first line of treatment in major depressive disorder (MDD) are known to exert negative effects on the endocrine system and fertility. The aim of the present study was to investigate the possible endocrine disrupting effect of six SSRIs...... in the pathway. Furthermore, all SSRIs relatively increased the estrogen/androgen ratio, indicating stimulating effects on the aromatase. Our study demonstrates the potential of SSRIs to interfere with steroid production in the H295R cells around Cmax levels and indicates that these drugs should be investigated...... validated LC-MS/MS method. All 6 SSRIs were found to exert endocrine disrupting effects on steroid hormone synthesis at concentrations just around Cmax. Although the mechanisms of disruption were all different, they all resulted in decreased testosterone levels, some due to effects on CYP17, some earlier...

Assessment of the effects of the carbamazepine on the endogenous endocrine system of Daphnia magna.

Science.gov (United States)

Oropesa, A L; Floro, A M; Palma, P

2016-09-01

In the present study, the endocrine activity of the antiepileptic pharmaceutical carbamazepine (CBZ) in the crustacean Daphnia magna was assessed. To assess the hormonal activity of the drug, we exposed maternal daphnids and embryos to environmental relevant concentrations of CBZ (ranging from 10 to 200 μg/L) and to mixtures of CBZ with fenoxycarb (FEN; 1 μg/L). Chronic exposure to CBZ significantly decreased the reproductive output and the number of molts of D. magna at 200 μg/L. This compound induced the production of male offspring (12 ± 1.7 %), in a non-concentration-dependent manner, acting as a weak juvenile hormone analog. Results showed that this substance, at tested concentrations, did not antagonize the juvenoid action of FEN. Further, CBZ has shown to be toxic to daphnid embryos through maternal exposure interfering with their normal gastrulation and organogenesis stages but not producing direct embryo toxicity. These findings suggest that CBZ could act as an endocrine disruptor in D. magna as it decreases the reproductive output, interferes with sex determination, and causes development abnormality in offspring. Therefore, CBZ could directly affect the population sustainability.

Vinclozolin: a case study on the identification of endocrine active substances in the past and a future perspective.

Science.gov (United States)

van Ravenzwaay, Bennard; Kolle, Susanne N; Ramirez, Tzutzuy; Kamp, Hennicke G

2013-12-16

In the late 1980s vinclozolin was tested for prenatal developmental toxicity in rats for registration purposes in USA. At 1000mg/kgbw, 95% of all fetuses were female upon visual inspection (ano-genital distance determination). Anti-androgenic effects (AA) were also noted in a subsequent 2-generation study. These findings triggered mechanistic investigations at BASF and at US-EPA. Results published by the latter were the starting point of the endocrine disruption (ED) discussion in the 1990s. AA effects of vinclozolin are mediated by two metabolites, which have an antagonistic effect on the androgen receptor. Currently, determination of ED has become a major end-point in toxicology testing and the US-EPA has set up an elaborated testing paradigm to fulfill this requirement. Future screening for ED can be improved making use of new technologies. ED modes of action can be determined by three alternative (3R) methods. Steroid synthesis in H295R cells (1), androgen-receptor binding in modified yeast (2) and metabolomics (3). Using vinclozolin as a case study, results indicate: (1) an effect on steroid synthesis in vitro, (2) an antagonistic effect on the androgen receptor and (3) that the metabolome profile of vinclozolin is similar to that of other receptor mediated anti-androgens (e.g. flutamide). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Testosterone conjugating activities in invertebrates: are they targets for endocrine disruptors?

Science.gov (United States)

Janer, G; Sternberg, R M; LeBlanc, G A; Porte, C

2005-02-10

processes can serve as targets for endocrine disrupting chemicals.

The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

Energy Technology Data Exchange (ETDEWEB)

Buoso, Erica; Galasso, Marilisa; Ronfani, Melania [Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia (Italy); Papale, Angela; Galbiati, Valentina [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy); Eberini, Ivano [Laboratorio di Biochimica e Biofisica Computazionale, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan (Italy); Marinovich, Marina [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy); Racchi, Marco [Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12/14, 27100 Pavia (Italy); Corsini, Emanuela, E-mail: emanuela.corsini@unimi.it [Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano (Italy)

2017-06-15

We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system. - Highlights: • RACK1 expression can be induced by AR agonists with a consequent enhancement of the response to LPS. • RACK1 can be negatively modulated by the AR antagonists DDT and its main metabolite p,p′DDE. • RACK1 can be a relevant target of EDCs, representing a bridge between the endocrine system and the immune system.

The emerging role of the androgen receptor in bladder cancer.

Science.gov (United States)

Lombard, Alan P; Mudryj, Maria

2015-10-01

Men are three to four times more likely to get bladder cancer than women. The gender disparity characterizing bladder cancer diagnoses has been investigated. One hypothesis is that androgen receptor (AR) signaling is involved in the etiology and progression of this disease. Although bladder cancer is not typically described as an endocrine-related malignancy, it has become increasingly clear that AR signaling plays a role in bladder tumors. This review summarizes current findings regarding the role of the AR in bladder cancer. We discuss work demonstrating AR expression in bladder cancer and its role in promoting formation and progression of tumors. Additionally, we discuss the therapeutic potential of targeting the AR in this disease. © 2015 Society for Endocrinology.

Selected endocrine disrupting compounds (vinclozolin, flutamide, ketoconazole and dicofol): effects on survival, occurrence of males, growth, molting and reproduction of Daphnia magna.

Science.gov (United States)

Haeba, Maher H; Hilscherová, Klára; Mazurová, Edita; Bláha, Ludek

2008-05-01

Pollution-induced endocrine disruption in vertebrates and invertebrates is a worldwide environmental problem, but relatively little is known about effects of endocrine disrupting compounds (EDCs) in planktonic crustaceans (including Daphnia magna). Aims of the present study were to investigate acute 48 h toxicity and sub-chronic (4-6 days) and chronic (21 days) effects of selected EDCs in D. magna. We have investigated both traditional endpoints as well as other parameters such as sex determination, maturation, molting or embryogenesis in order to evaluate the sensitivity and possible use of these endpoints in ecological risk assessment. We have studied effects of four model EDCs (vinclozolin, flutamide, ketoconazole and dicofol) on D. magna using (i) an acute 48 h immobilization assay, (ii) a sub-chronic, 4-6 day assay evaluating development and the sex ratio of neonates, and (iii) a chronic, 21 day assay studying number of neonates, sex of neonates, molting frequency, day of maturation and the growth of maternal organisms. Acute EC50 values in the 48 h immobilization test were as follows (mg/L): dicofol 0.2, ketoconazole 1.5, flutamide 2.7, vinclozolin >3. Short-term, 4-6 day assays with sublethal concentrations showed that the sex ratio in Daphnia was modulated by vinclozolin (decreased number of neonate males at 1 mg/L) and dicofol (increase in males at 0.1 mg/L). Flutamide (up to 1 mg/L) had no effect on the sex of neonates, but inhibited embryonic development at certain stages during chronic assay, resulting in abortions. Ketoconazole had no significant effects on the studied processes up to 1 mg/L. Sex ratio modulations by some chemicals (vinclozolin and dicofol) corresponded to the known action of these compounds in vertebrates (i.e. anti-androgenicity and anti-oestrogenicity, respectively). Our study revealed that some chemicals known to affect steroid-regulated processes in vertebrates can also affect sublethal endpoints (e.g. embryonic sex determination

Verification of responses of Japanese medaka (Oryzias latipes) to anti-androgens, vinclozolin and flutamide, in short-term assays.

Science.gov (United States)

Nakamura, Ataru; Takanobu, Hitomi; Tamura, Ikumi; Yamamuro, Masumi; Iguchi, Taisen; Tatarazako, Norihisa

2014-05-01

Various testing methods for the detection of the endocrine disruptive activities of chemicals have been developed in freshwater fish species. However, a few relatively easier specific methods for detecting anti-androgenic activities are available for fish. The aim of this study was to verify the papillary process in Japanese medaka (Oryzias latipes) as an indicator of the anti-androgenic activity of chemicals. Japanese medaka were exposed to two types of anti-androgenic compounds, vinclozolin and flutamide, using two short-term assays; one was conformed to the existing short-term reproduction assay using adult fish (adult test) and the other was a test based on the same methods but using juvenile fish at the beginning of exposure (juvenile test). Significant decreases in male papillary processes were observed in the juvenile test treated with the highest concentration of both antiandrogens (640 µg l(-1) vinclozolin and 1000 µg l(-1) flutamide); however, no significant effects were observed in the adult test. Consequently, our results indicate that papillary processes in Japanese medaka can be used as the end-point for screening the anti-androgenic activity of chemicals using juvenile fish for a specific period based on the existing short-term reproduction assay. Copyright © 2013 John Wiley & Sons, Ltd.

Radioimmunoassay of the androgen function at healthy children

International Nuclear Information System (INIS)

Milanov, S.; Grigorova, R.; Koparanova, O.

1998-01-01

The androgen function at 67 healthy children aged 1-18 years is studied. Three age groups (1-6 yrs., n=28; 7-12 yrs., n=19; 12-18 yrs., n=20) are examined. Measurements have been done of testosterone (T), Δ-4 androstenedione (Δ-4-A) and sex hormone binding globulin (SHBG) by RIA kits of the Merieux. 17-α-hydroxyprogesterone (17α-OHP), the basic precursor os the androgens, has been measured in the serum by the same RIA kits. An increase in T and Δ-4-A levels with age is observed with significantly higher levels for 12-18 year, compared to those of 1 - 6 years (p<0.02, p<0.002) and 7-12 years (p<0.001). There is reliably higher secretion of T and Δ-4-A in boys, compared to that in 12-18 year girls (p<0.01), while in groups of smaller children only a tendency has been established, probably due to the higher SD. Decrease of the SHBG levels with age has been determined. The lowest levels belong to the binding protein in boys of 12-18 (35.93 ± 8.19 nmol/l)), compared to the other boys as well as in girls in the groups of smaller children (p<0.01). SHBG correlates strong inversely with the levels of T and (Δ-4-A in the 12-18 year boys (8.05 ± 4.4 nmol/l; 19.9 ± 5.7 nmol/l). Probably the higher levels of the two androgens determine the decrease to the binding capacity of the SHBG between 7 and 18 age during sexual development in boys. Reliable difference between the levels of 17α OHP in the smaller groups (1 month - 1 yrs.; 7 - 12 yrs.), compared to the group od 12 - 17 yrs. (p<0.01) have been found. The present study determines referent ranges of the serum levels of T, Δ-4-A, SHBG and 17α OHP in healthy children aged 1 - 18 yrs. and provides information about androgen function in this age period. These hormones are important markers of androgen profile in many endocrine diseases in both sexes and the established reference range will serve for a prompt diagnosis and a regular therapeutic control in CAN, PCOS, hyperandrogenism etc

The current preference for the immuno-analytical ELISA method for quantitation of steroid hormones (endocrine disruptor compounds) in wastewater in South Africa.

Science.gov (United States)

Manickum, Thavrin; John, Wilson

2015-07-01

The availability of national test centers to offer a routine service for analysis and quantitation of some selected steroid hormones [natural estrogens (17-β-estradiol, E2; estrone, E1; estriol, E3), synthetic estrogen (17-α-ethinylestradiol, EE2), androgen (testosterone), and progestogen (progesterone)] in wastewater matrix was investigated; corresponding internationally used chemical- and immuno-analytical test methods were reviewed. The enzyme-linked immunosorbent assay (ELISA) (immuno-analytical technique) was also assessed for its suitability as a routine test method to quantitate the levels of these hormones at a sewage/wastewater treatment plant (WTP) (Darvill, Pietermaritzburg, South Africa), over a 2-year period. The method performance and other relevant characteristics of the immuno-analytical ELISA method were compared to the conventional chemical-analytical methodology, like gas/liquid chromatography-mass spectrometry (GC/LC-MS), and GC-LC/tandem mass spectrometry (MSMS), for quantitation of the steroid hormones in wastewater and environmental waters. The national immuno-analytical ELISA technique was found to be sensitive (LOQ 5 ng/L, LOD 0.2-5 ng/L), accurate (mean recovery 96%), precise (RSD 7-10%), and cost-effective for screening and quantitation of these steroid hormones in wastewater and environmental water matrix. A survey of the most current international literature indicates a fairly equal use of the LC-MS/MS, GC-MS/MS (chemical-analytical), and ELISA (immuno-analytical) test methods for screening and quantitation of the target steroid hormones in both water and wastewater matrix. Internationally, the observed sensitivity, based on LOQ (ng/L), for the steroid estrogens E1, E2, EE2, is, in decreasing order: LC-MSMS (0.08-9.54) > GC-MS (1) > ELISA (5) (chemical-analytical > immuno-analytical). At the national level, the routine, unoptimized chemical-analytical LC-MSMS method was found to lack the required sensitivity for meeting environmental

Chlropyrifos-methyl shows anti-androgenic activity without estrogenic activity in rats

International Nuclear Information System (INIS)

Kang, Hwan Goo; Jeong, Sang Hee; Cho, Joon Hyoung; Kim, Dong Gyu; Park, Jong Myung; Cho, Myung Haing

2004-01-01

Chlorpyrifos-methyl (CPM), an organophosphate insecticide, widely used for grain storage and agriculture, has been suspected as endocrine disrupter by a few in vitro studies. This study was performed to investigate the (anti-) estrogenicity and (anti-) androgenicity of CPM in vivo using immature rat uterotrophic assay and rat Hershberger assay. CPM with or without 17β-estradiol were administered to 20 days old female rats to investigate its (anti-) estrogenic activity. Uterine and vaginal weight, uterine epithelial cell height were not affected by the treatment of CPM (2, 10, 50, 250 mg/kg). CPM 250 mg/kg potentiated relative vagina weight in 17β-estradiol treated immature female rats without any changing of uterine weight. Relative liver weight was increased with decrease of body weight by CPM 250 mg/kg treatment. Uterine cell proliferation tested with bromodeoxyuridine labeling index was not observed in CPM treated rats. CPM with or without testosterone propionate were administered to castrated rat of 51 days old for 10 days to investigate the (anti-)androgenic activity,. The weight of relative and absolute androgen-dependent accessory sex organs; seminal vesicle with coagulating glands (SV/CG), ventral prostate gland (VP), glans penis (GP), levator ani plus bulbocarvernosus muscle (LABC) and Cowper's gland (CG,) were unchanged by the treatment of CPM alone. While CPM induced the increase of relative adrenal gland weight, CPM 50 mg/kg decreased the weights of CV/CG, VP, CG and LABC without change of GP without changing of GP when it was treated with TP. In conclusion, CPM dose not show estrogenic and anti-estrogenic activity in immature female rats, but it represents anti-androgenic activity by inhibition of the TP-stimulated increase of the weight of accessory sex organs

TR{alpha}- and TSH-mRNA levels after temporal exposition with methimazole in zebrafish, Danio rerio

Energy Technology Data Exchange (ETDEWEB)

Schulz, A.E.I.; Stocker, A.; Hollosi, L.; Schramm, K.W. [Inst. of Ecological Chemistry, GSF - National Research Center for Environment and Health (Germany)

2004-09-15

The group of dioxin and dioxin-like substances are highly persistent in the environment. There are evidences from present investigations that a variety of substances are capable of disrupting the endocrine system in the aquatic environment. These substances are called endocrine disruptors. Dioxin and related compounds can act as endocrine disruptors. Aquatic animals like amphibian and fish are especially affected of the impact of these compounds. Investigations concerned so far in particular the domain of reproduction biology and the thyroid axis especially. Recent investigations showed that the TR{alpha}-mRNA level change after a short temporal expression with T3, methimazole and amiodarone. The objective of the project is to identify effects of thyroid endocrine disruptors on the regulation of gene expression of the thyroid receptors TR{alpha}a, TR{beta} and thyroid stimulating hormone TSH and associated effects on other system. In preliminary studies the effects of the drug methimazole as model substance on gene expression of TR{alpha} and TSH were investigated. Methimazole is an inhibitor of the thyroid peroxidase so that the formation of thyroid hormones is disrupted.

Androgen responses to reproductive competition of males pursuing either fixed or plastic alternative reproductive tactics.

Science.gov (United States)

von Kuerthy, Corinna; Ros, Albert F H; Taborsky, Michael

2016-11-15

Alternative reproductive tactics (ARTs), which can be plastic or fixed for life, may be characterized by distinct hormonal profiles. The relative plasticity hypothesis predicts flexible androgen regulation for adult males pursuing plastic tactics, but a less flexible regulation for males using a fixed tactic throughout life. Furthermore, androgen profiles may respond to changes in the social environment, as predicted by the social reciprocity models of hormone/behaviour interactions. The cichlid fish Lamprologus callipterus provides a rare opportunity to study the roles of androgens for male ARTs within a single species, because fixed and plastic ARTs coexist. We experimentally exposed males to competitors pursuing either the same or different tactics to test predictions of the relative plasticity and the social reciprocity models. Androgen profiles of different male types partly comply with predictions derived from the relative plasticity hypothesis: males of the plastic bourgeois/sneaker male trajectory showed different 11-ketotestosterone (11-KT) levels when pursuing either bourgeois or parasitic sneaker male behaviours. Surprisingly, males pursuing the fixed dwarf male tactic showed the highest free and conjugated 11-KT and testosterone (T) levels. Our experimental social challenges significantly affected the free 11-KT levels of bourgeois males, but the androgen responses did not differ between challenges involving different types of competitors. Furthermore, the free T-responses of the bourgeois males correlated with their aggressive behaviour exhibited against competitors. Our results provide new insights into the endocrine responsiveness of fixed and plastic ARTs, confirming and refuting some predictions of both the relative plasticity and the social reciprocity models. © 2016. Published by The Company of Biologists Ltd.

