Diethylstilbestrol and Other Estrogens in the Environment (original) (raw)
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Diethylstilbestrol and other estrogens in the environment*1
Fundamental and applied toxicology, 1984
Many environmental agents of diverse chemical structure possess estrogenic activity. Other hormonal activities do not Seem to be so widespread through different chemical classes. Some compounds such as the mycotoxin, zearalenone, are metabolized from weakly active to more estrogenic forms and may thus be considered proestrogens. Metabolism of potent xenobiotics, such as diethylstilbestrol (DES), may result in relatively less hormonally active compounds as well as reactive intermediates associated with long-term toxicities. Weakly estrogenic xenobiotics may be physiologically significant if they persist in the body or when there is continuous exposure; some compounds with no apparent estrogen-receptor-binding affinity may exert estrogenic effects through indirect mechanisms. Estrogenic materials as part ofthe environment derive from natural (e.g., plant estrogens or mycotoxins) and synthetic (e.g., DES or DDT) sources. In some cases, environmental compounds may be potent estrogens which are used for their hormonal activity, or in other cases, they are weak estrogens in which hormonal activity is an inadvertant function; an example of the former case is DES as a growth-promoting agent for cattle, an example of the latter, kepone. Elucidation of the structural basis of estrogenic activity is the critical step awaited in this area. 0 1984 Society of Toxicology.
Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs
Proceedings of the National Academy of Sciences, 1978
The diethylstilbestrol (DES) metabolite (8dienestrol), which had been identified in mouse, rat, monkey, and human urine, and two proposed metabolic intermediates (diethylstilbestrol a,a'-epqxide and a,a'-dihydroxy DES) were synthesized and their estrogenic activities determined. In addition, three DES analogs, a-dienestrol, DES-dihydroxy diethyl phenanthrene (DES-phenanthrene), and 14a-ethyl, 4a-hydroxyphenyl)indanyl-5-ol (indanyl-DES), were studied. Estrogenic activities of the compounds in vivo were determined by the immature mouse uterine weight bioassay; in vitro, their estradiol receptor binding activity (competitive equilibrium binding, sucrose gradient analysis, and association rate inhibition assays) was determined. Results of the mouse uterine weight bioassay gave the following order of estrogenicity: DES > a-dienestrol > DES-epoxide > indanyl-DES > dihydroxy DES > #-dienestrol > DES-phenanthrene. Results of competitive equilibrium binding analyses of these compounds with estradiol-17ft for the mouse uterine cytosol receptor followed the same order seen for the bioassay, except for indanyl-DES. DES, indanyl-DES, and a-dienestrol had the greatest affinities (Ka values approxi-
Environmental Health Perspectives, 1995
Concerns have been raised regarding the role of environmental and dietary estrogens as possible contributors to an increased incidence of various abnormalities in estrogen-target tissues of both sexes. These abnormalities include breast cancer, endometriosis, fibroids, and uterine adenocarcinoma in females, as well as alterations in sex differentiation, decreased sperm concentrations, benign prostatic hyperplasia, prostatic cancer, testicular cancer, and reproductive problems in males. Whether these concerns are valid remains to be determined; however, studies with the potent synthetic estrogen diethylstilbestrol (DES) suggest that exogenous estrogen exposure during critical stages of development can result in permanent cellular and molecular alterations in the exposed organism. These alterations manifest themselves in the female and male as structural, functional, or long-term pathological changes including neoplasia. Although DES has potent estrogenic activity, it may be used as a model compound to study the effects of weaker environmental estrogens, many of which may fit into the category of endocrine disruptors.-Environ Health
Estrogens and environmental estrogens
Biomedicine & Pharmacotherapy, 2002
The natural female sex hormone estrogens binds once inside the cell to a protein receptor to form a 'ligand-hormone receptor complex'. The binding activates the hormone receptor, which triggers specific cellular processes. The activated hormone receptor then turns on specific genes, causing cellular changes that lead to responses typical of a ligand-hormone receptor complex. Estrogens (especially estradiol) bring out the feminine characteristics, control reproductive cycles and pregnancy, influence skin, bone, the cardiovascular system and immunity. Natural hormones are more potent than any of the known synthetic environmental estrogens (except drugs such as diethylstilbestrol [DES]). Estrogen production varies according to different factors (gender, age