Estrogenic environmental chemicals and drugs: Mechanisms for effects on the developing male urogenital system

Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA.
The Journal of steroid biochemistry and molecular biology (Impact Factor: 3.63). 07/2011; 127(1-2):83-95. DOI: 10.1016/j.jsbmb.2011.07.005
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ABSTRACT Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures.

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Available from: Catherine A Richter, Jul 25, 2014
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    • "Only a small proportion (<1%) of the receptor pool need to be occupied by ligand to initiate a response, and so activation occurs at low hormone levels. At high hormone levels, signals may fall via receptor downregulation [39, 40]. The most significant effect was seen with DHT, where AUT cells showed the least growth suppression and mitochondrial upregulation (see the middle columns of Figures 1 and 2 as compared to the right and left columns). "
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    ABSTRACT: It has been postulated that androgen overexposure in a susceptible person leads to excessive brain masculinization and the autism spectrum disorder (ASD) phenotype. In this study, the responses to estradiol (E2), dihydrotestosterone (DHT), and dichlorodiphenyldichloroethylene (DDE) on B-lymphocytes from ASD subjects and controls are compared. B cells were obtained from 11 ASD subjects, their unaffected fraternal twins, and nontwin siblings. Controls were obtained from a different cell bank. Lactate dehydrogenase (LDH) and sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction levels were measured after incubation with different concentrations of E2, DHT, and DDE. XTT/LDH ratio, representative of mitochondria number per cell, was calculated. E2, DHT, and DDE all cause "U"-shaped growth curves, as measured by LDH levels. ASD B cells show less growth depression compared to siblings and controls (P < 0.01). They also have reduced XTT/LDH ratios (P < 0.01) when compared to external controls, whereas siblings had values of XTT/LDH between ASD and external controls. B-lymphocytes from people with ASD exhibit a differential response to E2, DHT, and hormone disruptors in regard to cell growth and mitochondrial upregulation when compared to non-ASD siblings and external controls. Specifically, ASD B-lymphocytes show significantly less growth depression and less mitochondrial upregulation when exposed to these effectors. A mitochondrial deficit in ASD individuals is implied.
    Journal of Toxicology 11/2013; 2013(11):159810. DOI:10.1155/2013/159810
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    • "Testis sections were examined by TUNEL assay (in situ cell death detection kit, Fluorescein, Roche Diagnostics, Mannheim, Germany). Prostate histopathology criteria included the presence of vacuoles, atrophic epithelial layer of ducts and hyperplasia of prostatic duct epithelium as previously described [52,53]. No prostatic intraepithelial neoplasia (PIN) lesions were observed in the prostates. "
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    ABSTRACT: Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease. Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm. The F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity. Observations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.
    BMC Medicine 10/2013; 11(1):228. DOI:10.1186/1741-7015-11-228 · 7.25 Impact Factor
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    • "Millions of children are conceived by women while on contraceptive pills containing EE. Albeit most do not show conspicuous congenital abnormalities, long-term reproductive consequences may ensue in adulthood (88). Breastfeeding is another significant period of exposure to ED (89). "
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    ABSTRACT: Over recent decades, epidemiological studies have been reporting worrisome trends in the incidence of human infertility rates. Extensive detection of industrial chemicals in human serum, seminal plasma, and follicular fluid has led the scientific community to hypothesize these compounds may disrupt hormonal homeostasis, leading to a vast array of physiological impairments. Numerous synthetic and natural substances have endocrine disruptive effects, acting through several mechanisms. The main route of exposure to these chemicals is the ingestion of contaminated food and water. They may disturb intrauterine development, resulting in irreversible effects and may also induce transgenerational effects. This review aims to review and summarize the major scientific developments on the topic of human infertility associated with exposure to endocrine disruptors, integrating epidemiological and experimental evidence. The PubMed database was used to search for articles published up to 31st May 2013. Current data suggest that environmental levels of endocrine disruptors may affect the development and functioning of the reproductive system in both genders, particularly in foetuses, causing developmental and reproductive disorders, including infertility. Endocrine disruptors may be blamed for the rising incidence of human reproductive disorders. This constitutes a serious public health issue that should not be overlooked. The exposure of pregnant women and infants to endocrine disruptors is of great concern. Therefore, precautionary avoidance of exposure to endocrine disruptors is a prudent attitude in order to protect humans and wildlife from permanent harmful effects on fertility.
    Endocrine Connections 08/2013; 2(3). DOI:10.1530/EC-13-0036
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