Vitamin D, PCOS and androgens in men: a systematic review

Directory of Open Access Journals (Sweden)

Christian Trummer

2018-03-01

Full Text Available Background: Accumulating evidence from animal and human studies suggests that vitamin D is involved in many functions of the reproductive system in both genders. Aim: The aim of this review was to provide an overview on the effects of vitamin D on polycystic ovary syndrome (PCOS in women and androgen metabolism in men. Methods: We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017. Results and discussion: The vitamin D receptor and vitamin D-metabolizing enzymes are found in reproductive tissues of women and men. In women, vitamin D status has been associated with several features of PCOS. In detail, cross-sectional data suggest a regulatory role of vitamin D in PCOS-related aspects such as ovulatory dysfunction, insulin resistance as well as hyperandrogenism. Moreover, results from randomized controlled trials (RCTs suggest that vitamin D supplementation may be beneficial for metabolic, endocrine and fertility aspects in PCOS. In men, vitamin D status has been associated with androgen levels and hypogonadism. Further, there is some evidence for a favorable effect of vitamin D supplementation on testosterone concentrations, although others failed to show a significant effect on testosterone levels. Conclusion: In summary, vitamin D deficiency is associated with adverse fertility outcomes including PCOS and hypogonadism, but the evidence is insufficient to establish causality. High-quality RCTs are needed to further evaluate the effects of vitamin D supplementation in PCOS women as well as on androgen levels in men.

Incorporating Health Impacts from Exposure to Chemicals in Food Packaging in LCA

DEFF Research Database (Denmark)

Ernstoff, Alexi; Trier, Xenia; Jolliet, Oliver

2014-01-01

Life cycle assessments (LCA) on the environmental and public health impacts of food and beverage packaging materials have found some advantages to plastic over glass. Entirely missing from these evaluations are the health impacts of possible chemical, e.g. endocrine dis-ruptor, exposure through...... migration of chemicals from the packaging into the food product. We build a framework based on a life cycle perspective to predict which chemicals may be in a package that are not intentionally added ingredients, and we apply this approach to the US EPA’s CPCAT database. In total we find 1,154 chemicals...... within the CPCAT database related to food-contact materials; out of these 107 are potential endocrine disruptors according to the TEDX list of endocrine disruptors. We also build a framework in an effort to begin harmonizing LCA to include health impacts of chemical exposure related to food packaging...

The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS.

Science.gov (United States)

Baculescu, N

2013-03-15

Polycystic ovary syndrome (PCOS), one of the most common and complex endocrine disorders affecting up to 15 % of reproductive age women, is considered a predominantly hyperandrogenic syndrome according to the Androgen Excess Society. It is generally accepted that androgens determine the characteristic features of PCOS; in this context, a hyperactive androgen receptor (AR) at the levels of the GnRH pulse generator in the hypothalamus and at the granulosa cells in the ovary, skeletal muscle or adipocytes senses initially normal testosterone and dihydrotestosterone as biochemical hyperandrogenism and might be a crucial connection between the vicious circles of the PCOS pathogenesis. Polymorphism of the AR gene has been associated with different androgen pattern diseases. Several studies have demonstrated an association between AR with increased activity encoded by shorter CAG repeat polymorphism in the exon 1 of the AR gene and PCOS, although there are conflicting results in this field. The phenomenon is more complex because the AR activity is determined by the epigenetic effect of X chromosome inactivation (XCI). Moreover, we must evaluate the AR as a dynamic heterocomplex, with a large number of coactivators and corepressors that are essential to its function, thus mediating tissue-specific effects. In theory, any of these factors could modify the activity of AR, which likely explains the inconsistent results obtained when this activity was quantified by only the CAG polymorphism in PCOS.

The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

International Nuclear Information System (INIS)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

2010-01-01

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Molecular basis of androgen insensitivity

NARCIS (Netherlands)

Brinkmann, A.; Jenster, G.; Ris-Stalpers, C.; van der Korput, H.; Brüggenwirth, H.; Boehmer, A.; Trapman, J.

1996-01-01

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the

Endocrine and molecular investigations in a cohort of 25 adolescent males with prominent/persistent pubertal gynecomastia.

Science.gov (United States)

Paris, F; Gaspari, L; Mbou, F; Philibert, P; Audran, F; Morel, Y; Biason-Lauber, A; Sultan, C

2016-03-01

Pubertal gynecomastia is a common condition observed in up to 65% of adolescent males. It is usually idiopathic and tends to regress within 1-2 years. In this descriptive cross-sectional study, we investigated 25 adolescent males with prominent (>B3) and/or persistent (>2 years) pubertal gynecomastia (P/PPG) to determine whether a hormonal/genetic defect might underline this condition. Endocrine investigation revealed the absence of hormonal disturbance for 18 boys (72%). Three patients presented Klinefelter syndrome and three a partial androgen insensitivity syndrome (PAIS) as a result of p.Ala646Asp and p.Ala45Gly mutations of the androgen receptor gene. The last patient showed a 17α-hydroxylase/17,20-lyase deficiency as a result of a compound heterozygous mutation of the CYP17A1 gene leading to p.Pro35Thr(P35T) and p.Arg239Stop(R239X) in the P450c17 protein. Enzymatic activity was analyzed: the mutant protein bearing the premature stop codon R239X showed a complete loss of 17α-hydroxylase and 17,20-lyase activity. The mutant P35T seemed to retain 15-20% of 17α-hydroxylase and about 8-10% of 17,20-lyase activity. This work demonstrates that P/PPG had an endocrine/genetic cause in 28% of our cases. PAIS may be expressed only by isolated gynecomastia as well as by 17α-hydroxylase/17,20-lyase deficiency. Isolated P/PPG is not always a 'physiological' condition and should thus be investigated through adequate endocrine and genetic investigations, even though larger studies are needed to better determine the real prevalence of genetic defects in such patients. © 2016 American Society of Andrology and European Academy of Andrology.

From 'omics to otoliths: responses of an estuarine fish to endocrine disrupting compounds across biological scales.

Science.gov (United States)

Brander, Susanne M; Connon, Richard E; He, Guochun; Hobbs, James A; Smalling, Kelly L; Teh, Swee J; White, J Wilson; Werner, Inge; Denison, Michael S; Cherr, Gary N

2013-01-01

Endocrine disrupting chemicals (EDCs) cause physiological abnormalities and population decline in fishes. However, few studies have linked environmental EDC exposures with responses at multiple tiers of the biological hierarchy, including population-level effects. To this end, we undertook a four-tiered investigation in the impacted San Francisco Bay estuary with the Mississippi silverside (Menidia audens), a small pelagic fish. This approach demonstrated links between different EDC sources and fish responses at different levels of biological organization. First we determined that water from a study site primarily impacted by ranch run-off had only estrogenic activity in vitro, while water sampled from a site receiving a combination of urban, limited ranch run-off, and treated wastewater effluent had both estrogenic and androgenic activity. Secondly, at the molecular level we found that fish had higher mRNA levels for estrogen-responsive genes at the site where only estrogenic activity was detected but relatively lower expression levels where both estrogenic and androgenic EDCs were detected. Thirdly, at the organism level, males at the site exposed to both estrogens and androgens had significantly lower mean gonadal somatic indices, significantly higher incidence of severe testicular necrosis and altered somatic growth relative to the site where only estrogens were detected. Finally, at the population level, the sex ratio was significantly skewed towards males at the site with measured androgenic and estrogenic activity. Our results suggest that mixtures of androgenic and estrogenic EDCs have antagonistic and potentially additive effects depending on the biological scale being assessed, and that mixtures containing androgens and estrogens may produce unexpected effects. In summary, evaluating EDC response at multiple tiers is necessary to determine the source of disruption (lowest scale, i.e. cell line) and what the ecological impact will be (largest scale, i

Androgen receptor activation: a prospective therapeutic target for bladder cancer?

Science.gov (United States)

Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

2017-03-01

Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

Androgen Bioassay for the Detection of Nonlabeled Androgenic Compounds in Nutritional Supplements.

Science.gov (United States)

Cooper, Elliot R; McGrath, Kristine C Y; Li, XiaoHong; Heather, Alison K

2018-01-01

Both athletes and the general population use nutritional supplements. Athletes often turn to supplements hoping that consuming the supplement will help them be more competitive and healthy, while the general population hopes to improve body image or vitality. While many supplements contain ingredients that may have useful properties, there are supplements that are contaminated with compounds that are banned for use in sport or have been deliberately adulterated to fortify a supplement with an ingredient that will produce the advertised effect. In the present study, we have used yeast cell and mammalian cell androgen bioassays to characterize the androgenic bioactivity of 112 sports supplements available from the Australian market, either over the counter or via the Internet. All 112 products did not declare an androgen on the label as an included ingredient. Our findings show that six out of 112 supplements had strong androgenic bioactivity in the yeast cell bioassay, indicating products spiked or contaminated with androgens. The mammalian cell bioassay confirmed the strong androgenic bioactivity of five out of six positive supplements. Supplement 6 was metabolized to weaker androgenic bioactivity in the mammalian cells. Further to this, Supplement 6 was positive in a yeast cell progestin bioassay. Together, these findings highlight that nutritional supplements, taken without medical supervision, could expose or predispose users to the adverse consequences of androgen abuse. The findings reinforce the need to increase awareness of the dangers of nutritional supplements and highlight the challenges that clinicians face in the fast-growing market of nutritional supplements.

Microbial degradation of endocrine disruptors

Czech Academy of Sciences Publication Activity Database

Křesinová, Zdena; Svobodová, Kateřina; Cajthaml, Tomáš

2009-01-01

Roč. 103, č. 3 (2009), s. 200-207 ISSN 0009-2770 R&D Projects: GA MŠk LC06066; GA AV ČR KJB600200613 Institutional research plan: CEZ:AV0Z50200510 Keywords : WHITE-ROT FUNGI * ALKYLPHENOL POLYETHOXYLATE SURFACTANTS * POWDERED ACTIVATED CARBON Subject RIV: EE - Microbiology, Virology Impact factor: 0.717, year: 2009

Characterization of estrogen and androgen activity of food contact materials by different in vitro bioassays (YES, YAS, ERα and AR CALUX and chromatographic analysis (GC-MS, HPLC-MS.

Directory of Open Access Journals (Sweden)

Johannes Mertl

Full Text Available Endocrine active substances (EAS show structural similarities to natural hormones and are suspected to affect the human endocrine system by inducing hormone dependent effects. Recent studies with in vitro tests suggest that EAS can leach from packaging into food and may therefore pose a risk to human health. Sample migrates from food contact materials were tested for estrogen and androgen agonists and antagonists with different commonly used in vitro tests. Additionally, chemical trace analysis by GC-MS and HPLC-MS was used to identify potential hormone active substances in sample migrates. A GC-MS method to screen migrates for 29 known or potential endocrine active substances was established and validated. Samples were migrated according to EC 10/2011, concentrated by solid phase extraction and tested with estrogen and androgen responsive reporter gene assays based on yeast cells (YES and YAS or human osteoblast cells (ERα and AR CALUX. A high level of agreement between the different bioassays could be observed by screening for estrogen agonists. Four out of 18 samples tested showed an estrogen activity in a similar range in both, YES and ERα CALUX. Two more samples tested positive in ERα CALUX due to the lower limits of detection in this assay. Androgen agonists could not be detected in any of the tested samples, neither with YAS nor with AR CALUX. When testing for antagonists, significant differences between yeast and human cell-based bioassays were noticed. Using YES and YAS many samples showed a strong antagonistic activity which was not observed using human cell-based CALUX assays. By GC-MS, some known or supposed EAS were identified in sample migrates that showed a biological activity in the in vitro tests. However, no firm conclusions about the sources of the observed hormone activity could be obtained from the chemical results.

Histological characterization of peppermint shrimp ( Lysmata wurdemanni) androgenic gland

Science.gov (United States)

Liu, Xin; Zhang, Dong; Lin, Tingting

2017-12-01

The androgenic gland (AG) is an important endocrine gland for male reproductive function in crustaceans. In the present study, we investigated the histological characteristics of the androgenic gland of peppermint shrimp, Lysmata wurdemanni. The peppermint shrimp matures as male first, then some individuals may become euhermaphrodite after several moltings (transitional phase). Euhermaphrodite-phase shrimp acts as male at intermolts. However, it can be fertilized as a female immediately after molting. Considering the male reproductive function acts in its lifespan except for at larval stages, and female reproductive system starts to develop at transitional phase, we hypothesized that AG activity might be reduced to allow and promote vitellogenesis onset in early transitional phase and the following euhermaphrodite phase. So AG cell structure might be different in three phases in L. wurdemanni. The results showed that AG exists in the male in transitional and euhermaphrodite phases. The gland cell clusters surrounding the ejaculatory ducts locate at the roots of the fifth pereopods. The nucleus diameters are similar in the three phases while the nucleus- to-cell ratio is the lowest in euhermaphrodite phase. Our results indicated that for the individuals that will become euhermaphrodite, the cellular structure of AG changes since transitional phase. Male reproductive function which is still available in euhermaphrodite-phase shrimp should be due to the existence of the gland.

Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

NARCIS (Netherlands)

D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

1994-01-01

textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated

Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

Science.gov (United States)

Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

2008-07-01

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure.

Science.gov (United States)

Fragkaki, A G; Angelis, Y S; Koupparis, M; Tsantili-Kakoulidou, A; Kokotos, G; Georgakopoulos, C

2009-02-01

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone introduced for therapeutic purposes providing enhanced anabolic potency with reduced androgenic effects. Androgens mediate their action through their binding to the androgen receptor (AR) which is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system. This paper reviews some of the wide spectrum of testosterone and synthetic AAS structure modifications related to the intended enhancement in anabolic activity. The structural features of steroids necessary for effective binding to the AR and those which contribute to the stipulation of the androgenic and anabolic activities are also presented.

The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

2010-12-10

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Androgens and alopecia.

Science.gov (United States)

Kaufman, Keith D

2002-12-30

Androgens have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Androgenetic alopecia, referred to as male pattern hair loss (MPHL) in men and female pattern hair loss (FPHL) in women, is due to the progressive miniaturization of scalp hair. Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men. The development of finasteride, a type 2-selective 5alphaR inhibitor, further advanced our understanding of the role of DHT in the pathophysiology of scalp alopecia. Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies. In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL. Histopathological evaluation of scalp biopsies confirmed that finasteride treatment produced no benefit on scalp hair in these women. These findings suggest that MPHL and FPHL are distinct clinical entities, with disparate pathophysiologies. Studies that elucidate the molecular mechanisms by which androgens regulate hair growth would provide greater understanding of these differences. Copyright 2002 Elsevier Science Ireland Ltd.

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

International Nuclear Information System (INIS)

Zhang, Zheng; Jin, Bo; Jin, Yaqiong; Huang, Shengquan; Niu, Xiaohua; Mao, Zebin; Xin, Dianqi

2017-01-01

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

Effect of pharmaceutical potential endocrine disruptor compounds on protein disulfide isomerase reductase activity using di-eosin-oxidized-glutathione.

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Danièle Klett

Full Text Available BACKGROUND: Protein Disulfide Isomerase (PDI in the endoplasmic reticulum of all cells catalyzes the rearrangement of disulfide bridges during folding of membrane and secreted proteins. As PDI is also known to bind various molecules including hormones such as estradiol and thyroxin, we considered the hypothesis that adverse effects of endocrine-disrupter compounds (EDC could be mediated through their interaction with PDI leading to defects in membrane or secreted proteins. METHODOLOGY/PRINCIPAL FINDINGS: Taking advantage of the recent description of the fluorescence self quenched substrate di-eosin-oxidized-glutathione (DiE-GSSG, we determined kinetically the effects of various potential pharmaceutical EDCs on the in-vitro reductase activity of bovine liver PDI by measuring the fluorescence of the reaction product (E-GSH. Our data show that estrogens (ethynylestradiol and bisphenol-A as well as indomethacin exert an inhibition whereas medroxyprogesteroneacetate and nortestosterone exert a potentiation of bovine PDI reductase activity. CONCLUSIONS: The present data indicate that the tested EDCs could not only affect endocrine target cells through nuclear receptors as previously shown, but could also affect these and all other cells by positively or negatively affecting PDI activity. The substrate DiE-GSSG has been demonstrated to be a convenient substrate to measure PDI reductase activity in the presence of various potential EDCs. It will certainly be usefull for the screening of potential effect of all kinds of chemicals on PDI reductase activity.

High levels of endocrine pollutants in US streams during low flow due to insufficient wastewater dilution

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Rice, Jacelyn; Westerhoff, Paul

2017-08-01

Wastewater discharges from publicly owned treatment works are a significant source of endocrine disruptors and other contaminants to the aquatic environment in the US. Although remaining pollutants in wastewater pose environmental risks, treated wastewater is also a primary source of stream flow, which in turn is critical in maintaining many aquatic and riparian wildlife habitats. Here we calculate the dilution factor--the ratio of flow in the stream receiving discharge to the flow of wastewater discharge--for over 14,000 receiving streams in the continental US using streamflow observations and a spatially explicit watershed-scale hydraulic model. We found that wastewater discharges make up more than 50% of in-stream flow for over 900 streams. However, in 1,049 streams that experienced exceptional low-flow conditions, the dilution factors in 635 of those streams fell so low during those conditions that the safety threshold for concentrations of one endocrine disrupting compound was exceeded, and in roughly a third of those streams, the threshold was exceeded for two compounds. We suggest that streams are vulnerable to public wastewater discharge of contaminants under low-flow conditions, at a time when wastewater discharges are likely to be most important for maintaining stream flow for smaller sized river systems.

Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.

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De Laere, Bram; van Dam, Pieter-Jan; Whitington, Tom; Mayrhofer, Markus; Diaz, Emanuela Henao; Van den Eynden, Gert; Vandebroek, Jean; Del-Favero, Jurgen; Van Laere, Steven; Dirix, Luc; Grönberg, Henrik; Lindberg, Johan

2017-08-01

Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations. Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of

The impact of pesticides on oxidative stress level in human organism and their activity as an endocrine disruptor.

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Jabłońska-Trypuć, Agata; Wołejko, Elżbieta; Wydro, Urszula; Butarewicz, Andrzej

2017-07-03

Pesticides cause serious environmental and health problems both to humans and animals. The aim of this review is to discuss selected herbicides and fungicides regarding their mode of action and their influence on basic oxidative stress parameters and endocrine disruption properties tested in selected cell cultures in vitro. Because of numerous difficulties which animal studies are subject to, cell cultures are an excellent experimental model reflecting human exposure to different pesticides through all relevant routes. This experimental model can be used to monitor aggregate and cumulative pesticide exposures.

The influence of control group reproduction on the statistical power of the Environmental Protection Agency’s medaka Extended One-Generation Reproduction Test (MEOGRT)

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Because of various Congressional mandates to protect the environment from endocrine disrupting chemicals (EDCs), the United States Environmental Protection Agency (USEPA) initiated the Endocrine Disruptor Screening Program. In the context of this framework, the Office of Research...

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Directory of Open Access Journals (Sweden)

Marcel Cerqueira Cesar Machado

Full Text Available Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and

Genotoxic effects of environmental endocrine disruptors on the aquatic insect Chironomus riparius evaluated using the comet assay.

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Martínez-Paz, Pedro; Morales, Mónica; Martínez-Guitarte, José Luis; Morcillo, Gloria

2013-12-12

Genotoxicity is one of the most important toxic endpoints in chemical toxicity testing and environmental risk assessment. The aim of this study was to evaluate the genotoxic potential of various environmental pollutants frequently found in aquatic environments and characterized by their endocrine disrupting activity. Monitoring of DNA damage was undertaken after in vivo exposures of the aquatic larvae of the midge Chironomus riparius, a model organism that represents an abundant and ecologically relevant macroinvertebrate, widely used in freshwater toxicology. DNA-induced damage, resulting in DNA fragmentation, was quantified by the comet assay after short (24 h) and long (96 h) exposures to different concentrations of the selected toxicants: bisphenol A (BPA), nonylphenol (NP), pentachlorophenol (PCP), tributyltin (TBT) and triclosan (TCS). All five compounds were found to have genotoxic activity as demonstrated by significant increases in all the comet parameters (%DNA in tail, tail length, tail moment and Olive tail moment) at all tested concentrations. Persistent exposure did not increase the extent of DNA damage, except for TCS at the highest concentration, but generally there was a reduction in DNA damage thought to be associated with the induction of the detoxification processes and repairing mechanisms. Comparative analysis showed differences in the genotoxic potential between the chemicals, as well as significant time and concentration-dependent variations, which most likely reflect differences in the ability to repair DNA damage under the different treatments. The present report demonstrates the sensitivity of the benthic larvae of C. riparius to these environmental genotoxins suggesting its potential as biomonitor organism in freshwater ecosystems. The results obtained about the DNA-damaging potential of these environmental pollutants reinforce the need for additional studies on the genotoxicity of endocrine active substances that, by linking genotoxic

Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

Science.gov (United States)

Corbould, A

2008-10-01

Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd.

Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus.

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Habert, René; Livera, Gabriel; Rouiller-Fabre, Virginie

2014-01-01

Phthalates provide one of the most documented example evidencing how much we must be cautious when using the traditional paradigm based on extrapolation of experimental data from rodent studies for human health risk assessment of endocrine disruptors (EDs). Since foetal testis is known as one of the most sensitive targets of EDs, phthalate risk assessment is routinely based on the capacity of such compounds to decrease testosterone production by the testis or to impair masculinization in the rat during foetal life. In this paper, the well-established inhibiting effects of phthalates of the foetal Leydig cells function in the rat are briefly reviewed. Then, data obtained in humans and other species are carefully analysed. Already in January 2009, using the organotypic culture system named Fetal Testis Assay (FeTA) that we developed, we reported that phthalates might not affect testosterone production in human foetal testes. Several recent experimental studies using xenografts confirm the absence of detectable anti-androgenic effect of phthalates in the human foetal testes. Epidemiological studies led to contradictory results. Altogether, these findings suggest that phthalates effects on foetal Leydig cells are largely species-specific. Consequently, the phthalate threshold doses that disturb foetal steroidogenesis in rat testes and that are presently used to define the acceptable daily intake levels for human health protection must be questioned. This does not mean that phthalates are safe because these compounds have many deleterious effects upon germ cell development that may be common to the different studied species including human. More generally, the identification of common molecular, cellular or/and phenotypic targets in rat and human testes should precede the choice of the toxicological endpoint in rat to accurately assess the safety threshold of any ED in humans.

Quality of life issues relating to endocrine treatment options

DEFF Research Database (Denmark)

Iversen, P

1999-01-01

Recent interest has focused on the use of hormone therapy in prostate cancer for both the management of patients with non-metastatic disease and as a neoadjuvant or adjuvant to curative therapies. This has resulted in patients with fewer symptoms being treated for longer periods of time. Endocrine...... treatments for prostate cancer, such as castration, combined androgen blockade and non-steroidal antiandrogen monotherapy, have shown similar results in terms of time to progression and survival. The main difference between these treatments is their impact on patients' quality of life. Instruments...... for measuring health-related quality of life should assess both overall and disease-specific quality of life. Data from two large studies of bicalutamide monotherapy show that this non-steroidal antiandrogen is associated with significant health-related quality of life advantages in the treatment of patients...

Uterotrophic and Hershberger assays for endocrine disruption properties of plastic food contact materials polypropylene (PP) and polyethylene terephthalate (PET).

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Chung, Bu Young; Kyung, Minji; Lim, Seong Kwang; Choi, Seul Min; Lim, Duck Soo; Kwack, Seung Jun; Kim, Hyung Sik; Lee, Byung-Mu

2013-01-01

Plasticizers or plastic materials such as phthalates, bisphenol-A (BPA), and styrene are widely used in the plastic industry and are suspected endocrine-disrupting chemicals (EDC). Although plastic materials such as polypropylene (PP) and polyethylene terephthalate (PET) are not EDC and are considered to be safe, their potential properties as EDC have not been fully investigated. In this study, plastic samples eluted from plastic food containers (PP or PET) were investigated in Sprague-Dawley rats using Hershberger and uterotrophic assays. In the Hershberger assay, 6-wk-old castrated male rats were orally treated for 10 consecutive days with plastic effluent at 3 different doses (5 ml/kg) or vehicle control (corn oil, 1 ml/100 g) to determine the presence of both anti-androgenic and androgenic effects. Testosterone (0.4 mg/ml/kg) was subcutaneously administered for androgenic evaluation as a positive control, whereas testosterone (0.4 mg/ml/kg) and flutamide (3 mg/kg/day) were administered to a positive control group for anti-androgenic evaluation. The presence of any anti-androgenic or androgenic activities of plastic effluent was not detected. Sex accessory tissues such as ventral prostate or seminal vesicle showed no significant differences in weight between treated and control groups. For the uterotrophic assay, immature female rats were treated with plastic effluent at three different doses (5 ml/kg), with vehicle control (corn oil, 1 ml/100 g), or with ethinyl estradiol (3 μg/kg/d) for 3 d. There were no significant differences between test and control groups in vagina or uterine weight. Data suggest that effluents from plastic food containers do not appear to produce significant adverse effects according to Hershberger and uterotrophic assays.

Androgen Receptor Signaling in Bladder Cancer

Science.gov (United States)

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

Androgen Receptor Signaling in Bladder Cancer

Directory of Open Access Journals (Sweden)

Peng Li

2017-02-01

Full Text Available Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

NARCIS (Netherlands)

L.J. Blok (Leen); G.T.G. Chang; M. Steenbeek-Slotboom (M.); W.M. van Weerden (Wytske); H.G. Swarts; J.J.H.H.M. de Pont (J. J H H M); G.J. van Steenbrugge (Gert Jan); A.O. Brinkmann (Albert)

1999-01-01

textabstractThe β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of

EDSP Tier 2 test (T2T) guidances and protocols are delivered, including web-based guidance for diagnosing and scoring, and evaluating EDC-induced pathology in fish and amphibian

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The Agency’s Endocrine Disruptor Screening Program (EDSP) consists of two tiers. The first tier provides information regarding whether a chemical may have endocrine disruption properties. Tier 2 tests provide confirmation of ED effects and dose-response information to be us...

Towards an integrated biosensor array for simultaneous and rapid multi-analysis of endocrine disrupting chemicals

International Nuclear Information System (INIS)

Scognamiglio, Viviana; Pezzotti, Italo; Pezzotti, Gianni; Cano, Juan; Manfredonia, Ivano; Buonasera, Katia; Arduini, Fabiana; Moscone, Danila; Palleschi, Giuseppe; Giardi, Maria Teresa

2012-01-01

Highlights: ► A multitask biosensor for the detection of endocrine disrupting chemicals is proposed. ► The sensing system employ an array of biological recognition elements. ► Amperometric and optical transduction methods are provided in an integrated biosensor together with flow control systems. ► The biosensing device results in an integrated, automatic and portable system for environmental and agrifood application. - Abstract: In this paper we propose the construction and application of a portable multi-purpose biosensor array for the simultaneous detection of a wide range of endocrine disruptor chemicals (EDCs), based on the recognition operated by various enzymes and microorganisms. The developed biosensor combines both electrochemical and optical transduction systems, in order to increase the number of chemical species which can be monitored. Considering to the maximum residue level (MRL) of contaminants established by the European Commission, the biosensor system was able to detect most of the chemicals analysed with very high sensitivity. In particular, atrazine and diuron were detected with a limit of detection of 0.5 nM, with an RSD% less than 5%; paraoxon and chlorpyrifos were revealed with a detection of 5 μM and 4.5 μM, respectively, with an RSD% less than 6%; catechol and bisphenol A were identified with a limit of detection of 1 μM and 35 μM respectively, with an RSD% less than 5%.

Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

OpenAIRE

Chadha, D.; Pache, T.D.; Huikeshoven, Frans; Brinkmann, Albert; Kwast, Theo

1994-01-01

textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsexual female patients. This was compared with AR expression in the ovaries and uteri of premenopausal and postmenopausal women not receiving treatment and in 10 ovaries of female patients with polycy...

Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline

Science.gov (United States)

Legro, Richard S.; Arslanian, Silva A.; Ehrmann, David A.; Hoeger, Kathleen M.; Murad, M. Hassan; Pasquali, Renato; Welt, Corrine K.

2013-01-01

Objective: The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS). Participants: An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer developed the guideline. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. Conclusions: We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight

Selected personal care products and endocrine disruptors in biosolids: an Australia-wide survey.

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Langdon, Kate A; Warne, Michael St J; Smernik, Ronald J; Shareef, Ali; Kookana, Rai S

2011-02-15

Personal care products (PCPs) and endocrine disrupting compounds (EDCs) are groups of organic contaminants that have been detected in biosolids around the world. There is a shortage of data on these types on compounds in Australian biosolids, making it difficult to gain an understanding of their potential risks in the environment following land application. In this study, 14 biosolids samples were collected from 13 Australian wastewater treatment plants (WWTPs) to determine concentrations of eight compounds that are PCPs and/or EDCs: 4-t-octylphenol (4tOP), 4-nonylphenol (4NP), triclosan (TCS), bisphenol A (BPA), estrone (E1), 17β-estradiol (E2), estriol (E3) and 17α-ethinylestradiol (EE2). Concentration data were evaluated to determine if there were any differences between samples that had undergone anaerobic or aerobic treatment. The concentration data were also compared to other Australian and international data. Only 4tOP, 4NP, TCS, and BPA were detected in all samples and E1 was detected in four of the 14 samples. Their concentrations ranged from 0.05 to 3.08 mg/kg, 0.35 to 513 mg/kg, treatment showed significantly higher concentrations of the compounds than those obtained from WWTPs that used aerobic treatment. Overall, 4NP, TCS and BPA concentrations in Australian biosolids were lower than global averages (by 42%, 12% and 62%, respectively) and 4tOP concentrations were higher (by 25%), however, of these differences only that for BPA was statistically significant. The European Union limit value for NP in biosolids is 50 mg/kg, which 4 of the 14 samples in this study exceeded. Copyright © 2010 Elsevier B.V. All rights reserved.

Delta(9)-tetrahydrocannabinol inhibits 17beta-estradiol-induced proliferation and fails to activate androgen and estrogen receptors in MCF7 human breast cancer cells.

Science.gov (United States)

von Bueren, A O; Schlumpf, M; Lichtensteiger, W

2008-01-01

Delta(9)-tetrahydrocannabinol (THC) exerts palliative effects in cancer patients, but produces adverse effects on the endocrine and reproductive systems. Experimental evidence concerning such effects is controversial. Whether THC exhibits estrogenic or androgenic activity in vitro was investigated. Estrogenic effects of THC were analyzed in vitro by measuring the proliferation of estrogen-sensitive MCF7 cells. Androgenic activity was investigated by the A-Screen assay that measures androgen-dependent inhibition of proliferation of the androgen receptor (AR)-positive human mammary carcinoma cell line, MCF7-AR1. In contrast to 17beta-estradiol, included as positive control with an EC50 value (concentration required for 50% of maximal 17beta-estradiol-induced proliferation) of 1.00 x 10(-12) M, THC failed to induce cell proliferation in the MCF7 cell line at concentrations between 10(-13) and 10(-4) M. THC inhibited 17beta-estradiol-induced proliferation in wild-type MCF7 and MCF7-AR1 cells, with an IC50 value of 2.6 x 10(-5) M and 9 x 10(-6) M, respectively. THC failed to act as an estrogen, but antagonized 17beta-estradiol-induced proliferation. This effect was independent of the AR expression level.

High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam Study.

Science.gov (United States)

Meun, Cindy; Franco, Oscar H; Dhana, Klodian; Jaspers, Loes; Muka, Taulant; Louwers, Yvonne; Ikram, M Arfan; Fauser, Bart C J M; Kavousi, Maryam; Laven, Joop S E

2018-02-01

Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism. In PCOS, hyperandrogenism has been associated with metabolic disturbances which increase the risk for cardiovascular disease (CVD). To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. The Rotterdam Study, a prospective population-based cohort study. Median follow up was 11.36 years. General community. 2578 women aged over 55. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, menopause by surgical intervention or at an unnatural age (age 62). None. Linear, logistic, and cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and SHBG with coronary artery calcium, carotid intima media thickness (IMT), pulse wave velocity, peripheral artery disease and incidence of coronary heart disease, stroke, and CVD. Mean age (standard deviation) was 70.19 (8.71) years and average time since menopause 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity [β (95%CI): 0.009 (0.000;0.018)]. Highest quartile dehydroepiandrosterone [β (95%CI): -0.008 (-0.015;-0.001)] and androstenedione [β (95%CI): -0.010 (-0.017;-0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, coronary heart disease, or cardiovascular disease. Postmenopausal high androgen levels were not associated with an increased risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated. Copyright © 2018 Endocrine Society

Exposure to modern, widespread environmental endocrine disrupting chemicals and their effect on the reproductive potential of women: an overview of current epidemiological evidence.

Science.gov (United States)

Karwacka, Anetta; Zamkowska, Dorota; Radwan, Michał; Jurewicz, Joanna

2017-07-31

Growing evidence indicates that exposure to widespread, environmental contaminants called endocrine disruptors (EDCs) negatively affects animal and human reproductive health and has been linked to several diseases including infertility. This review aims to evaluate the impact of environmental exposure to endocrine disrupting chemicals [phthalates, parabens, triclosan, bisphenol A (BPA), organochlorine (PCBs) and perfluorinated (PFCs) compounds] on the reproductive potential among women, by reviewing most recently published literature. Epidemiological studies focusing on EDCs exposure and reproductive potential among women for the last 16 years were identified by a search of the PUBMED, MEDLINE, EBSCO and TOXNET literature databases. The results of the presented studies show that exposure to EDCs impacts the reproductive potential in women, measured by ovarian reserve and by assisted reproductive technology outcomes. Exposure to environmental endocrine disrupting chemicals decrease: (i) oestradiol levels (BPA); (ii) anti-Müllerian hormone concentrations (PCBs); (iii) antral follicle count (BPA, parabens, phthalates); (iv) oocyte quality (BPA, triclosan, phthalates, PCBs); (v) fertilization rate (PFCs, PCBs); (vi) implantation (BPA, phthalates, PCBs); (vii) embryo quality (triclosan, PCBs, BPA); (viii) rate of clinical pregnancy and live births (parabens, phthalates). The studies were mostly well-designed and used prospective cohorts with the exposure assessment based on the biomarker of exposure. Considering the suggested health effects, more epidemiological data is urgently needed to confirm the presented findings.

Endocrine Disrupting Chemicals (EDCs)

Science.gov (United States)

... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... Hormones and Health › Endocrine Disrupting Chemicals (EDCs) The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) EDCs Myth vs. ...

Androgen Receptor Signaling in Bladder Cancer

OpenAIRE

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in u...

Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells

Science.gov (United States)

Ma, Yi; Yang, Hao-Zheng; Xu, Long-Mei; Huang, Yi-Ran; Dai, Hui-Li; Kang, Xiao-Nan

2015-01-01

Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID:25745956

Evaluation of Endocrine Disrupting Effects of Nitrate after In Utero Exposure in Rats and of Nitrate and Nitrite in the H295R and T-Screen Assay

DEFF Research Database (Denmark)

Hansen, Pernille Reimer; Taxvig, Camilla; Christiansen, Sofie

2009-01-01

/l. At GD21, fetuses were examined for anogenital distance, plasma thyroxine levels, testicular and plasma levels of testosterone and progesterone, and testicular testosterone production and histopathology. In addition, endocrine disrupting activity of nitrate and nitrite were studied in two in vitro assays......Animal studies have shown that nitrate acts as an endocrine disrupter affecting the androgen production in adult males. This raises a concern for more severe endocrine disrupting effects after exposure during the sensitive period of prenatal male sexual development. As there are no existing studies...... of effects of nitrate on male sexual development, the aim of the study was to examine how in utero exposure to nitrate would affect male rat fetuses. Pregnant dams were dosed with nitrate in the drinking water from gestational day (GD) 7 to GD21 at the following dose levels 17.5, 50, 150, 450, and 900 mg...

Survey of ecotoxicologically-relevant reproductive endpoint coverage within the ECOTOX database across ToxCast ER agonists (ASCCT)

Science.gov (United States)

The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) has been charged with screening thousands of chemicals for their potential to affect the endocrine systems of humans and wildlife. In vitro high throughput screening (HTS) assays have been proposed as a way to prioritize...

Dual Effects of Phytoestrogens Result in U-Shaped Dose-Response Curves

DEFF Research Database (Denmark)

Almstrup, Kristian; Fernández, Mariana F.; Petersen, Jørgen Holm

2002-01-01

Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay...

Androgen regulation of the androgen receptor coregulators

International Nuclear Information System (INIS)

Urbanucci, Alfonso; Waltering, Kati K; Suikki, Hanna E; Helenius, Merja A; Visakorpi, Tapio

2008-01-01

The critical role of the androgen receptor (AR) in the development of prostate cancer is well recognized. The transcriptional activity of AR is partly regulated by coregulatory proteins. It has been suggested that these coregulators could also be important in the progression of prostate cancer. The aim of this study was to identify coregulators whose expression is regulated by either the androgens and/or by the expression level of AR. We used empty vector and AR cDNA-transfected LNCaP cells (LNCaP-pcDNA3.1, and LNCaP-ARhi, respectively), and grew them for 4 and 24 hours in the presence of dihydrotestosterone (DHT) at various concentrations. The expression of 25 AR coregulators (SRC1, TIF2, PIAS1, PIASx, ARIP4, BRCA1, β-catenin, AIB3, AIB1, CBP, STAT1, NCoR1, AES, cyclin D1, p300, ARA24, LSD1, BAG1L, gelsolin, prohibitin, JMJD2C, JMJD1A, MAK, PAK6 and MAGE11) was then measured by using real-time quantitative RT-PCR (Q-RT-PCR). Five of the coregulators (AIB1, CBP, MAK, BRCA1 and β-catenin) showed more than 2-fold induction and 5 others (cyclin D1, gelsolin, prohibitin, JMJD1A, and JMJD2C) less than 2-fold induction. Overexpression of AR did not affect the expression of the coregulators alone. However, overexpression of AR enhanced the DHT-stimulated expression of MAK, BRCA1, AIB1 and CBP and reduced the level of expression of β-catenin, cyclinD1 and gelsolin. In conclusion, we identified 5 coactivators whose expression was induced by androgens suggesting that they could potentiate AR signaling. Overexpression of AR seems to sensitize cells for low levels of androgens

Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome.

Science.gov (United States)

Saito, Reiko; Yamamoto, Yukiyo; Goto, Motohide; Araki, Shunsuke; Kubo, Kazuyasu; Kawagoe, Rinko; Kawada, Yasusada; Kusuhara, Koichi; Igarashi, Maki; Fukami, Maki

2014-01-01

Although tamoxifen has been shown to be fairly safe and effective for idiopathic pubertal gynecomastia, it remains unknown whether it is also beneficial for gynecomastia associated with endocrine disorders. Here, we report the effect of tamoxifen on pubertal gynecomastia in 2 siblings with partial androgen insensitivity syndrome (PAIS). Cases 1 and 2 presented with persistent pubertal gynecomastia at 13 and 16 years of age, respectively. Physical examinations revealed breast of Tanner stage 3 and normal male-type external genitalia in both cases. Clinical features such as female-type pubic hair and borderline small testis indicated mildly impaired masculinization. Molecular analysis identified a previously reported p.Arg789Ser mutation in the androgen receptor gene (AR) in the 2 cases. Two months of oral administration of tamoxifen ameliorated gynecomastia to Tanner stage 2 with no adverse events. Additional treatment with testosterone enanthate showed negligible effects on body hair and penile length. Hormone values of the 2 cases during tamoxifen treatment remained similar to those in previously reported untreated patients with PAIS. The results indicate that tamoxifen was effective in treating pubertal gynecomastia in these 2 patients with PAIS and may be considered as a therapeutic option in this situation pending further studies.

Scientific Issues Relevant to Setting Regulatory Criteria to Identify Endocrine-Disrupting Substances in the European Union.

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Slama, Rémy; Bourguignon, Jean-Pierre; Demeneix, Barbara; Ivell, Richard; Panzica, Giancarlo; Kortenkamp, Andreas; Zoeller, R Thomas

2016-10-01

Endocrine disruptors (EDs) are defined by the World Health Organization (WHO) as exogenous compounds or mixtures that alter function(s) of the endocrine system and consequently cause adverse effects in an intact organism, or its progeny, or (sub)populations. European regulations on pesticides, biocides, cosmetics, and industrial chemicals require the European Commission to establish scientific criteria to define EDs. We address the scientific relevance of four options for the identification of EDs proposed by the European Commission. Option 1, which does not define EDs and leads to using interim criteria unrelated to the WHO definition of EDs, is not relevant. Options 2 and 3 rely on the WHO definition of EDs, which is widely accepted by the scientific community, with option 3 introducing additional categories based on the strength of evidence (suspected EDs and endocrine-active substances). Option 4 adds potency to the WHO definition, as a decision criterion. We argue that potency is dependent on the adverse effect considered and is scientifically ambiguous, and note that potency is not used as a criterion to define other particularly hazardous substances such as carcinogens and reproductive toxicants. The use of potency requires a context that goes beyond hazard identification and corresponds to risk characterization, in which potency (or, more relevantly, the dose-response function) is combined with exposure levels. There is scientific agreement regarding the adequacy of the WHO definition of EDs. The potency concept is not relevant to the identification of particularly serious hazards such as EDs. As is common practice for carcinogens, mutagens, and reproductive toxicants, a multi-level classification of ED based on the WHO definition, and not considering potency, would be relevant (corresponding to option 3 proposed by the European Commission). Slama R, Bourguignon JP, Demeneix B, Ivell R, Panzica G, Kortenkamp A, Zoeller RT. 2016. Scientific issues relevant

PCOS Forum: research in polycystic ovary syndrome today and tomorrow.

Science.gov (United States)

Pasquali, Renato; Stener-Victorin, Elisabet; Yildiz, Bulent O; Duleba, Antoni J; Hoeger, Kathleen; Mason, Helen; Homburg, Roy; Hickey, Theresa; Franks, Steve; Tapanainen, Juha S; Balen, Adam; Abbott, David H; Diamanti-Kandarakis, Evanthia; Legro, Richard S

2011-04-01

To summarize promising areas of investigation into polycystic ovary syndrome (PCOS) and to stimulate further research in this area. Summary of a conference held by international researchers in the field of polycystic ovary syndrome. Potential areas of further research activity include the analysis of predisposing conditions that increase the risk of PCOS, particularly genetic background and environmental factors, such as endocrine disruptors and lifestyle. The concept that androgen excess may contribute to insulin resistance needs to be re-examined from a developmental perspective, since animal studies have supported the hypothesis that early exposure to modest androgen excess is associated with insulin resistance. Defining alterations of steroidogenesis in PCOS should quantify ovarian, adrenal and extraglandular contribution, as well as clearly define blood reference levels by some universal standard. Intraovarian regulation of follicle development and mechanisms of follicle arrest should be further elucidated. Finally, PCOS status is expected to have long-term consequences in women, specifically the development of type 2 diabetes, cardiovascular diseases and hormone dependent cancers. Identifying susceptible individuals through genomic and proteomic approaches would help to individualize therapy and prevention. There are several intriguing areas for future research in PCOS. A potential limitation of our review is that we focused selectively on areas we viewed as the most controversial. © 2011 Blackwell Publishing Ltd.

Androgen deficiency in male patients diagnosed with ANCA-associated vasculitis: a cause of fatigue and reduced health-related quality of life?

Science.gov (United States)

Tuin, Janneke; Sanders, Jan-Stephan F; Buhl, Birgit M; van Beek, André P; Stegeman, Coen A

2013-01-01

Low testosterone levels in men are associated with fatigue, limited physical performance and reduced health-related quality of life (HRQOL); however, this relationship has never been assessed in patients with anti-neutrophil cytoplasmic antibodies (ANCA) -associated vasculitides (AAV). The aim of this study was to assess the prevalence of androgen deficiency and to investigate the role of testosterone in fatigue, limited physical condition and reduced HRQOL in men with AAV. Male patients with AAV in remission were included in this study. Fatigue and HRQOL were assessed by the multi-dimensional fatigue inventory (MFI)-20 and RAND-36 questionnaires. Seventy male patients with a mean age of 59 years (SD 12) were included. Scores of almost all subscales of both questionnaires were significantly worse in patients compared to controls. Mean total testosterone and free testosterone levels were 13.8 nmol/L (SD 5.6) and 256 pmol/L (SD 102), respectively. Androgen deficiency (defined according to Endocrine Society Clinical Practice Guidelines) was present in 47% of patients. Scores in the subscales of general health perception, physical functioning and reduced activity were significantly worse in patients with androgen deficiency compared to patients with normal androgen levels. Testosterone and age were predictors for the RAND-36 physical component summary in multiple linear regression analysis. Testosterone, age, vasculitis damage index (VDI) and C-reactive protein (CRP) were associated with the MFI-20 subscale of general fatigue. This study showed that androgen deficiency was present in a substantial number of patients with AAV. Testosterone was one of the predictors for physical functioning and fatigue. Testosterone may play a role in fatigue, reduced physical performance and HRQOL in male patients with AAV.

Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part I: Bisphenol A and octylphenol as xeno-estrogens.

Science.gov (United States)

Oehlmann, J; Schulte-Oehlmann, U; Tillmann, M; Markert, B

2000-12-01

The effects of suspected endocrine disrupting chemicals on freshwater and marine prosobranch species were analysed in laboratory experiments. In this first publication, the responses of the freshwater snail Marisa cornuarietis and of the marine prosobranch Nucella lapillus to the xeno-estrogenic model compounds bisphenol A (BPA) and octylphenol (OP) are presented at nominal concentration ranges between 1 and 100 micrograms/L. Marisa was exposed during 5 months using adult specimens and in a complete life-cycle test for 12 months. In both experiments, the xeno-estrogens induced a complex syndrome of alterations in female Marisa referred to as "superfemales" at the lowest concentrations. Affected specimens were characterised by the formation of additional female organs, an enlargement of the accessory pallial sex glands, gross malformations of the pallial oviduct section resulting in an increased female mortality, and a massive stimulation of oocyte and spawning mass production. The effects of BPA and OP were comparable at the same nominal concentrations. An exposure to OP resulted in inverted U-type concentration response relationships for egg and spawning mass production. Adult Nucella from the field were tested for three months in the laboratory. As in Marisa, superfemales with enlarged accessory pallial sex glands and an enhancement of oocyte production were observed. No oviduct malformations were found probably due to species differences in the gross anatomical structure of the pallial oviduct. A lower percentage of exposed specimens had ripe sperm stored in their vesicula seminalis and additionally male Nucella exhibited a reduced length of penis and prostate gland when compared to the control. Because statistically significant effects were observed at the lowest nominal test concentrations (1 microgram BPA or OP/L), it can be assumed that even lower concentrations may have a negative impact on the snails. The results show that prosobranchs are sensitive to

Using the Health Belief Model to Illustrate Factors That Influence Risk Assessment during Pregnancy and Implications for Prenatal Education about Endocrine Disruptors

Science.gov (United States)

Qiu, Xing; Chen, Shaw-Ree; Barrett, Emily S.; Velez, Marissa; Conn, Kelly; Heinert, Sara

2014-01-01

Endocrine disrupting chemicals (EDCs) such as Bisphenol A (BPA) and phthalates are ubiquitous in our environment and a growing body of research indicates that EDCs may adversely affect human development. Fetal development is particularly susceptible to EDC exposure, and prenatal care providers are being asked to educate women about the risks of…

Dynamic endocrine responses to stress: evidence for energetic constraints and status dependence in breeding male green turtles.

Science.gov (United States)

Jessop, Tim S; Knapp, Rosemary; Whittier, Joan M; Limpus, Col J

2002-03-01

During reproduction, male vertebrates may exhibit a continuum of interactions between sex and adrenal steroids during stressful events, the outcome of which may be important in either reducing or promoting male reproductive success. We studied adult male green turtles (Chelonia mydas) to examine if they altered plasma corticosterone (CORT) and androgen levels in response to a standardized capture/restraint stressor as potential mechanisms to maintain reproductive activity during stressful events. At the population level, we found that migrant breeding males had a significantly smaller CORT response to the capture/restraint stressor compared to nonbreeding males and that this decreased response coincided with the generally poorer body condition of migrant breeders. In contrast, plasma androgen levels decreased significantly in response to the capture/restraint stressor in migrant breeding males, but not in nonbreeding and pre-migrant breeding males. For individual migrant breeding males, the magnitude of their CORT and androgen responses to the capture/restraint stressor was highly correlated with their body condition and body length, respectively. Our results demonstrate that male green turtles exhibit complex interactions in their endocrine responses to a capture/restraint stressor and that variation in these interactions is associated with differences in males' reproductive, energetic, and physical state. We hypothesize that interplay between physical status and plasma hormone responses to stressors could have important consequences for male green turtle reproduction.

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

Science.gov (United States)

Biron, Eric; Bédard, François

2016-07-01

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biosensors and environmental health

National Research Council Canada - National Science Library

Preedy, Victor R; Patel, Vinood B

2012-01-01

.... Coverage includes personal toxicity testing, soil and risk assessment, pesticide, insecticides, parasites, nitrate, endocrine disruptors, heavy metals, food contamination, whole cell bioreporters...

Towards an integrated biosensor array for simultaneous and rapid multi-analysis of endocrine disrupting chemicals

Energy Technology Data Exchange (ETDEWEB)

Scognamiglio, Viviana, E-mail: viviana.scognamiglio@mlib.ic.cnr.it [IC-CNR Istituto di Cristallografia, AdR1 Dipartimento Agroalimentare - Via Salaria Km 29.3 00015, Rome (Italy); Pezzotti, Italo; Pezzotti, Gianni; Cano, Juan; Manfredonia, Ivano [Biosensor S.r.l. - Via degli Olmetti 44 00060 Formello, Rome (Italy); Buonasera, Katia [IC-CNR Istituto di Cristallografia, AdR1 Dipartimento Agroalimentare - Via Salaria Km 29.3 00015, Rome (Italy); Arduini, Fabiana; Moscone, Danila; Palleschi, Giuseppe [Universita di Roma Tor Vergata, Dipartimento di Scienze e Tecnologie Chimiche - Via della Ricerca Scientifica 00133, Rome (Italy); Giardi, Maria Teresa [IC-CNR Istituto di Cristallografia, AdR1 Dipartimento Agroalimentare - Via Salaria Km 29.3 00015, Rome (Italy)

2012-11-02

Highlights: Black-Right-Pointing-Pointer A multitask biosensor for the detection of endocrine disrupting chemicals is proposed. Black-Right-Pointing-Pointer The sensing system employ an array of biological recognition elements. Black-Right-Pointing-Pointer Amperometric and optical transduction methods are provided in an integrated biosensor together with flow control systems. Black-Right-Pointing-Pointer The biosensing device results in an integrated, automatic and portable system for environmental and agrifood application. - Abstract: In this paper we propose the construction and application of a portable multi-purpose biosensor array for the simultaneous detection of a wide range of endocrine disruptor chemicals (EDCs), based on the recognition operated by various enzymes and microorganisms. The developed biosensor combines both electrochemical and optical transduction systems, in order to increase the number of chemical species which can be monitored. Considering to the maximum residue level (MRL) of contaminants established by the European Commission, the biosensor system was able to detect most of the chemicals analysed with very high sensitivity. In particular, atrazine and diuron were detected with a limit of detection of 0.5 nM, with an RSD% less than 5%; paraoxon and chlorpyrifos were revealed with a detection of 5 {mu}M and 4.5 {mu}M, respectively, with an RSD% less than 6%; catechol and bisphenol A were identified with a limit of detection of 1 {mu}M and 35 {mu}M respectively, with an RSD% less than 5%.

Androgenic alopecia and dutasteride in hair mesotherapy: A short review

Directory of Open Access Journals (Sweden)

Estela B Busanello

2018-02-01

Full Text Available Androgenic alopecia (AGA is the most common cause of patterned hair loss in predisposed men and women. AGA is a multifactorial and polygenetic condition, affecting up to 80% of men and 40-50% of women during life. AGA is characterized by a gradual reduction of the anagen and increase in telagen phase, leading to a progressive follicle miniaturization. As a consequence, terminal hairs are converted into vellus hairs decreasing hair density. The pathophysiology of AGA is heterogeneous and highly complex. A diverse combination of genetical factors, endocrine abnormalities, circulating androgens, drugs, diet and microinflammation in hair follicles of each individual are related to this condition. However, it is well known that androgens are the major modulators of male AGA but their specific action on female AGA is still under debate. Circulating testosterone is converted by 5a-reductase in 5a-dihydrotestosterone (DHT in the periphery, a decrease of anagen phase occur, anticipating catagen phase in a complex process involving apoptosis as probably microinflammation. In AGA treatment, mesotherapy is being used with 5a-reductase inhibitors, especially dutasteride, injected directly on scalp. Thus, this updated review summarized the injectable use of dutasteride based on data available on PubMed until March 2017. Dutasteride, a second-generation inhibitor of 5a-reductase is more potent than finasteride due to the capability of inhibit types 1 and 2 of the enzyme. The efficacy and safety of hair mesotherapy with dutasteride were reported by distinct groups and the best results were achieved when this compound was used in combination with other substances, increasing hair growth. This result could be explained by the multifactorial pathophysiology of AGA, involving hair follicle sensitivity to DHT and microinflammation. Therefore, a multi-therapeutic approach seems to be more effective in AGA management. In conclusion, more studies are needed to

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

Science.gov (United States)

Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

2016-01-01

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

The multigenerational effects of water contamination and endocrine disrupting chemicals on the fitness of Drosophila melanogaster.

Science.gov (United States)

Quesada-Calderón, Suany; Bacigalupe, Leonardo Daniel; Toro-Vélez, Andrés Fernando; Madera-Parra, Carlos Arturo; Peña-Varón, Miguel Ricardo; Cárdenas-Henao, Heiber

2017-08-01

Water pollution due to human activities produces sedimentation, excessive nutrients, and toxic chemicals, and this, in turn, has an effect on the normal endocrine functioning of living beings. Overall, water pollution may affect some components of the fitness of organisms (e.g., developmental time and fertility). Some toxic compounds found in polluted waters are known as endocrine disruptors (ED), and among these are nonhalogenated phenolic chemicals such as bisphenol A and nonylphenol. To evaluate the effect of nonhalogenated phenolic chemicals on the endocrine system, we subjected two generations (F0 and F1) of Drosophila melanogaster to different concentrations of ED. Specifically, treatments involved wastewater, which had the highest level of ED (bisphenol A and nonylphenol) and treated wastewater from a constructed Heliconia psittacorum wetland with horizontal subsurface water flow (He); the treated wastewater was the treatment with the lowest level of ED. We evaluated the development time from egg to pupa and from pupa to adult as well as fertility. The results show that for individuals exposed to treated wastewater, the developmental time from egg to pupae was shorter in individuals of the F1 generation than in the F0 generation. Additionally, the time from pupae to adult was longer for flies growing in the H. psittacorum treated wastewater. Furthermore, fertility was lower in the F1 generation than in the F0 generation. Although different concentrations of bisphenol A and nonylphenol had no significant effect on the components of fitness of D. melanogaster (developmental time and fertility), there was a trend across generations, likely as a result of selection imposed on the flies. It is possible that the flies developed different strategies to avoid the effects of the various environmental stressors.

Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

International Nuclear Information System (INIS)

Olsen, Jan Roger; Azeem, Waqas; Hellem, Margrete Reime; Marvyin, Kristo; Hua, Yaping; Qu, Yi; Li, Lisha; Lin, Biaoyang; Ke, XI- Song; Øyan, Anne Margrete; Kalland, Karl- Henning

2016-01-01

Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in

SECONDARY (ENDOCRINE HYPERTENSION: LECTURE

Directory of Open Access Journals (Sweden)

M. Yu. Yukina

2016-01-01

Full Text Available Hypertension is a  very common disease with high morbidity and reduction in quality of life. Endocrine disorders are the most common cause of secondary hypertension affecting ~3% of the population. Primary aldosteronism can be the cause of endocrine hypertension more often than other endocrine disorders. Other less common causes of endocrine hypertension include Cushing syndrome, pheochromocytoma, thyroid disorders, and hyperparathyroidism. Endocrine hypertension is potentially curable if the underlying cause is identified and treated accordingly. Younger age at manifestation of resistance to multiple antihypertensive drugs, together with other clinical signs of an endocrine disorder, should raise the suspicion and prompt the appropriate evaluation.

Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

Directory of Open Access Journals (Sweden)

Day Wanda V

2005-04-01

Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

Science.gov (United States)

Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

2015-10-01

Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

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Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

Growing South Africa’s wealth through digital innovations: Digital innovation as a disruptor

CSIR Research Space (South Africa)

Williams, Quentin R

2017-10-01

Full Text Available This presentation briefly discusses problems/trends such as unemployment, lack of advanced skills, import-driven economy, and the nature of the South African ICT sector. Digital innovation is put forward as a disruptor of mentioned trends....

Endocrine-Manifestations of Cirrhosis and Liver Disease

Directory of Open Access Journals (Sweden)

M Khalili

2014-04-01

Full Text Available The liver is involved in the synthesis and metabolism of many kinds of hormones, various abnormalities hormone levels are found in advanced liver disease. For example the liver is, extremely sensitive to changes in insulin or glucagon levels. The liver is the primary organ of iron storage is frequently involved, diabetes is common in patients with iron overload and may be seen in cirrhosis. Chronic infection with HCV is associated with insulin resistance. Thyroid disease often accompanies chronic hepatitis C infection .Anti thyroid autoantibodies are also found in chronic HCV infection. Nonalcoholic liver disease (NAFLDas a most common cause of chronic liver disease in western world ,as well accompanied by Type 2 diabetes and hyperlipidemia. Hypopituitarism and hypothyroidism also have been in NAFLD.The patients with NAFLD and Hypopituitarism may be susceptible to central obesity, dyslipidemia and insulin resistance leading to disease progression. Hepatic cirrhosis as the end stage of chronic liver disease is also associated with hypogonadism and signs of feminization. The peripheral metabolism of steroids is altered in many of hypogonadism, low testosterone level decreased libido, infertility, reduced secondary sex hair and gynecomastia, reduced spermatogenesis and peritubular fibrosis are found in men with cirrhosis .The normal function of the hypothalamic-pituitary gonadal axis is affected in liver disease. In cirrhotic patients the estrogen/androgen ratio is usually increased, the level of testosterone and dihydroepiandosteron are reduced while the estradiol level are normal or slightly elevated, these alterations are dependent on the severity of the liver disease.Succsesfull orthotropic liver transplantation  leads to improvement of the sex hormone disturbances. The pathogenesis of gynecomastia is due to the loss of equilibrium between estrogen and androgen caused by a feminizing state but it is due to increased estrogen precursor in

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

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Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

Science.gov (United States)

Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

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2017-08-01

disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice

Directory of Open Access Journals (Sweden)

Luis Eduardo Prado Correia

2017-01-01

Full Text Available We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS. This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model.

Metabolite profiles of striped marsh frog (Limnodynastes peronii) larvae exposed to the anti-androgenic fungicides vinclozolin and propiconazole are consistent with altered steroidogenesis and oxidative stress.

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Melvin, Steven D; Leusch, Frederic D L; Carroll, Anthony R

2018-06-01

Amphibians use wetlands in urban and agricultural landscapes for breeding, growth and development. Fungicides and other pesticides used in these areas have therefore been identified as potential threats that could contribute towards amphibian population declines. However, relatively little is known about how such chemicals influence sensitive early life-stages or how short episodic exposures influence sub-lethal physiological and metabolic pathways. The present study applied untargeted metabolomics to evaluate effects in early post-hatch amphibian larvae exposed to the anti-androgenic fungicides vinclozolin and propiconazole. Recently hatched (Gosner developmental stage 25) striped marsh frog (Limnodynastes peronii) larvae were exposed for 96 h to vinclozolin at 17.5, 174.8 and 1748.6 nM and propiconazole at 5.8, 58.4 and 584.4 nM. Nuclear Magnetic Resonance (NMR) spectroscopy was performed on polar metabolites obtained from whole-body extracts. Both fungicides altered metabolite profiles compared to control animals at all concentrations tested, and there were notable differences between the two chemicals. Overall responses were consistent with altered steroidogenesis and/or cholesterol metabolism, with inconsistent responses between the two fungicides likely reflecting minor differences in the mechanisms of action of these chemicals. Broad down-regulation of the tricarboxylic acid (TCA) cycle was also observed and is indicative of oxidative stress. Interestingly, formic acid was significantly increased in larvae exposed to vinclozolin but not propiconazole, suggesting this metabolite may serve as a useful biomarker of exposure to androgen-receptor binding anti-androgenic contaminants. This study demonstrates the power of untargeted metabolomics for distinguishing between similarly acting, but distinct, pollutants and for unraveling non-endocrine responses resulting from exposure to known endocrine active contaminants. Copyright © 2018 Elsevier B.V. All

Polymer-immobilized ready-to-use recombinant yeast assays for the detection of endocrine disruptive compounds.

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Bittner, Michal; Jarque, Sergio; Hilscherová, Klára

2015-08-01

Recombinant yeast assays (RYAs) constitute a suitable tool for the environmental monitoring of compounds with endocrine disrupting activities, notably estrogenicity and androgenicity. Conventional procedures require yeast reconstitution from frozen stock, which usually takes several days and demands additional equipment. With the aim of applying such assays to field studies and making them more accessible to less well-equipped laboratories, we have optimized RYA by the immobilization of Saccharomyces cerevisiae cells in three different polymer matrices - gelatin, Bacto agar, and Yeast Extract Peptone Dextrose agar - to obtain a ready-to-use version for the fast assessment of estrogenic and androgenic potencies of compounds and environmental samples. Among the three matrices, gelatin showed the best results for both testosterone (androgen receptor yeast strain; AR-RYA) and 17β-estradiol (estrogen receptor yeast strain; ER-RYA). AR-RYA was characterized by a lowest observed effect concentration (LOEC), EC50 and induction factor (IF) of 1nM, 2.2nM and 51, respectively. The values characterizing ER-RYA were 0.4nM, 1.8nM, and 63, respectively. Gelatin immobilization retained yeast viability and sensitivity for more than 90d of storage at 4°C. The use of the immobilized yeast reduced the assay duration to only 3h without necessity of sterile conditions. Because immobilized RYA can be performed either in multiwell microplates or glass tubes, it allows multiple samples to be tested at once, and easy adaptation to existing portable devices for direct in-field applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

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Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Chiral dimethylamine flutamide derivatives-modeling, synthesis, androgen receptor affinities and carbon-11 labeling

International Nuclear Information System (INIS)

Jacobson, Orit; Laky, Desideriu; Carlson, Kathryn E.; Elgavish, Sharona; Gozin, Michael; Even-Sapir, Einat; Leibovitc, Ilan; Gutman, Mordechai; Chisin, Roland; Katzenellenbogen, John A.; Mishani, Eyal

2006-01-01

Most prostate cancers are androgen dependent upon initial diagnosis. On the other hand, some very aggressive forms of prostate cancer were shown to have lost the expression of the androgen receptor (AR). Although the AR is routinely targeted in endocrine treatment, the clinical outcome remains suboptimal. Therefore, it is crucial to demonstrate the presence and activity of the AR in each case of prostate cancer, before and after treatment. While noninvasive positron emission tomography (PET) has the potential to determine AR expression of tumor cells in vivo, fully optimized PET imaging agents are not yet available. Based on molecular modeling, three novel derivatives of hydroxyflutamide (Compounds 1-3) were designed and synthesized. They contain an electron-rich group (dimethylamine) located on the methyl moiety, which may confer a better stability to the molecule in vivo. Compounds 1-3 have AR binding that is similar or higher than that of the currently used commercial drugs. An automated carbon-11 radiolabeling route was developed, and the compounds were successfully labeled with a 10-15% decay-corrected radiochemical yield, 99% radiochemical purity and a specific activity of 4Ci/μmol end of bombardment (n=15). These labeled biomarkers may facilitate the future quantitative molecular imaging of AR-positive prostate cancer using PET and may also allow for image-guided treatment of prostate cancer

Elevated expression of steroidogenesis pathway genes; CYP17, GATA6 and StAR in prenatally androgenized rats.

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Jahromi, Marziyeh Salehi; Tehrani, Fahimeh Ramezani; Noroozzadeh, Mahsa; Zarkesh, Maryam; Ghasemi, Asghar; Zadeh-Vakili, Azita

2016-11-15

It is believed that excess androgen exposure of the fetus, via altered gene expression, causes hyperandrogenism a key feature of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate expression of Cytochrome P450-17 (CYP17), GATA-binding protein (GAGT6) and Steroidogenic acute regulatory protein (StAR), genes of adult female rats prenatally exposed to androgen excess, closely reflect endocrine and ovarian disturbances of PCOS in women, by comparing them during different phases of estrus cycle with those of non-treated rats. Both the adult prenatally testosterone exposed and control rats (n=23, each) were divided into four groups based on their observed vaginal smear (proestrus, estrus, metestrus and diestrus) and the relative expression of CYP17, GATA6 and StAR genes was measured in ovarian theca cells using Cyber-green Real-Time PCR. Serum sex steroid hormones and gonadotropins levels were measured using the ELISA method; a comparison of these two groups showed that there was an overall increase in the studied genes (CYP17; 2.39 fold change, 95% CI: 1.23-3.55; PPCOS. Copyright © 2016 Elsevier B.V. All rights reserved.

Androgen circle of polycystic ovary syndrome.

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Homburg, Roy

2009-07-01

Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

Electrochemical detection of a powerful estrogenic endocrine disruptor: ethinylestradiol in water samples through bioseparation procedure.

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Martínez, Noelia A; Pereira, Sirley V; Bertolino, Franco A; Schneider, Rudolf J; Messina, Germán A; Raba, Julio

2012-04-20

The synthetic estrogen ethinylestradiol (EE2) is an active component of oral contraceptives (OCs), considered as an endocrine disrupting compound (EDC). It is excreted from humans and released via sewage treatment plant effluents into aquatic environments. EDCs are any environmental pollutant chemical that, once incorporated into an organism, affects the hormonal balance of various species including humans. Its presence in the environment is becoming of great importance in water quality. This paper describes the development of an accurate, sensitive and selective method for capture, preconcentration and determination of EE2 present in water samples using: magnetic particles (MPs) as bioaffinity support for the capture and preconcentration of EE2 and a glassy carbon electrode modified with multi-walled carbon nanotubes (MWCNTs/GCE) as detection system. The capture procedure was based on the principle of immunoaffinity, the EE2 being extracted from the sample using the anti-EE2 antibodies (anti-EE2 Ab) which were previously immobilized on MPs. Subsequently the analyte desorption was done employing a sulfuric acid solution and the determination of the EE2 in the pre-concentrated solution was carried out by square wave voltammetry (SWV). This method can be used to determine EE2 in the range of 0.035-70 ng L(-1) with a detection limit (LOD) of 0.01 ng L(-1) and R.S.D.levels. Copyright © 2012 Elsevier B.V. All rights reserved.

The promotion on cell growth of androgen-dependent prostate cancer by antimony via mimicking androgen activity.