and reproductive cycles). Women produce more estrogen than men and the production is more abundant during fetal development than in the postmenopausal period. Most natural estrogens are short-lived, do not accumulate in tissue and are easily broken down in the liver. In contrast to natural estrogens, estrogenic drugs such as ethynylestradiol diethylstilbestrol (DES), synthetic environmental estrogens such as ß-hexachlorocyclohexane (ß-HCH), polychlorinated biphenyls (PCBs), o, p, p'DDT, 4-nonylphenol (NP) and phytoestrogens such as isoflavones or lignans, are more stable and remain in the body longer than natural estrogens. Because most of these compounds are lipophilic, they tend to accumulate within the fat and tissue of animals and humans. Thus, depending on the natural estrogen levels, environmental estrogens may have different influences (mimicking, blocking or cancelling out estrogen's effects) on estrogen activities. © 2002 Éditions scientifiques et médicales Elsevier SAS chemicals / estrogens / isoflavones / lignans / phytoestrogens
Antiestrogenic activity of anthropogenic and natural chemicals
Environmental Science and Pollution Research, 1998
A number of natural and man-made chemicals possess antiestrogenic activity, i.e. they antagonize a broad spectrum of estrogeninduced responses in vertebrates. Examples of antiestrogens include dioxin, furan and PCB congeners, certain PAHs, pesticides and indol-3-carbinol derivatives. Major mechanisms of antiestrogenicity are antagonistic action of chemicals at the estrogen receptor, or binding of chemicals to the arylhydrocarbon (Ah) receptor and subsequent interaction with estrogen-responsive genes. Toxicological consequences resulting from antiestrogenic activity have not been conclusively demonstrated to date, although antiestrogenic compounds could critically affect sensitive reproductive and developmental processes. Abbreviations : AhR = arylhydrocarbon receptor, E2 = 17Gestradiol, X = xenobiotic, E2R = estrogen receptor, ERE = estrogen responsive element on the DNA, P450 = cytochrome P450 gene or enzyme, XRE = xenobiotic (or dioxin) responsive element on the DNA
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. #
APMIS, 2001
Newbold RR. Effects of developmental exposure to diethylstilbestrol (DES) in rodents: clues for other environmental estrogens. APMIS 200 1 ;(Suppl. 103) 109:S26 1-7 1. The synthetic estrogen diethylstilbestrol (DES) is a potent perinatal endocrine disrupter. In humans and experimental animal models, exposure to DES during critical periods of differentiation permanently alters estrogen target tissues subsequently resulting in structural, functional, and long-term abnormalities including neoplasia in reproductive tract tissues. Using the developmentally exposed rodent model, multiple mechanisms have been identified that play a role in DES-induced toxic effects. Although DES is a potent estrogen, it can be used as a model compound to predict the effects of other environmental estrogens. It was, therefore, of particular interest that very low doses of DES were found to adversely affect fertility and increase tumor incidence. These effects were seen at environmentally relevant estrogen dose levels. Not surprising, new studies verify that DES effects are not unique; when other environmental chemicals with estrogenic activity were tested in the experimental rodent model, developmental exposure was shown to result in an increased incidence of neoplasia, including uterine adenocarcinoma, similar to that shown following DES exposure. Finally, a growing number of reports suggest that some adverse effects can be passed on to subsequent generations, although the mechanisms involved in these transgenerational events remain unknown. These data point out the possibility that environmental estrogens and other endocrine disrupting compounds are indeed valid suspects in the alarming rise in adverse reproductive health consequences in human and wildlife populations.
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.
Environmental Health Perspectives, 1996
oestroge res e in gee any st. Second, emicals al aY YS w W. An assayed f r.dimminteracr6on with hiE. na compeatiton bind-ad5 chemicals~wee tested in the etrogen~responsiv-C.7hma ratcancer camdwitkalplasinad containig o respoee elements line _sgene. T1gether these assays have identifIedtnroanstabolites of DDT .o,p'-'-I>DDD,tta-veestro c activty Inte , pous studies had reported metabolites were nonestrogenic an whole animal modek. tlahlor, the most freide t Sitas a ianto or displyed weak ty in the c i asa T antifunga agent beo6mylhad no estrogenic .. s fir a morec pee chraceizto of chmials wit estoeic accMtiyw Key3
Current Medicinal Chemistry, 2010
Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and structural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added anthropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects.