Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.

Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.

[1]  Wade V Welshons,et al.  Bisphenol A is released from used polycarbonate animal cages into water at room temperature. , 2003, Environmental health perspectives.

[2]  Y. Taketani,et al.  Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. , 2002, Human reproduction.

[3]  D. Zalko,et al.  Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CD1 mice. , 2002, Environmental health perspectives.

[4]  I. Chahoud,et al.  Parent bisphenol A accumulation in the human maternal-fetal-placental unit. , 2002, Environmental health perspectives.

[5]  A. Kortenkamp,et al.  Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. , 2002, Environmental health perspectives.

[6]  J. K. Day,et al.  Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low versus high doses. , 2002, Toxicology and applied pharmacology.

[7]  M. Mendelsohn.  Genomic and nongenomic effects of estrogen in the vasculature. , 2002, The American journal of cardiology.

[8]  T. Guo,et al.  Genistein modulates splenic natural killer cell activity, antibody-forming cell response, and phenotypic marker expression in F(0) and F(1) generations of Sprague-Dawley rats. , 2002, Toxicology and applied pharmacology.

[9]  R. Peterson,et al.  2,3,7,8-tetrachlorodibenzo-p-dioxin interacts with endogenous estradiol to disrupt prostate gland morphogenesis in male rat fetuses. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[10]  Alvaro Puga,et al.  The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. , 2002, Molecular cancer therapeutics.

[11]  Myles Brown,et al.  Molecular Determinants for the Tissue Specificity of SERMs , 2002, Science.

[12]  Hajime Watanabe,et al.  Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. , 2002, Reproductive toxicology.

[13]  B. Shin,et al.  MATERNAL-FETAL DISPOSITION OF BISPHENOL A IN PREGNANT SPRAGUE-DAWLEY RATS , 2002, Journal of toxicology and environmental health. Part A.

[14]  H. Yokota,et al.  Developmental increases in rat hepatic microsomal UDP-glucuronosyltransferase activities toward xenoestrogens and decreases during pregnancy. , 2002, Environmental health perspectives.

[15]  R. Faith,et al.  A novel endocrine-disrupting agent in corn with mitogenic activity in human breast and prostatic cancer cells. , 2002, Environmental health perspectives.

[16]  Weida Tong,et al.  Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree-based model with structural alerts. , 2001, Environmental health perspectives.

[17]  G. Prins,et al.  Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: I. Effects on the Prostate Gland1 , 2001, Biology of reproduction.

[18]  J. Latendresse,et al.  Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. , 2001, Reproductive toxicology.

[19]  G. Prins,et al.  Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: II. Effects on Male Puberty and the Reproductive Tract , 2001, Biology of reproduction.

[20]  K. Carroll,et al.  Chronic exposure to 17α-ethinylestradiol and bisphenol A-effects on development and reproduction in the freshwater invertebrate Chironomus riparius (Diptera: Chironomidae) , 2001 .

[21]  C. Sonnenschein,et al.  Prenatal Exposure to Low Doses of Bisphenol A Alters the Periductal Stroma and Glandular Cell Function in the Rat Ventral Prostate1 , 2001, Biology of reproduction.

[22]  E. Levin.  highlighted topics Genome and Hormones: Gender Differences in Physiology Invited Review: Cell localization, physiology, and nongenomic actions of estrogen receptors , 2001 .

[23]  C. Sonnenschein,et al.  In Utero Exposure to Bisphenol A Alters the Development and Tissue Organization of the Mouse Mammary Gland , 2001 .

[24]  C. Osborne,et al.  Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. , 2001, Cancer research.

[25]  C. Tohyama,et al.  Bisphenol‐A Affects Spermatogenesis in the Adult Rat Even at a Low Dose , 2001 .

[26]  J. Sumpter,et al.  Reproductive effects of long-term exposure to Bisphenol A in the fathead minnow (Pimephales promelas). , 2001, Environmental science & technology.

[27]  R. Newbold,et al.  Uterine adenocarcinoma in mice treated neonatally with genistein. , 2001, Cancer research.

[28]  J. W. Thornton.  Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Haseman,et al.  Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17alpha-ethinyl oestradiol. , 2001, Human reproduction.

[30]  T. Croley,et al.  Estrogenic potency of chemicals detected in sewage treatment plant effluents as determined by in vivo assays with Japanese medaka (Oryzias latipes) , 2001, Environmental toxicology and chemistry.

[31]  E. Falkenstein,et al.  Nongenomically initiated steroid actions , 2000, European journal of clinical investigation.

[32]  Bernd Markert,et al.  Effects of Endocrine Disruptors on Prosobranch Snails (Mollusca: Gastropoda) in the Laboratory. Part I: Bisphenol A and Octylphenol as Xeno-Estrogens , 2000, Ecotoxicology.

[33]  M. Gage,et al.  Reduced sperm counts in guppies (Poecilia reticulata) following exposure to low levels of tributyltin and bisphenol A , 2000, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[34]  S. Oishi,et al.  Disposition of orally administered 2,2-Bis(4-hydroxyphenyl)propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses. , 2000, Environmental health perspectives.

[35]  J. Thornton,et al.  Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Crews,et al.  Endocrine Disruptors: Present Issues, Future Directions , 2000, The Quarterly Review of Biology.

[37]  C. Gupta.  The role of estrogen receptor, androgen receptor and growth factors in diethylstilbestrol-induced programming of prostate differentiation , 2000, Urological Research.

[38]  D. Janszen,et al.  Effect of different sampling designs on outcome of endocrine disruptor studies. , 2000, Reproductive toxicology.

[39]  C. Gupta.  Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. , 2000 .

[40]  Y. Taketani,et al.  Estrogen receptor-mediated effects of a xenoestrogen, bisphenol A, on preimplantation mouse embryos. , 2000, Biochemical and biophysical research communications.

[41]  Kristina A. Thayer,et al.  Environmental toxins: Exposure to bisphenol A advances puberty , 1999, Nature.

[42]  J Ashby,et al.  Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero. , 1999, Regulatory toxicology and pharmacology : RTP.

[43]  C. Behl,et al.  The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  L. R. Harris,et al.  Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  J. Ashby.  Dose levels of 0.01-0.2 microg/kg/day diethylstilbestrol are not suitable for use as a positive control in endocrine toxicity studies. , 1999, Regulatory toxicology and pharmacology : RTP.

[46]  W. Welshons,et al.  Developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[47]  H Grøn,et al.  Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  D. Gaylor,et al.  No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much? , 1999, Environmental health perspectives.

[49]  W. Welshons,et al.  Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice , 1999, Toxicology and industrial health.

[50]  R. Einspanier,et al.  Amphibians as a model to study endocrine disruptors: II. Estrogenic activity of environmental chemicals in vitro and in vivo. , 1999, The Science of the total environment.

[51]  T. Grotmol,et al.  A sensitive zonagenetic assay for rapid in vitro assessment of estrogenic potency of xenobiotics and mycotoxins. , 1999, Environmental health perspectives.

[52]  T. Wiese,et al.  Rapid screening of environmental chemicals for estrogen receptor binding capacity. , 1998, Environmental health perspectives.

[53]  Kevin W. Gaido,et al.  Bisphenol A interacts with the estrogen receptor α in a distinct manner from estradiol , 1998, Molecular and Cellular Endocrinology.

[54]  N. Stern,et al.  Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. , 1998, Hypertension.

[55]  W. Welshons,et al.  The Effective Free Fraction of Estradiol and Xenoestrogens in Human Serum Measured by Whole Cell Uptake Assays: Physiology of Delivery Modifies Estrogenic Activity , 1998, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[56]  P. Cooke,et al.  A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and Behavior , 1998, Toxicology and industrial health.

[57]  E. Calabrese,et al.  The Dose Determines the Stimulation (and Poison): Development of A Chemical Hormesis Database , 1997 .

[58]  J. McLachlan,et al.  Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. , 1997, Cancer research.

[59]  R. Bigsby,et al.  The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. , 1997, Endocrinology.

[60]  K A Thayer,et al.  Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[61]  P. Dollé,et al.  Developmental functions of mammalian Hox genes. , 1997, Molecular human reproduction.

[62]  R P STEPHENSON,et al.  A MODIFICATION OF RECEPTOR THEORY , 1997, British journal of pharmacology and chemotherapy.

[63]  A. McCollam,et al.  Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. , 1997, Environmental health perspectives.

[64]  M D Shelby,et al.  Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. , 1996, Environmental Health Perspectives.

[65]  Tudor I. Oprea,et al.  Ligand-based identification of environmental estrogens. , 1996, Chemical research in toxicology.

[66]  F. Olea-Serrano,et al.  Estrogenicity of resin-based composites and sealants used in dentistry. , 1996, Environmental health perspectives.

[67]  N. Olea,et al.  Development of a marker of estrogenic exposure in human serum. , 1995, Clinical chemistry.

[68]  M. Montano,et al.  Free estradiol in serum and brain uptake of estradiol during fetal and neonatal sexual differentiation in female rats. , 1995, Biology of reproduction.

[69]  R. Newbold.  Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. , 1995, Environmental health perspectives.

[70]  Julia A. Taylor,et al.  Lithium‐stimulated proliferation and alteration of phosphoinositide metabolites in MCF‐7 human breast cancer cells , 1995, Journal of cellular physiology.

[71]  Julia A. Taylor,et al.  Relationship of growth stimulated by lithium, estradiol, and EGF to phospholipase C activity in MCF-7 human breast cancer cells , 1995, Breast Cancer Research and Treatment.

[72]  N. Olea,et al.  Xenoestrogens released from lacquer coatings in food cans. , 1995, Environmental health perspectives.

[73]  W. Welshons,et al.  Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during fetal life on subsequent territorial behaviour in male mice. , 1995, Toxicology letters.

[74]  G. Prins,et al.  The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. , 1995, Endocrinology.

[75]  J. Sumpter,et al.  Environmentally persistent alkylphenolic compounds are estrogenic. , 1994, Endocrinology.

[76]  J. McLachlan,et al.  Developmental estrogenization and prostatic neoplasia , 1994, The Prostate.

[77]  D G Hoel,et al.  Nonlinearity of dose-response functions for carcinogenicity. , 1994, Environmental health perspectives.

[78]  D. Feldman,et al.  Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. , 1993, Endocrinology.

[79]  B. Zhu.  The competitive and noncompetitive antagonism of receptor-mediated drug actions in the presence of spare receptors. , 1993, Journal of pharmacological and toxicological methods.

[80]  H. Adlercreutz,et al.  Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[81]  M. Brandi,et al.  Relaxin influences the growth of MCF‐7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration , 1992, Cancer.

[82]  G. Rottinghaus,et al.  pH-dependent cytotoxicity of contaminants of phenol red for MCF-7 breast cancer cells. , 1991, Endocrinology.

[83]  C. Sonnenschein,et al.  p-Nonyl-phenol: an estrogenic xenobiotic released from "modified" polystyrene. , 1991, Environmental health perspectives.

[84]  D M Sheehan,et al.  Estradiol Down-Regulation of the Rat Uterine Estrogen Receptor , 1991, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[85]  V. Jordan,et al.  Endocrine pharmacology of antiestrogens as antitumor agents. , 1990, Endocrine reviews.

[86]  G. Rottinghaus,et al.  A Sensitive Bioassay for Detection of Dietary Estrogens in Animal Feeds , 1990, Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc.

[87]  Davis Jm,et al.  U-shaped dose-response curves: their occurrence and implications for risk assessment. , 1990, Journal of toxicology and environmental health.

[88]  J. Gorski,et al.  Estrogen binding is a noncooperative process in primary rat uterine cells. , 1990, Endocrinology.

[89]  C. Mendel.  The free hormone hypothesis: a physiologically based mathematical model. , 1989, Endocrine reviews.

[90]  F. S. Saal,et al.  Sexual differentiation in litter-bearing mammals: influence of sex of adjacent fetuses in utero. , 1989 .

[91]  W. Welshons,et al.  Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. , 1987, European journal of cancer & clinical oncology.

[92]  G. Calaf,et al.  Stimulation of breast cancer cellsin vitro by the environmental estrogen enterolactone and the phytoestrogen equol , 1987, Breast Cancer Research and Treatment.

[93]  Carole A. Kimmel,et al.  The developmental toxicity of bisphenol A in rats and mice. , 1987, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[94]  G. Stancel,et al.  Accumulation of basement membrane components in interface between gastric carcinoma cells and fibroblasts in vitro. , 1986, British Journal of Cancer.

[95]  B. Katzenellenbogen,et al.  Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[96]  S. Hsu,et al.  Discovery and epidemiology of PCB poisoning in Taiwan: a four-year followup. , 1985, Environmental health perspectives.

[97]  V. Jordan.  Biochemical pharmacology of antiestrogen action. , 1984, Pharmacological reviews.

[98]  P. Dannies,et al.  17β-ESTRADIOL HAS A BIPHASIC EFFECT ON GH CELL GROWTH1 , 1983 .

[99]  W. Poznanski.  Basic and Clinical Endocrinology. , 1982 .

[100]  B. Katzenellenbogen,et al.  Zearalenones: characterization of the estrogenic potencies and receptor interactions of a series of fungal beta-resorcylic acid lactones. , 1979, Endocrinology.

[101]  W. McGuire,et al.  Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. , 1978, The Journal of biological chemistry.

[102]  M. Lippman,et al.  The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. , 1976, Cancer research.

[103]  J. McLachlan,et al.  The fate of diethylstilbestrol in the pregnant mouse. , 1976, The Journal of pharmacology and experimental therapeutics.

[104]  T. O. Fox.  Androgen- and estrogen-binding macromolecules in developing mouse brain: biochemical and genetic evidence. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[105]  M. Lippman,et al.  Oestrogen-responsive human breast cancer in long term tissue culture , 1975, Nature.

[106]  A. Long,et al.  A human cell line from a pleural effusion derived from a breast carcinoma. , 1973, Journal of the National Cancer Institute.

[107]  M. Nickerson.  Receptor Occupancy and Tissue Response , 1956, Nature.

[108]  R. Furchgott,et al.  The pharmacology of vascular smooth muscle. , 1955, Pharmacological reviews.

[109]  I. Chahoud,et al.  In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina. , 2002, Neoplasia.

[110]  S. Kashiwada,et al.  Estrogenic influences of estradiol-17 beta, p-nonylphenol and bis-phenol-A on Japanese medaka (Oryzias latipes) at detected environmental concentrations. , 2001, Water science and technology : a journal of the International Association on Water Pollution Research.

[111]  T. Yano,et al.  Preimplantation exposure to bisphenol A advances postnatal development. , 2001, Reproductive toxicology.

[112]  E. Oberdörster.  Hormonally Active Agents in the Environment , 2001 .

[113]  G. R. Barrie Webster,et al.  Hormonally Active Agents in the Environment , 2001 .

[114]  E. Oberdörster,et al.  Alteration of [14C]-Testosterone Metabolism After Chronic Exposure of Daphnia magna to Tributyltin , 1998, Archives of environmental contamination and toxicology.

[115]  B. Galef,et al.  Effects of intrauterine position on the behavior and genital morphology of litter‐bearing rodents , 1998 .

[116]  C. Finch,et al.  Natural history and mechanisms of reproductive aging in humans, laboratory rodents, and other selected vertebrates. In: Knobil E, Neill JD, eds. , 1994 .

[117]  T. Colborn,et al.  Chemically-induced alterations in sexual and functional development : the wildlife/human connection , 1992 .

[118]  T. M. Forrester,et al.  Short-term effects of physiological and pharmacological doses of estradiol on estrogen receptor and uterine growth. , 1991, Journal of receptor research.

[119]  D. Wegman,et al.  Investigation of reports of sexual dysfunction among male chemical workers manufacturing stilbene derivatives. , 1990, American journal of industrial medicine.

[120]  F. Pakdel,et al.  Identification and estrogen induction of two estrogen receptors (ER) messenger ribonucleic acids in the rainbow trout liver: sequence homology with other ERs. , 1989, Molecular endocrinology.

[121]  F. V. vom Saal.  Sexual differentiation in litter-bearing mammals: influence of sex of adjacent fetuses in utero. , 1989, Journal of animal science.

[122]  P. Härkönen,et al.  Interaction of male and female sex hormones in cultured rat prostate , 1987, The Prostate.

[123]  W. Branham,et al.  Dissociation of estrogen-induced uterine growth and ornithine decarboxylase activity in the postnatal rat. , 1987, Teratogenesis, carcinogenesis, and mutagenesis.

[124]  J. Shiloach,et al.  Evolutionary aspects of the endocrine and nervous systems. , 1986, Recent progress in hormone research.

[125]  P. Dannies,et al.  17 beta-Estradiol has a biphasic effect on gh cell growth. , 1983, Endocrinology.

[126]  Albertini.  Free Hormones In Blood , 1982 .

[127]  G. Pamnani,et al.  Available , 1981 .

[128]  R. King,et al.  Steroid-cell interactions , 1974 .

[129]  L. J. Fischer,et al.  Development in the newborn rat of the conjugation and de-conjugation processes involved in the enterohepatic circulation of diethylstilboestrol. , 1972, Xenobiotica; the fate of foreign compounds in biological systems.

[130]  L. Kier.  Molecular Orbital Theory In Drug Research , 1971 .

[131]  P. Sexton,et al.  Molecular Pharmacology , 1965, Nature.