Science.gov (United States)

Zhang, Changwen; Li, Penghao; Wen, Yingwu; Feng, Guowei; Liu, Yu; Zhang, Yangyi; Xu, Yong; Zhang, Zhihong

2018-05-15

Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Prenatal and adult androgen activities in alcohol dependence.

Science.gov (United States)

Lenz, B; Mühle, C; Braun, B; Weinland, C; Bouna-Pyrrou, P; Behrens, J; Kubis, S; Mikolaiczik, K; Muschler, M-R; Saigali, S; Sibach, M; Tanovska, P; Huber, S E; Hoppe, U; Eichler, A; Heinrich, H; Moll, G H; Engel, A; Goecke, T W; Beckmann, M W; Fasching, P A; Müller, C P; Kornhuber, J

2017-07-01

Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Data for Summary of the Development the US Environmental Protection Agency’s Medaka Extended One Generation Reproduction Test (MEOGRT) Using Data from Nine Multigenerational Medaka Tests

Data.gov (United States)

U.S. Environmental Protection Agency — In response to various legislative mandates the United States Environmental Protection Agency (USEPA) formed its Endocrine Disruptor Screening Program (EDSP), which...

Sex differences in androgen receptors of the human mamillary bodies are related to endocrine status rather than to sexual orientation or transsexuality

NARCIS (Netherlands)

Kruijver, F. P.; Fernández-Guasti, A.; Fodor, M.; Kraan, E. M.; Swaab, D. F.

2001-01-01

In a previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally, men had stronger nuclear AR immunoreactivity (AR-ir) than women. The strongest nuclear labeling was found in the caudal hypothalamus in the mamillary body complex

Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction.

Science.gov (United States)

Ahmed, R G

2013-12-01

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that can severely disrupt the endocrine system. In the present study, early-weaned male rats were administered a single dose of 2,3,6-2',5'-pentachlorinated biphenyl (PCB 95; 32 mg/kg per day, by i.p. injection) for two consecutive days (postnatal days (PNDs) 15 and 16) and killed 24 and 48 h after the administration of the last dose. Compared with the control group, administration of PCB 95 induced a reduction (Pcolloidal contents at PND 18. The dyshormonogenesis and thyroid dysgenesis may be attributed to the elevation of DNA fragmentation at PNDs 17 and 18. Furthermore, this hypothyroid state revealed higher (Pinsulin at both PNDs compared with the control group. Interestingly, the body weight of the neonates in the PCB 95 group exhibited severe decreases throughout the experimental period in relation to that of the control group. These results imply that PCB 95 may act as a disruptor of the developmental hypothalamic-pituitary-thyroid axis. Hypothyroidism caused by PCB 95 may impair the adipokine axis, fat metabolism, and in general postnatal development. Thus, further studies need to be carried out to understand this concept.

Treatment of Anabolic-Androgenic Steroid Dependence: Emerging Evidence and Its Implications

Science.gov (United States)

Kanayama, Gen; Brower, Kirk J.; Wood, Ruth I.; Hudson, James I.; Pope, Harrison G.

2010-01-01

Currently, few users of anabolic-androgenic steroids (AAS) seek substance-abuse treatment. But this picture may soon change substantially, because illicit AAS use did not become widespread until the 1980s, and consequently the older members of this AAS-using population—those who initiated AAS as youths in the 1980s—are only now reaching middle age. Members of this group, especially those who have developed AAS dependence, may therefore be entering the age of risk for cardiac and psychoneuroendocrine complications sufficient to motivate them for substance-abuse treatment. We suggest that this treatment should address at least three etiologic mechanisms by which AAS dependence might develop. First, individuals with body-image disorders such as “muscle dysmorphia” may become dependent on AAS for their anabolic effects; these body-image disorders may respond to psychological therapies or pharmacologic treatments. Second, AAS suppress the male hypothalamic-pituitary-gonadal axis via their androgenic effects, potentially causing hypogonadism during AAS withdrawal. Men experiencing prolonged dysphoric effects or frank major depression from hypogonadism may desire to resume AAS, thus contributing to AAS dependence. AAS-induced hypogonadism may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function, and may necessitate antidepressant treatments in cases of depression inadequately responsive to endocrine therapies alone. Third, human and animal evidence indicates that AAS also possess hedonic effects, which likely promote dependence via mechanisms shared with classical addictive drugs, especially opioids. Indeed, the opioid antagonist naltrexone blocks AAS dependence in animals. By inference, pharmacological and psychosocial treatments for human opioid dependence might also benefit AAS-dependent individuals. PMID:20188494

Surgical strategies in endocrine tumors

NARCIS (Netherlands)

Schreinemakers, J.M.J.

2010-01-01

Endocrine surgery has become more custom-made throughout the years. Endocrine tumors can be sporadic or develop as part of familial syndromes. Several familial syndromes are known to cause endocrine tumors. The most common are multiple endocrine neoplasia (MEN) syndromes type 1, 2A and 2B. This

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

Science.gov (United States)

Bonde, Jens Peter; Flachs, Esben Meulengracht; Rimborg, Susie; Glazer, Clara Helene; Giwercman, Aleksander; Ramlau-Hansen, Cecilia Høst; Hougaard, Karin Sørig; Høyer, Birgit Bjerre; Hærvig, Katia Keglberg; Petersen, Sesilje Bondo; Rylander, Lars; Specht, Ina Olmer; Toft, Gunnar; Bräuner, Elvira Vaclavik

2016-12-01

% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Endocrine myopathy: Case-based review

Directory of Open Access Journals (Sweden)

Babul Reddy Hanmayyagari

2016-01-01

Full Text Available Endocrine myopathy means muscle weakness in the presence of an abnormal endocrine state. Most of the endocrine disorders are associated with myopathy and it is usually reversible with correction of the underlying disturbance, though, there is an increasing knowledge of the metabolic effects of hormones, endocrine myopathy is a less recognized and often overlooked entity in clinical practice. Here, we describe this association in three of our patients, then, we discuss systematically about endocrine myopathy.

OECD validation of the Hershberger assay in Japan: phase 2 dose response of methyltestosterone, vinclozolin, and p,p'-DDE.

Science.gov (United States)

Yamasaki, Kanji; Sawaki, Masakuni; Ohta, Ryo; Okuda, Hirokazu; Katayama, Seiichi; Yamada, Tomoya; Ohta, Takafumi; Kosaka, Tadashi; Owens, William

2003-01-01

The Organisation for Economic Co-operation and Development has initiated the development of new guidelines for the screening and testing of potential endocrine disruptors. The Hershberger assay is one of the assays selected for validation based on the need for in vivo screening to detect androgen agonists or antagonists by measuring the response of five sex accessory organs and tissues of castrated juvenile male rats: the ventral prostate, the seminal vesicles with coagulating glands, the levator ani and bulbocavernosus muscle complex, the Cowper's glands, and the glans penis. The phase 1 feasibility demonstration stage of the Hershberger validation program has been successfully completed with a single androgen agonist and a single antagonist as reference substances. The phase 2 validation program employs a range of additional androgen agonists and antagonists as well as 5alpha-reductase inhibitors. Seven Japanese laboratories have contributed phase 2 validation studies of the Hershberger assay using methyltestosterone, vinclozolin, and 2,2-bis (4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE). The methyltestosterone doses were 0, 0.05, 0.5, 5, and 50 mg/kg/day, and the vinclozolin and p,p'-DDE doses were 0, 3, 10, 30, and 100 mg/kg/day. All chemicals were orally administered by gavage for 10 consecutive days. In the antagonist version of the assay using vinclozolin and p,p'-DDE, 0.2 mg/kg/day of testosterone propionate was coadministered by subcutaneous injection. All five accessory sex preproductive organs and tissues consistently responded with statistically significant changes in weight within a narrow window. Therefore, the Japanese studies support the Hershberger assay as a reliable and reproducible screening assay for the detection of androgen agonistic and antagonistic effects. PMID:14644666

Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union.

Science.gov (United States)

Trasande, Leonardo; Zoeller, R Thomas; Hass, Ulla; Kortenkamp, Andreas; Grandjean, Philippe; Myers, John Peterson; DiGangi, Joseph; Bellanger, Martine; Hauser, Russ; Legler, Juliette; Skakkebaek, Niels E; Heindel, Jerrold J

2015-04-01

Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of €157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of €109 billion that differed modestly from base case probability inputs. EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in

A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Directory of Open Access Journals (Sweden)

Corrado Lodovico Galli

Full Text Available Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs and their metabolites towards the ligand binding domain (LBD of the androgen receptor (AR in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three. This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

A computational approach to evaluate the androgenic affinity of iprodione, procymidone, vinclozolin and their metabolites.

Science.gov (United States)

Galli, Corrado Lodovico; Sensi, Cristina; Fumagalli, Amos; Parravicini, Chiara; Marinovich, Marina; Eberini, Ivano

2014-01-01

Our research is aimed at devising and assessing a computational approach to evaluate the affinity of endocrine active substances (EASs) and their metabolites towards the ligand binding domain (LBD) of the androgen receptor (AR) in three distantly related species: human, rat, and zebrafish. We computed the affinity for all the selected molecules following a computational approach based on molecular modelling and docking. Three different classes of molecules with well-known endocrine activity (iprodione, procymidone, vinclozolin, and a selection of their metabolites) were evaluated. Our approach was demonstrated useful as the first step of chemical safety evaluation since ligand-target interaction is a necessary condition for exerting any biological effect. Moreover, a different sensitivity concerning AR LBD was computed for the tested species (rat being the least sensitive of the three). This evidence suggests that, in order not to over-/under-estimate the risks connected with the use of a chemical entity, further in vitro and/or in vivo tests should be carried out only after an accurate evaluation of the most suitable cellular system or animal species. The introduction of in silico approaches to evaluate hazard can accelerate discovery and innovation with a lower economic effort than with a fully wet strategy.

Genetics Home Reference: androgen insensitivity syndrome

Science.gov (United States)

... Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. People with this ... characteristics or signs of both male and female sexual development. Complete androgen insensitivity syndrome occurs when the body ...

Detection of estrogen receptor endocrine disruptor potency of commonly used organochlorine pesticides using the LUMI-CELL ER bioassay

Energy Technology Data Exchange (ETDEWEB)

Gordon, J D; Chu, A C; Clark, G C [Xenobiotic Detection Systems, Inc., Durham, NC (United States); Chu, M D [Alta Analytical Perspectives, Wilmington, NC (United States); Denison, M S [Dept. of Environmental Toxicology, Univ. of California, Davis, CA (United States)

2004-09-15

In order to detect the endocrine disrupting potency of organochlorine pesticides and other compounds, BG-1 (human ovarian carcinoma) cells containing a stably transfected estrogenresponsive luciferase reporter gene plasmid (BG1Luc4E2), was used. This cell line, termed the LUMI-CELL trademark ER estrogenic cell bioassay system, responds in a time-, dose dependent- and chemical-specific manner with the induction of luciferase gene expression in response to exposure to estrogen (but not other steroid hormones) and estrogenic chemicals in a high-throughput screening (HTPS) format6. Here we describe studies in which the LUMI-CELL trademark ER estrogenic cell bioassay system was used for high throughput screening (HTPS) analysis of the estrogenic disrupting potency of several commonly used pesticides and organochlorines: p,p'DDT; p,p'-DDE; DDD; {alpha}a-chlordane; {psi}-chlordane; Kepone; Methoxychlor; Vinclozolin; Fenarimol; 2,4,5-Trichlorophenoxyacetic Acid; and Dieldrin. Our results demonstrate the utility of XDS's LUMI-CELL trademark ER bioassay HTPS system for screening chemicals for estrogenic activity.

Hypochlorite Oxidation of Select Androgenic Steroids

Science.gov (United States)

Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

Androgenic alopecia; the risk–benefit ratio of Finasteride

Directory of Open Access Journals (Sweden)

David L. Rowland

2018-04-01

Full Text Available Finasteride is currently approved and largely used as a therapeutic option for androgenetic alopecia. Apparently a safe drug and effective at the onset, several concerns appeared over time regarding the frequency and magnitude of finasteride adverse effects, which in some cases seem to be even irreversible. This paper presents administration of finasteride in androgenic alopecia from two distinct perspectives. On one hand, androgenic alopecia is a condition that affects especially the self-image and esteem, aspects that are subjective, namely changeable and thus relative. On the other hand, this condition presents a multifactorial etiology, androgens being only in part involved. In addition, androgens have their own physiological roles within the body, so that any androgenic suppression should be carefully advised. Yet, adverse effects induced by Finasteride are only in part documented and treatable. Finally, alternative therapeutic approaches (like topical finasteride become available, so that the oral administration of Finasteride for androgenic alopecia should be in our opinion reevaluated. As a conclusion, a very detailed and informed discussion should take place with such patients accepting to start a therapy with finasteride for androgenic alopecia.

Contribution of the Endocrine Perspective in the Evaluation of Endocrine Disrupting Chemical Effects

DEFF Research Database (Denmark)

Bourguignon, Jean-Pierre; Juul, Anders; Franssen, Delphine

2016-01-01

Debate makes science progress. In the field of endocrine disruption, endocrinology has brought up findings that substantiate a specific perspective on the definition of endocrine disrupting chemicals (EDCs), the role of the endocrine system and the endpoints of hormone and EDC actions among other...... issues. This paper aims at discussing the relevance of the endocrine perspective with regard to EDC effects on pubertal timing. Puberty involves particular sensitivity to environmental conditions. Reports about the advancing onset of puberty in several countries have led to the hypothesis...

A mixture of an environmentally realistic concentration of a phthalate and herbicide reduces testosterone in male fathead minnow (Pimephales promelas) through a novel mechanism of action

OpenAIRE

Crago, Jordan; Klaper, Rebecca

2012-01-01

Several chemicals that are used by humans, such as pesticides and plastics, are released into the aquatic environment through wastewater and runoff and have been shown to be potent disruptors of androgen synthesis at high concentrations. Although many of these chemicals have been studied in isolation, a large amount of uncertainty remains over how fish respond to low concentrations of anti-androgenic mixtures, which more accurately reflects how such chemicals are present in the aquatic enviro...

Modulation of Androgen Receptor Transcriptional Activity

NARCIS (Netherlands)

H.Y. Wong (Hao Yun)

2009-01-01

textabstractAndrogens, testosterone (T) and 5a-dihydrotestosterone (DHT), are important for male and female physiology, in particular for male sexual differentiation, development of secondary male characteristics and spermatogenesis. These hormones exert their actions by binding to the androgen

[Fluorine-18 labeled androgens and progestins; imaging agents for tumors of prostate and breast]: Technical progress report, February 1, 1987-January 31, 1988

International Nuclear Information System (INIS)

Katzenellenbogen, J.A.

1987-01-01

This project develops fluorine-18 labeled steroids that possess high binding affinity and selectivity for androgen and progesterone receptors and can be used as positron-emission tomographic imaging agents for prostate tumors and breast tumors, respectively. These novel diagnostic agents may enable an accurate estimation of tumor dissemination, such as metastasis of prostate cancer and lymph node involvement of breast cancer, and an in vivo determination of the endocrine responsiveness of these tumors. They will provide essential information for the selection of alternative therapies thereby improving the management of prostate and breast cancer patients. 14 refs., 1 tab

An androgenic agricultural contaminant impairs female reproductive behaviour in a freshwater fish.

Directory of Open Access Journals (Sweden)

Minna Saaristo

Full Text Available Endocrine disrupting chemicals (EDCs are a large group of environmental pollutants that can interfere with the endocrine system function of organisms at very low levels. One compound of great concern is trenbolone, which is widely used as a growth promoter in the cattle industry in many parts of the world. The aim of this study was to test how short-term (21-day exposure to an environmentally relevant concentration of 17β-trenbolone (measured concentration 6 ng/L affects reproductive behaviour and fin morphology in the eastern mosquitofish (Gambusia holbrooki. The mosquitofish is a sexually dimorphic livebearer with males inseminating females using their modified anal fin, the gonopodium, as an intromittent organ. Although the species has a coercive mating system, females are able to exert some control over the success of male mating attempts by selectively associating with, or avoiding, certain males over others. We found that females exposed to trenbolone approached males less and spent more time swimming away from males than non-exposed (control females. By contrast, we found no difference in the behaviour of exposed and non-exposed males. Furthermore, exposure did not affect the anal fin morphology of males or females. This is the first study to demonstrate that exposure to an androgenic EDC can impair female (but not male behaviour. Our study illustrates how anthropogenic contaminants can have sex-specific effects, and highlights the need to examine the behavioural responses of environmental contaminants in both sexes.

Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

Science.gov (United States)

Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

2000-01-01

We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

Embryonic treatment with xenobiotics disrupts steroid hormone profiles in hatchling red-eared slider turtles (Trachemys scripta elegans).

