Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways (original) (raw)
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Endocrine disruptors: update on xenoestrogens
International Archives of Occupational and Environmental Health, 2000
Endocrine disruptors and their possible impact on human and animal health have become a topic of discussion and an area of active research in toxicology. A focus has been on xenoestrogens, i.e., environmental chemicals with estrogenic activity. In principle, there is agreement that such compounds, in high doses, may cause developmental, reproductive and tumorigenic effects (``hazard''). A matter of controversy is the question of risks associated with xenoestrogens under realistic (low) exposure scenarios; this is due to uncertainty on how to assess the interactions of exogenous compounds with the endocrine system and its complex regulation. Our overview will address topics including: consequences from previous clinical use of the potent estrogen diethylstilbestrol with particular emphasis on dose-response relationships, other observations in humans exposed to estrogenic chemicals in an occupational context, and available information on exposure levels of synthetic and naturally occurring estrogens in the diet. Together with a critical appraisal of methods to detect and quantitate the estrogenic activity of synthetic and naturally occurring chemicals, novel aspects in the risk assessment for endocrine active compounds are discussed.
Human exposure to endocrine-disrupting chemicals: assessing the total estrogenic xenobiotic burden
TrAC Trends in Analytical Chemistry, 1997
has been hypothesized between adverse effects on human and wildlife reproductive health and a number of chemical substances capable of altering hormonal homeostasis. A testing system to screen for endocrine activities and the development of appropriate biomarkers of cumulative exposure are required. This article reports the work of our group in the following areas: (i) the identification of chemical agents with estrogenic hormonal activity, (ii) existing evidence on forms and sources of human exposure, and (iii) developing a methodology to assess the total estrogenic burden, defined as the estrogenic activity in a bioassay of human samples from which ovarian estrogens have been previously eliminated. 0 1997 Elsevier Science B.V.
An updated review of environmental estrogen and androgen mimics and antagonists
The Journal of Steroid Biochemistry and Molecular Biology, 1998
For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Manmade compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate¯asks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 m mg of bisphenol-A were retrieved from saliva collected during the ®rst hour after polymerization. Other xenoestrogens recently identi®ed among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male ®sh were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identi®ed antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors. #
Environmental Health Perspectives, 2000
Environmental chemicals with estrogenic activities have been suggested to be associated with deleterious effet in animals and humans. To characterize estrogenic chemicals and their mechanisms of action, we established in vitro and cell culture assays that detect human estrogen receptor a (hERa)-mediated estrogenicity. First, we assayed chemicals to determine their ability to modulate direct interaction between the hERa and the steroid receptor coactivator-1 (SRC-1) and in a competition binding assay to displace 17j-estradiol (E2). Scond, we teted the chemical for estrogen-associated transcriptional activity in the yeast estrogen screen and in the estrogenresponsive MCF-7 human breast cancer cell line. The chemicals investigated in this study were o,p'-DDT (racemic miu and enantiomers), nonylphenol mixtre (NPm), and two poorly analyzed compounds in the environment, namely, tris-4-(chlorophenyl)methane (Tris-H) and tris-4-(chlorophenyl)methanol (Tris-OH). In both yeast and MCF-7 cells, we determined estrogenic activity via the estrogen receptor (ER) for o,p'-DDT, NPm, and for the very first time, Tris-H and Tris-OH. However, unlike estrogens, none of these xenobiotics seemed to be able to induce ERISRC-1 interactions, most likely because the conformation of the activated receptor would not allow direct contacts with this coactivator. However, these compounds were able to inhibit [3H]-E2 binding to hER, which reveals a direct interaction with the receptor. In conclusion, the test compounds are estrogen mimics, but their molecular mechanism of action appears to be different from that of the natural hormone as revealed by the receptorbcoactivator interaction analysis. KIy work: coactivator SRC-1, environmental chemicals, estrogen receptor at, MCF-7 cells, transcriptional activity, xenoestrogen, yeast. Environ We thank J. Diezi and P. Kucera for stimulating discussions and P. Balaguer for providing the MCF-7 stable transfected cell line.
New Modes of Action for Endocrine-Disrupting Chemicals
Molecular Endocrinology, 2006
Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that “may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate.” The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-medi...
Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement
Endocrine Reviews, 2009
There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor gamma, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness.
Journal of Steroid Biochemistry and Molecular Biology, 1998
For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Manmade compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate¯asks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 m mg of bisphenol-A were retrieved from saliva collected during the ®rst hour after polymerization. Other xenoestrogens recently identi®ed among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male ®sh were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identi®ed antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors. #