Science.gov (United States)

Willingham, E; Rhen, T; Sakata, J T; Crews, D

2000-01-01

Many compounds in the environment capable of acting as endocrine disruptors have been assayed for their developmental effects on morphogenesis; however, few studies have addressed how such xenobiotics affect physiology. In the current study we examine the effects of three endocrine-disrupting compounds, chlordane, trans-nonachlor, and the polychlorinated biphenyl (PCB) mixture Aroclor 1242, on the steroid hormone concentrations of red-eared slider turtle (Trachemys scripta elegans) hatchlings treated in ovo. Basal steroid concentrations and steroid concentrations in response to follicle-stimulating hormone were examined in both male and female turtles treated with each of the three compounds. Treated male turtles exposed to Aroclor 1242 or chlordane exhibited significantly lower testosterone concentrations than controls, whereas chlordane-treated females had significantly lower progesterone, testosterone, and 5[alpha]-dihydrotestosterone concentrations relative to controls. The effects of these endocrine disruptors extend beyond embryonic development, altering sex-steroid physiology in exposed animals. Images Figure 1 Figure 2 PMID:10753091

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes.

Science.gov (United States)

Marcondes, Rodrigo Rodrigues; Carvalho, Kátia Cândido; Giannocco, Gisele; Duarte, Daniele Coelho; Garcia, Natália; Soares-Junior, José Maria; da Silva, Ismael Dale Cotrim Guerreiro; Maliqueo, Manuel; Baracat, Edmund Chada; Maciel, Gustavo Arantes Rosa

2017-08-01

Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

A PRACTICAL APPROACH TO THE DETECTION OF ANDROGEN RECEPTOR GENE-MUTATIONS AND PEDIGREE ANALYSIS IN FAMILIES WITH X-LINKED ANDROGEN INSENSITIVITY

NARCIS (Netherlands)

RISSTALPERS, C; HOOGENBOEZEM, T; SLEDDENS, HFBM; VERLEUNMOOIJMAN, MCT; DEGENHART, HJ; DROP, SLS; HALLEY, DJJ; Oosterwijk, Jan; HODGINS, MB; TRAPMAN, J; BRINKMANN, AO

Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

A practical approach to the detection of androgen receptor gene mutations and pedigree analysis in families with x-linked androgen insensitivity

NARCIS (Netherlands)

Ris-Stalpers, C.; Hoogenboezem, T.; Sleddens, H. F.; Verleun-Mooijman, M. C.; Degenhart, H. J.; Drop, S. L.; Halley, D. J.; Oosterwijk, J. C.; Hodgins, M. B.; Trapman, J.

1994-01-01

Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

Androgens as double-edged swords: Induction and suppression of follicular development.

Science.gov (United States)

Pan, Jie-Xue; Zhang, Jun-Yu; Ke, Zhang-Hong; Wang, Fang-Fang; Barry, John A; Hardiman, Paul J; Qu, Fan

2015-01-01

Androgens, which are mediated via the androgen receptor (AR), play important roles in normal follicular development and female fertility. However, just like a double-edged sword, besides the positive effects of androgen on follicular development, abnormal androgen levels, especially as in hyperandrogenism, seriously suppress normal follicular development. A crucial balance exists between the importance of androgens in follicular development and their negative effects when in excess. As the first meiotic division and epigenetic reprogramming are two critical events in oogenesis, abnormal androgen levels or deficiency in androgen/AR signaling in the ovary may affect these vital events. Oocytes have a tendency to develop genomic instability, thus resulting in an increasing incidence of unpredictable adult diseases. Although many studies have explored the effects of androgens and AR on follicular development, the conclusions are controversial and there has been no thorough review of this topic. This review focuses on the roles of androgens in the physiological process of follicular development, summarizes new insights into the roles of androgens in the arrested development of follicles, and discusses the potential risk of adult diseases originating from abnormal follicular androgen levels or androgen receptor signals, which may determine areas for future studies.

Androgens regulate gene expression in avian skeletal muscles.

Directory of Open Access Journals (Sweden)

Matthew J Fuxjager

Full Text Available Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus, zebra finch (Taenopygia guttata, and ochre-bellied flycatcher (Mionectes oleagieus. Because skeletal muscles that control wing movement make up the bulk of a bird's body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T up-regulated expression of parvalbumin (PV and insulin-like growth factor I (IGF-I, two genes whose products enhance cellular Ca(2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction.

Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

Science.gov (United States)

Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

2012-01-01

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

Endocrine system: part 1.

Science.gov (United States)

Johnstone, Carolyn; Hendry, Charles; Farley, Alistair; McLafferty, Ella

2014-05-27

This article, which forms part of the life sciences series and is the first of two articles on the endocrine system, examines the structure and function of the organs of the endocrine system. It is important that nurses understand how the endocrine system works and its role in maintaining health. The role of the endocrine system and the types, actions and control of hormones are explored. The gross structure of the pituitary and thyroid glands are described along with relevant physiology. Several disorders of the thyroid gland are outlined. The second article examines growth hormone, the pancreas and adrenal glands.

Homology-modeled ligand-binding domains of medaka estrogen receptors and androgen receptors: A model system for the study of reproduction

International Nuclear Information System (INIS)

Cui Jianzhou; Shen Xueyan; Yan Zuowei; Zhao Haobin; Nagahama, Yoshitaka

2009-01-01

Estrogen and androgen and their receptors play critical roles in physiological processes such as sexual differentiation and development. Using the available structural models for the human estrogen receptors alpha and beta and androgen receptor as templates, we designed in silico agonist and antagonist models of medaka estrogen receptor (meER) alpha, beta-1, and beta-2, and androgen receptor (meAR) alpha and beta. Using these models, we studied (1) the structural relationship between the ligand-binding domains (LBDs) of ERs and ARs of human and medaka, and (2) whether medaka ER and AR can be potential models for studying the ligand-binding activities of various agonists and antagonists of these receptors by docking analysis. A high level of conservation was observed between the sequences of the ligand-binding domains of meERα and huERα, meERβ1 and huERβ, meERβ2, and huERβ with 62.8%, 66.4%, and 65.1% identity, respectively. The sequence conservation between meARα and huAR, meARβ, and huAR was found with 70.1% and 61.0% of identity, respectively. Thirty-three selected endocrine disrupting chemicals (EDCs), including both agonists and antagonists, were docked into the LBD of ER and AR, and the corresponding docking score for medaka models and human templates were calculated. In order to confirm the conservation of the overall geometry and the binding pocket, the backbone root mean square deviation (RMSD) for Cα atoms was derived from the structure superposition of all 10 medaka homology models to the six human templates. Our results suggested conformational conservation between the ERs and ARs of medaka and human, Thus, medaka could be highly useful as a model system for studies involving estrogen and androgen interaction with their receptors.

Inverse Regulation of DHT Synthesis Enzymes 5α-Reductase Types 1 and 2 by the Androgen Receptor in Prostate Cancer.

Science.gov (United States)

Audet-Walsh, Étienne; Yee, Tracey; Tam, Ingrid S; Giguère, Vincent

2017-04-01

5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2. Copyright © 2017 Endocrine Society.

Mitochondrial disease and endocrine dysfunction.

Science.gov (United States)

Chow, Jasmine; Rahman, Joyeeta; Achermann, John C; Dattani, Mehul T; Rahman, Shamima

2017-02-01

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases.

Molecular mechanism of endocrine system impairment by 17α-methyltestosterone in gynogenic Pengze crucian carp offspring.

Science.gov (United States)

Zheng, Yao; Chen, Jiazhang; Liu, Yan; Gao, Jiancao; Yang, Yanping; Zhang, Yingying; Bing, Xuwen; Gao, Zexia; Liang, Hongwei; Wang, Zaizhao

2016-06-01

The effects of synthetic androgen 17α-methyltestosterone (MT) on endocrine impairment were examined in crucian carp. Immature 7-month old mono-female Pengze crucian carp (Pcc) F2 offspring were exposed to 50 and 100 μg/L of MT (week 2, 4, and 8). Gonadosomatic index, hepatosomatic index and intestine weight altered considerably and oocyte development was repressed. In the treatment groups, ovarian 11-ketotestosterone decreased, whereas 17β-estradiol and testosterone increased, and ovarian aromatase activities increased at week 4. However, in the brain tissue, those values significantly decreased. Quantitative RT-PCR analysis demonstrated changes in steroid receptor genes and upregulation of steroidogenic genes (Pcc-3bhsd, Pcc-11bhsd2 Pcc-cyp11a1), while the other three steroidogenic genes (Pcc-cyp17a1, Pcc-cyp19a1a and Pcc-star) decreased from week 4 to week 8. Ovarian, hepatic Pcc-vtg B and vitellogenin concentration increased in both 50 and 100 μg/L of MT exposure groups. This study adds further information regarding the effects of androgens on the development of previtellogenic oocytes, which suggests that MT could directly target estrogen signaling pathway, or indirectly affect steroidogenesis and vitellogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring.

Science.gov (United States)

Abbott, David H; Bruns, Cristin R; Barnett, Deborah K; Dunaif, Andrea; Goodfriend, Theodore L; Dumesic, Daniel A; Tarantal, Alice F

2010-11-01

Discrete fetal androgen excess during early gestation in rhesus monkeys (Macaca mulatta) promotes endocrine antecedents of adult polycystic ovary syndrome (PCOS)-like traits in female offspring. Because developmental changes promoting such PCOS-like metabolic dysfunction remain unclear, the present study examined time-mated, gravid rhesus monkeys with female fetuses, of which nine gravid females received 15 mg of testosterone propionate (TP) subcutaneously daily from 40 to 80 days (first to second trimesters) of gestation [term, mean (range): 165 (155-175) days], whereas an additional six such females received oil vehicle injections over the same time interval. During gestation, ultrasonography quantified fetal growth measures and was used as an adjunct for fetal blood collections. At term, all fetuses were delivered by cesarean section for postnatal studies. Blood samples were collected from dams and infants for glucose, insulin, and total free fatty acid (FFA) determinations. TP injections transiently accelerated maternal weight gain in dams, very modestly increased head diameter of prenatally androgenized (PA) fetuses, and modestly increased weight gain in infancy compared with concurrent controls. Mild to moderate glucose intolerance, with increased area-under-the-curve circulating insulin values, occurred in TP-injected dams during an intravenous glucose tolerance test in the early second trimester. Moreover, reduced circulating FFA levels occurred in PA fetuses during a third trimester intravenous glucagon-tolbutamide challenge (140 days gestation), whereas excessive insulin sensitivity and increased insulin secretion relative to insulin sensitivity occurred in PA infants during an intravenous glucose-tolbutamide test at ∼1.5 mo postnatal age. Data from these studies suggest that experimentally induced fetal androgen excess may result in transient hyperglycemic episodes in the intrauterine environment that are sufficient to induce relative increases in

Endocrine-disruptor molecular responses, occurrence of intersex and gonado-histopathological changes in tilapia species from a tropical freshwater dam (Awba Dam) in Ibadan, Nigeria

International Nuclear Information System (INIS)

Adeogun, Aina O.; Onibonoje, Kolawole; Ibor, Oju R.; Omiwole, Roseline A.; Chukwuka, Azubuike V.; Ugwumba, Alex O.; Ugwumba, Adiaha A.A.; Arukwe, Augustine

2016-01-01

Highlights: • Occurrence and severity of intersex in Nigerian aquatic environment. • Estrogenic and reproductive developmental effects of effluents from a University community. • Biomarker of endocrine disruption in fish from a developing country. • Relationship between estrogenic responses and sediment contaminants burden in a dam used for University domestic water supply and for fisheries. • Possible health consequences of environmental contamination - Abstract: In the present study, the occurrence of endocrine disruptive responses in Tilapia species from Awba Dam has been investigated, and compared to a reference site (Modete Dam). The Awba Dam is a recipient of effluents from University of Ibadan (Nigeria) and several other anthropogenic sources. A total of 132 Tilapia species (Sarotherodon malenotheron (n = 57 and 32, males and females, respectively) and Tilapia guineensis (n = 23 and 20, males and females, respectively)) were collected from June to September 2014. At the reference site, samples of adult male and female S. melanotheron (48 males and 47 females) and T. guineensis (84 males and 27 females) were collected. Gonads were morphologically and histologically examined and gonadosomatic index (GSI) was calculated. Hepatic mRNA transcriptions of vitellogenin (Vtg) and zona radiata protein (Zrp) genes were analyzed using validated RT-qPCR. Significant increase in Vtg and Zrp transcripts were observed in male tilapias from Awba Dam, compared to males from the reference site. In addition, male tilapias from Awba Dam produced significantly higher Vtg and Zrp mRNA, compared to females in June and July. However, at the natural peak spawning period in August and September, females produced, significantly higher Vtg and Zrp mRNA, compared to males. Fish gonads revealed varying incidence of intersex with a striking presence of two (2) pairs of testes and a pair of ovary in S. melanotheron from Awba Dam. The entire fish population examined at Awba Dam

Endocrine-disruptor molecular responses, occurrence of intersex and gonado-histopathological changes in tilapia species from a tropical freshwater dam (Awba Dam) in Ibadan, Nigeria

Energy Technology Data Exchange (ETDEWEB)

Adeogun, Aina O.; Onibonoje, Kolawole; Ibor, Oju R.; Omiwole, Roseline A.; Chukwuka, Azubuike V.; Ugwumba, Alex O.; Ugwumba, Adiaha A.A. [Department of Zoology, University of Ibadan, Ibadan (Nigeria); Arukwe, Augustine, E-mail: arukwe@bio.ntnu.no [Department of Biology, Norwegian University of Science and Technology (NTNU), 7491 Trondheim (Norway)

2016-05-15

Highlights: • Occurrence and severity of intersex in Nigerian aquatic environment. • Estrogenic and reproductive developmental effects of effluents from a University community. • Biomarker of endocrine disruption in fish from a developing country. • Relationship between estrogenic responses and sediment contaminants burden in a dam used for University domestic water supply and for fisheries. • Possible health consequences of environmental contamination - Abstract: In the present study, the occurrence of endocrine disruptive responses in Tilapia species from Awba Dam has been investigated, and compared to a reference site (Modete Dam). The Awba Dam is a recipient of effluents from University of Ibadan (Nigeria) and several other anthropogenic sources. A total of 132 Tilapia species (Sarotherodon malenotheron (n = 57 and 32, males and females, respectively) and Tilapia guineensis (n = 23 and 20, males and females, respectively)) were collected from June to September 2014. At the reference site, samples of adult male and female S. melanotheron (48 males and 47 females) and T. guineensis (84 males and 27 females) were collected. Gonads were morphologically and histologically examined and gonadosomatic index (GSI) was calculated. Hepatic mRNA transcriptions of vitellogenin (Vtg) and zona radiata protein (Zrp) genes were analyzed using validated RT-qPCR. Significant increase in Vtg and Zrp transcripts were observed in male tilapias from Awba Dam, compared to males from the reference site. In addition, male tilapias from Awba Dam produced significantly higher Vtg and Zrp mRNA, compared to females in June and July. However, at the natural peak spawning period in August and September, females produced, significantly higher Vtg and Zrp mRNA, compared to males. Fish gonads revealed varying incidence of intersex with a striking presence of two (2) pairs of testes and a pair of ovary in S. melanotheron from Awba Dam. The entire fish population examined at Awba Dam

Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation

NARCIS (Netherlands)

H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); S. Ramnarain; M.C. Verleun-Mooijman; D.P.E. Satijn (David); J. Trapman (Jan); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

1997-01-01

textabstractIn the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a

Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.

Science.gov (United States)

Kumagai, Jinpei; Hofland, Johannes; Erkens-Schulze, Sigrun; Dits, Natasja F J; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H; van Weerden, Wytske M

2013-11-01

Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. © 2013 Wiley Periodicals, Inc.

Molecular mechanisms of androgen receptor functions

NARCIS (Netherlands)

K. Steketee (Karine)

2007-01-01

textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

International Nuclear Information System (INIS)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A.; Pinilla, Mabel G.; Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C.; McNerney, Eileen M.; Onate, Sergio A.

2015-01-01

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

2015-11-27

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

Science.gov (United States)

Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

2017-01-01

To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

78 FR 8128 - Request for Nominations of Experts to the EPA Office of Research and Development's Board of...

Science.gov (United States)

2013-02-05

... Program; Homeland Security Research Program; Human Health Risk Assessment Research Program; Safe and... --atmospheric physics Biology --biogeochemistry --cell biology --endocrinology (endocrine disruptors... analysis --uncertainty analysis Nanotechnology Public Health --children's health --community health...

Developmental programming: impact of excess prenatal testosterone on intrauterine fetal endocrine milieu and growth in sheep.

Science.gov (United States)

Veiga-Lopez, Almudena; Steckler, Teresa L; Abbott, David H; Welch, Kathleen B; MohanKumar, Puliyur S; Phillips, David J; Refsal, Kent; Padmanabhan, Vasantha

2011-01-01

Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ~147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64-66, 87-90, and 139-140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.

Update in endocrine autoimmunity.

Science.gov (United States)

Anderson, Mark S

2008-10-01

The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases. Rapid progress has recently been made in our understanding of the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and confirmed many new genes outside of the established role of the human leukocyte antigen locus with these diseases, and indicate an essential role of immune response pathways in these diseases. Progress has also been made in identifying new autoantigens and the development of new animal models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for potentially treating and reversing the underlying autoimmune process. Although autoimmune endocrine disorders are complex in etiology, these recent advances should help contribute to improved outcomes for patients with, or at risk for, these disorders.

Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

National Research Council Canada - National Science Library

Wiren, Kristine M; Jepsen, Karl

2006-01-01

.... We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone...

Illicit use of androgens and other hormones: recent advances.

Science.gov (United States)

Kanayama, Gen; Pope, Harrison G

2012-06-01

To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

Aplicación de membrana de nanofiltración para eliminar disruptores endocrinos en la potabilización del agua

OpenAIRE

Abi-Faiçal Castanheira, Ana Paula

2010-01-01

Muchas de las actividades humanas contribuyen al deterioro del medio ambiente debido a la gran variedad de residuos químicos vertidos. Algunas de estas sustancias químicas son bastante persistentes y causan serios efectos en los animales y en la salud humana en un largo período de tiempo, incluso cuando están presentes en concentraciones muy bajas (Kuramitz et al, 2002), como ocurre con los disruptores endocrinos (DEs). Un disruptor endocrino (DE), conforme a la definición de la Comisión de l...

Detection of estrogen receptor endocrine disruptor potency of commonly used organochlorine pesticides using the LUMI-CELL ER bioassay

Energy Technology Data Exchange (ETDEWEB)

Gordon, J.D.; Chu, A.C.; Clark, G.C. [Xenobiotic Detection Systems, Inc., Durham, NC (United States); Chu, M.D. [Alta Analytical Perspectives, Wilmington, NC (United States); Denison, M.S. [Dept. of Environmental Toxicology, Univ. of California, Davis, CA (United States)

2004-09-15

In order to detect the endocrine disrupting potency of organochlorine pesticides and other compounds, BG-1 (human ovarian carcinoma) cells containing a stably transfected estrogenresponsive luciferase reporter gene plasmid (BG1Luc4E2), was used. This cell line, termed the LUMI-CELL trademark ER estrogenic cell bioassay system, responds in a time-, dose dependent- and chemical-specific manner with the induction of luciferase gene expression in response to exposure to estrogen (but not other steroid hormones) and estrogenic chemicals in a high-throughput screening (HTPS) format6. Here we describe studies in which the LUMI-CELL trademark ER estrogenic cell bioassay system was used for high throughput screening (HTPS) analysis of the estrogenic disrupting potency of several commonly used pesticides and organochlorines: p,p'DDT; p,p'-DDE; DDD; {alpha}a-chlordane; {psi}-chlordane; Kepone; Methoxychlor; Vinclozolin; Fenarimol; 2,4,5-Trichlorophenoxyacetic Acid; and Dieldrin. Our results demonstrate the utility of XDS's LUMI-CELL trademark ER bioassay HTPS system for screening chemicals for estrogenic activity.

Antiproliferative effect of butyltin in MCF-7 cells

International Nuclear Information System (INIS)

Nielsen, J.B.; Rasmussen, T.H.

2004-01-01

Humans are exposed to tributyltin compounds primarily through the intake of marine food. Previous reports on toxic effects to humans are limited to a few in vitro studies giving conflicting results regarding their effects on the aromatase enzyme and androgen receptor (AR) responses. The present study evaluates the estrogenic potential of three butyltin compounds (mono-, di-, and tributyltin) in an in vitro system based on the E-Screen assay. None of the butyltin compounds tested was estrogenic in the concentration range assayed (0.01-1000 nM). However, both dibutyltin dichloride (DBT) (500 nM) and tributyltin chloride (TBT) (10 nM) inhibited 17β-estradiol-induced cell proliferation. DBT (500 nM) and TBT (10 nM) also significantly reduced testosterone-induced cell proliferation, and the inhibition by TBT was rescued by increasing the concentration of testosterone. The present study did not confirm the inhibition of aromatase as the mechanism for an endocrine effect of butyltin compounds; moreover, the inhibition of cell proliferation by DBT and TBT occurred at concentrations at which no cytotoxicity was observed. The exact mechanism by which TBT and DBT inhibit cell proliferation remains unexplained, but it might be essentially independent of the estrogen receptor. Therefore, these compounds may not be termed classical endocrine disruptors, but rather as compounds that cause a functional anti-estrogenic response

Toxicity of triphenyltin and tributyltin to the freshwater mudsnail Potamopyrgus antipodarum in a new sediment biotest.

Science.gov (United States)

Duft, Martina; Schulte-Oehlmann, Ulrike; Tillmann, Michaela; Markert, Bernd; Oehlmann, Jörg

2003-01-01

The effects of two suspected endocrine-disrupting chemicals, the xeno-androgens triphenyltin (TPT) and tributyltin (TBT), were investigated in a new whole-sediment biotest with the freshwater mudsnail Potamopyrgus antipodarum (Gastropoda, Prosobranchia). Artificial sediments were spiked with seven concentrations, ranging from 10 to 500 microg nominal TPT-Sn/kg dry weight and TBT-Sn/kg dry weight, respectively. We analyzed the responses of the test species after two, four, and eight weeks exposure. For both compounds, P. antipodarum exhibited a sharp decline in the number of embryos sheltered in its brood pouch in a time- and concentration-dependent manner in comparison to the control sediment. The number of new, still unshelled embryos turned out to be the most sensitive parameter. The lowest-observed-effect concentration (LOEC) was equivalent to the lowest administered concentration (10 microg/kg of each test compound) for most parameters and thus no no-observed-effect concentration (NOEC) could be established. The calculation of effect concentrations (EC10) resulted in even lower values for both substances (EC10 after eight weeks for unshelled embryos: 0.03 microg TPT-Sn/kg, EC10 after four weeks for unshelled embryos: 0.98 microg TBT-Sn/kg). Our results indicate that P. antipodarum is highly sensitive to both endocrine disruptors TPT and TBT at environmentally relevant concentrations.

Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

International Nuclear Information System (INIS)

Whang, Kee Suk

1967-01-01

Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma- 59 Fe-disappearance rate, RBC 59 Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

Androgen receptor-related diseases: what do we know?

Science.gov (United States)

Shukla, G C; Plaga, A R; Shankar, E; Gupta, S

2016-05-01

The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs. Because of AR's widely varied and important roles, its abnormalities have been identified in various diseases such as androgen insensitivity syndrome, spinal bulbar muscular atrophy, benign prostatic hyperplasia, and prostate cancer. This review provides an overview of the function of androgens and androgen-AR mediated diseases. In addition, the diseases delineated above are discussed with respect to their association with mutations and other post-transcriptional modifications in the AR. Finally, we present an introduction to the potential therapeutic application of most recent pharmaceuticals including miRNAs in prostate cancer that specifically target the transactivation function of the AR at post-transcriptional stages. © 2016 American Society of Andrology and European Academy of Andrology.

Conazole fungicides inhibit Leydig cell testosterone secretion and androgen receptor activation in vitro

Directory of Open Access Journals (Sweden)

Maarke J.E. Roelofs

2014-01-01

Full Text Available Conazole fungicides are widely used in agriculture despite their suspected endocrine disrupting properties. In this study, the potential (anti-androgenic effects of ten conazoles were assessed and mutually compared with existing data. Effects of cyproconazole (CYPRO, fluconazole (FLUC, flusilazole (FLUS, hexaconazole (HEXA, myconazole (MYC, penconazole (PEN, prochloraz (PRO, tebuconazole (TEBU, triadimefon (TRIA, and triticonazole (TRIT were examined using murine Leydig (MA-10 cells and human T47D-ARE cells stably transfected with an androgen responsive element and a firefly luciferase reporter gene. Six conazoles caused a decrease in basal testosterone (T secretion by MA-10 cells varying from 61% up to 12% compared to vehicle-treated control. T secretion was concentration-dependently inhibited after exposure of MA-10 cells to several concentrations of FLUS (IC50 = 12.4 μM or TEBU (IC50 = 2.4 μM in combination with LH. The expression of steroidogenic and cholesterol biosynthesis genes was not changed by conazole exposure. Also, there were no changes in reactive oxygen species (ROS formation that could explain the altered T secretion after exposure to conazoles. Nine conazoles decreased T-induced AR activation (IC50s ranging from 10.7 to 71.5 μM and effect potencies (REPs were calculated relative to the known AR antagonist flutamide (FLUT. FLUC had no effect on AR activation by T. FLUS was the most potent (REP = 3.61 and MYC the least potent (REP = 0.03 AR antagonist. All other conazoles had a comparable REP from 0.12 to 0.38. Our results show distinct in vitro anti-androgenic effects of several conazole fungicides arising from two mechanisms: inhibition of T secretion and AR antagonism, suggesting potential testicular toxic effects. These effects warrant further mechanistic investigation and clearly show the need for accurate exposure data in order to perform proper (human risk assessment of this class of compounds.

Pharmacodynamics of selective androgen receptor modulators.

Science.gov (United States)

Yin, Donghua; Gao, Wenqing; Kearbey, Jeffrey D; Xu, Huiping; Chung, Kiwon; He, Yali; Marhefka, Craig A; Veverka, Karen A; Miller, Duane D; Dalton, James T

2003-03-01

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

Treatment of anabolic-androgenic steroid dependence: Emerging evidence and its implications.

Science.gov (United States)

Kanayama, Gen; Brower, Kirk J; Wood, Ruth I; Hudson, James I; Pope, Harrison G

2010-06-01

Currently, few users of anabolic-androgenic steroids (AAS) seek substance abuse treatment. But this picture may soon change substantially, because illicit AAS use did not become widespread until the 1980s, and consequently the older members of this AAS-using population - those who initiated AAS as youths in the 1980s - are only now reaching middle age. Members of this group, especially those who have developed AAS dependence, may therefore be entering the age of risk for cardiac and psychoneuroendocrine complications sufficient to motivate them for substance abuse treatment. We suggest that this treatment should address at least three etiologic mechanisms by which AAS dependence might develop. First, individuals with body image disorders such as "muscle dysmorphia" may become dependent on AAS for their anabolic effects; these body image disorders may respond to psychological therapies or pharmacological treatments. Second, AAS suppress the male hypothalamic-pituitary-gonadal axis via their androgenic effects, potentially causing hypogonadism during AAS withdrawal. Men experiencing prolonged dysphoric effects or frank major depression from hypogonadism may desire to resume AAS, thus contributing to AAS dependence. AAS-induced hypogonadism may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function, and may necessitate antidepressant treatments in cases of depression inadequately responsive to endocrine therapies alone. Third, human and animal evidence indicates that AAS also possess hedonic effects, which likely promote dependence via mechanisms shared with classical addictive drugs, especially opioids. Indeed, the opioid antagonist naltrexone blocks AAS dependence in animals. By inference, pharmacological and psychosocial treatments for human opioid dependence might also benefit AAS-dependent individuals. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Discovery and therapeutic promise of selective androgen receptor modulators.

Science.gov (United States)

Chen, Jiyun; Kim, Juhyun; Dalton, James T

2005-06-01

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.

Possibility of radioimmunoassay using for the estimation of endocrine status in autoimmune pathology

International Nuclear Information System (INIS)

Piven', N.V.; Mrochek, A.G.

2000-01-01

Usability of radioimmunoassay (RIA) for assessing the functioning and potentialities of different hormonal systems was studied as well as pathogenetic role of revealed violations and interconnection of them and clinical symptomatology and the type of therapy performed in case of pathology (illustrated by the case of rheumatoid arthritis (RA)). RIA method was used to assess the features of function of gonads, adrenal cortex and pituitary body - thyroid system in RA patients (45-60 y.o.) by means of study of the concentration of corresponding hormones and regulatory proteins in combination with pharmacological load of adrenocorticotropic hormone (ACTH) before and after the therapy. Grave violations in endocrine homeostasis were found in the form of androgen-extragen disbalance, adrenal insufficiency and hypothyrosis in combination with hormone level dissociation resulted from pharmacological sample with ACTH. Revealed violations are connected with clinical symptomatology, criticality and lingering of disease [ru

Three novel and two known androgen receptor gene mutations ...

Indian Academy of Sciences (India)

gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. J. Genet. ... signal and a C-terminal. Keywords. androgen insensitivity syndrome; androgen receptor; truncation mutation; N-terminal domain; XY sex reversal. .... and an increased risk of gonadal tumour. Mutations in SRY.

Investigating apical adverse effects of four endocrine active substances in the freshwater gastropod Lymnaea stagnalis.

Science.gov (United States)

Giusti, Arnaud; Lagadic, Laurent; Barsi, Alpar; Thomé, Jean-Pierre; Joaquim-Justo, Célia; Ducrot, Virginie

2014-09-15

The hermaphroditic gastropod Lymnaea stagnalis is proposed as a candidate species for the development of OECD guidelines for testing of the reprotoxicity of chemicals, including endocrine active substances (EASs). Up to now, only a few putative EASs have been tested for their reproductive toxicity in this species. In this study, we investigate the effects of four EASs with different affinities to the vertebrate estrogen and androgen receptors (chlordecone as an estrogen; cyproterone acetate, fenitrothion and vinclozolin as anti-androgens) on the reproduction of L. stagnalis in a 21-day semi-static test. Testosterone and 17α-ethinylestradiol (EE2) were used as the reference compounds. The tested EASs had no significant effect on growth and survival at the tested concentration ranges (ng to μg/L). Classical reproduction endpoints (i.e., oviposition and fecundity) were not responsive to the tested chemicals, except for chlordecone and 17α-ethinylestradiol, which hampered reproduction from 19.6 μg/L and 17.6 μg/L, respectively. The frequency of polyembryonic eggs, used as an additional endpoint, demonstrated the effects of all compounds except EE2. The molecular pathways, which are involved in such reproduction impairments, remain unknown. Our results suggest that egg quality is a more sensitive endpoint as compared to other reproductive endpoints commonly assessed in mollusk toxicity tests. Copyright © 2014 Elsevier B.V. All rights reserved.

Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program.

Science.gov (United States)

Kim, Catherine; Aroda, Vanita R; Goldberg, Ronald B; Younes, Naji; Edelstein, Sharon L; Carrion-Petersen, MaryLou; Ehrmann, David A

2018-02-01

It is unclear whether relative elevations in androgens or irregular menses (IM) are associated with greater cardiometabolic risk among women who are already overweight and glucose intolerant. We conducted a secondary analysis of the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). Participants included women with sex hormone measurements who did not use exogenous estrogen (n = 1422). We examined whether free androgen index (FAI) or IM was associated with diabetes risk during the DPP/DPPOS or with coronary artery calcification (CAC) at DPPOS year 10. Models were adjusted for menopausal status, age, race or ethnicity, randomization arm, body mass index (BMI), and hemoglobin A1c. Women had an average age of 48.2 ± 9.9 years. Elevations in FAI and IM were associated with greater BMI, waist circumference, and blood pressure and lower adiponectin. FAI was not associated with diabetes risk during the DPP/DPPOS [hazard ratio (HR) 0.97; 95% confidence interval (CI), 0.93 to 1.02] or increased odds of CAC [odds ratio (OR) 1.06; 95% CI, 0.92 to 1.23]. IM was also not associated with diabetes risk during the DPP/DPPOS (HR 1.07; 95% CI, 0.87 to 1.31) or increased odds of CAC (OR 0.89; 95% CI, 0.53 to 1.49). Women who had both relative elevations in FAI and IM had similar diabetes risk and odds of CAC as women without these conditions. Differences by treatment arm and menopausal status were not observed. Among midlife women who were already glucose intolerant and overweight, androgen concentrations and IM did not additionally contribute to increased risk for diabetes or CAC. Copyright © 2017 Endocrine Society

DDT in zebra mussels from Lake Maggiore (N. Italy): level of contamination and endocrine disruptions.

Science.gov (United States)

Binelli, Andrea; Bacchetta, Renato; Mantecca, Paride; Ricciardi, Francesco; Provini, Alfredo; Vailati, Giovanni

2004-08-10

The DDT contamination of Lake Maggiore (Northern Italy) has been monitored since a serious pollution event occurred in 1996. To assess the environmental risk associated with this contamination, bioaccumulation data coupled with histopathological markers were evaluated on zebra mussel populations from two different contaminated sites from April 2001 to April 2002. Biomonitoring results showed high DDT pollution in 2001 because of a flood which transported DDTs still contained in the sediments of a polluted river to the lake. DDT concentrations reached values of 4-5 microg/g lipids, higher than those recorded in other industrialized countries but comparable to levels measured in developing ones. In the ovaries of the most highly polluted mussels, histological analyses showed a delay in oocyte maturation and a high incidence of pathological pictures mainly referable to oocyte degeneration and haemocytic infiltration. Moreover, despite the presence of mature sperms, in 2001 first male gamete release occurred about 2 months later than in females. These results indicated a neuroendocrine interference of DDT on Dreissena polymorpha reproduction and also showed that these invertebrates can be successfully used to evaluate ecological implications due to exposure to endocrine disruptors in freshwater environments.

Update in Endocrine Autoimmunity

OpenAIRE

Anderson, Mark S.

2008-01-01

Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

NIEHS/EPA CEHCs: Novel Methods to Assess Effects of Bisphenol A & Phthalates on Child Development - University of Illinois at Urbana-Champaign

Science.gov (United States)

At this center, researchers study the effects of two endocrine disruptors that are commonly used in pesticides, plastics and many other products and are also found in vehicle exhaust: bisphenol A (BPA) and phthalates.

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian