Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
Environ Health Perspect. Jun 2003; 111(8): 994–1006.
PMCID: PMC1241550
Research Article

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

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (208K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Sheehan DM, Branham WS. Dissociation of estrogen-induced uterine growth and ornithine decarboxylase activity in the postnatal rat. Teratog Carcinog Mutagen. 1987;7(4):411–422. [PubMed]
  • Waller CL, Oprea TI, Chae K, Park HK, Korach KS, Laws SC, Wiese TE, Kelce WR, Gray LE., Jr Ligand-based identification of environmental estrogens. Chem Res Toxicol. 1996 Dec;9(8):1240–1248. [PubMed]
  • Hong Huixiao, Tong Weida, Fang Hong, Shi Leming, Xie Qian, Wu Jie, Perkins Roger, Walker John D, Branham William, Sheehan Daniel M. Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree-based model with structural alerts. Environ Health Perspect. 2002 Jan;110(1):29–36. [PMC free article] [PubMed]
  • Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV. Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect. 1997 Jan;105(1):70–76. [PMC free article] [PubMed]
  • Nagel SC, vom Saal FS, Welshons WV. The effective free fraction of estradiol and xenoestrogens in human serum measured by whole cell uptake assays: physiology of delivery modifies estrogenic activity. Proc Soc Exp Biol Med. 1998 Mar;217(3):300–309. [PubMed]
  • Nagel SC, vom Saal FS, Welshons WV. Developmental effects of estrogenic chemicals are predicted by an in vitro assay incorporating modification of cell uptake by serum. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):343–357. [PubMed]
  • Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev. 1989 Aug;10(3):232–274. [PubMed]
  • Hsu ST, Ma CI, Hsu SK, Wu SS, Hsu NH, Yeh CC, Wu SB. Discovery and epidemiology of PCB poisoning in Taiwan: a four-year followup. Environ Health Perspect. 1985 Feb;59:5–10. [PMC free article] [PubMed]
  • Quinn MM, Wegman DH, Greaves IA, Hammond SK, Ellenbecker MJ, Spark RF, Smith ER. Investigation of reports of sexual dysfunction among male chemical workers manufacturing stilbene derivatives. Am J Ind Med. 1990;18(1):55–68. [PubMed]
  • Morrissey RE, George JD, Price CJ, Tyl RW, Marr MC, Kimmel CA. The developmental toxicity of bisphenol A in rats and mice. Fundam Appl Toxicol. 1987 May;8(4):571–582. [PubMed]
  • Schönfelder Gilbert, Wittfoht Werner, Hopp Hartmut, Talsness Chris E, Paul Martin, Chahoud Ibrahim. Parent bisphenol A accumulation in the human maternal-fetal-placental unit. Environ Health Perspect. 2002 Nov;110(11):A703–A707. [PMC free article] [PubMed]
  • vom Saal FS. Sexual differentiation in litter-bearing mammals: influence of sex of adjacent fetuses in utero. J Anim Sci. 1989 Jul;67(7):1824–1840. [PubMed]
  • Newbold R. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect. 1995 Oct;103 (Suppl 7):83–87. [PMC free article] [PubMed]
  • Li S, Washburn KA, Moore R, Uno T, Teng C, Newbold RR, McLachlan JA, Negishi M. Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res. 1997 Oct 1;57(19):4356–4359. [PubMed]
  • Sheehan DM, Willingham E, Gaylor D, Bergeron JM, Crews D. No threshold dose for estradiol-induced sex reversal of turtle embryos: how little is too much? Environ Health Perspect. 1999 Feb;107(2):155–159. [PMC free article] [PubMed]
  • vom Saal FS, Timms BG, Montano MM, Palanza P, Thayer KA, Nagel SC, Dhar MD, Ganjam VK, Parmigiani S, Welshons WV. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2056–2061. [PMC free article] [PubMed]
  • Crews D, Willingham E, Skipper JK. Endocrine disruptors: present issues, future directions. Q Rev Biol. 2000 Sep;75(3):243–260. [PubMed]
  • Newbold RR, Banks EP, Bullock B, Jefferson WN. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res. 2001 Jun 1;61(11):4325–4328. [PubMed]
  • Wetherill Yelena B, Petre Christin E, Monk Kelly R, Puga Alvaro, Knudsen Karen E. The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells. Mol Cancer Ther. 2002 May;1(7):515–524. [PubMed]
  • Delclos KB, Bucci TJ, Lomax LG, Latendresse JR, Warbritton A, Weis CC, Newbold RR. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol. 2001 Nov-Dec;15(6):647–663. [PubMed]
  • Guo TL, White KL, Jr, Brown RD, Delclos KB, Newbold RR, Weis C, Germolec DR, McCay JA. 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. Toxicol Appl Pharmacol. 2002 Jun 15;181(3):219–227. [PubMed]
  • Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P. Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts. Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10751–10756. [PMC free article] [PubMed]
  • Thornton JW. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5671–5676. [PMC free article] [PubMed]
  • Falkenstein E, Wehling M. Nongenomically initiated steroid actions. Eur J Clin Invest. 2000 Dec;30 (Suppl 3):51–54. [PubMed]
  • Levin ER. Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol (1985) 2001 Oct;91(4):1860–1867. [PubMed]
  • Katzenellenbogen BS, Katzenellenbogen JA, Mordecai D. Zearalenones: characterization of the estrogenic potencies and receptor interactions of a series of fungal beta-resorcylic acid lactones. Endocrinology. 1979 Jul;105(1):33–40. [PubMed]
  • Pakdel F, Le Guellec C, Vaillant C, Le Roux MG, Valotaire Y. Identification and estrogen induction of two estrogen receptors (ER) messenger ribonucleic acids in the rainbow trout liver: sequence homology with other ERs. Mol Endocrinol. 1989 Jan;3(1):44–51. [PubMed]
  • White R, Jobling S, Hoare SA, Sumpter JP, Parker MG. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology. 1994 Jul;135(1):175–182. [PubMed]
  • Paige LA, Christensen DJ, Grøn H, Norris JD, Gottlin EB, Padilla KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3999–4004. [PMC free article] [PubMed]
  • Shang Yongfeng, Brown Myles. Molecular determinants for the tissue specificity of SERMs. Science. 2002 Mar 29;295(5564):2465–2468. [PubMed]
  • Favier B, Dollé P. Developmental functions of mammalian Hox genes. Mol Hum Reprod. 1997 Feb;3(2):115–131. [PubMed]
  • Fischer LJ, Weissinger JL. Development in the newborn rat of the conjugation and de-conjugation processes involved in the enterohepatic circulation of diethylstilboestrol. Xenobiotica. 1972 Jul;2(4):399–412. [PubMed]
  • Shah HC, McLachlan JA. The fate of diethylstilbestrol in the pregnant mouse. J Pharmacol Exp Ther. 1976 Jun;197(3):687–696. [PubMed]
  • LeRoith D, Delahunty G, Wilson GL, Roberts CT, Jr, Shemer J, Hart C, Lesniak MA, Shiloach J, Roth J. Evolutionary aspects of the endocrine and nervous systems. Recent Prog Horm Res. 1986;42:549–587. [PubMed]
  • Fox TO. Androgen- and estrogen-binding macromolecules in developing mouse brain: biochemical and genetic evidence. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4303–4307. [PMC free article] [PubMed]
  • Montano MM, Welshons WV, vom Saal FS. Free estradiol in serum and brain uptake of estradiol during fetal and neonatal sexual differentiation in female rats. Biol Reprod. 1995 Nov;53(5):1198–1207. [PubMed]
  • Welshons WV, Nagel SC, Thayer KA, Judy BM, Vom Saal FS. Low-dose bioactivity of xenoestrogens in animals: fetal exposure to low doses of methoxychlor and other xenoestrogens increases adult prostate size in mice. Toxicol Ind Health. 1999 Jan-Mar;15(1-2):12–25. [PubMed]
  • FURCHGOTT RF. The pharmacology of vascular smooth muscle. Pharmacol Rev. 1955 Jun;7(2):183–265. [PubMed]
  • NICKERSON M. Receptor occupancy and tissue response. Nature. 1956 Sep 29;178(4535):697–698. [PubMed]
  • STEPHENSON RP. A modification of receptor theory. Br J Pharmacol Chemother. 1956 Dec;11(4):379–393. [PMC free article] [PubMed]
  • Zhu BT. The competitive and noncompetitive antagonism of receptor-mediated drug actions in the presence of spare receptors. J Pharmacol Toxicol Methods. 1993 Apr;29(2):85–91. [PubMed]
  • Horwitz KB, McGuire WL. Nuclear mechanisms of estrogen action. Effects of estradiol and anti-estrogens on estrogen receptors and nuclear receptor processing. J Biol Chem. 1978 Nov 25;253(22):8185–8191. [PubMed]
  • Medlock KL, Forrester TM, Sheehan DM. Short-term effects of physiological and pharmacological doses of estradiol on estrogen receptor and uterine growth. J Recept Res. 1991;11(5):743–756. [PubMed]
  • Walent JH, Gorski J. Estrogen binding is a noncooperative process in primary rat uterine cells. Endocrinology. 1990 May;126(5):2383–2391. [PubMed]
  • Amara JF, Dannies PS. 17 beta-Estradiol has a biphasic effect on gh cell growth. Endocrinology. 1983 Mar;112(3):1141–1143. [PubMed]
  • Welshons WV, Jordan VC. Adaptation of estrogen-dependent MCF-7 cells to low estrogen (phenol red-free) culture. Eur J Cancer Clin Oncol. 1987 Dec;23(12):1935–1939. [PubMed]
  • Gupta C. Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals. Proc Soc Exp Biol Med. 2000 Jun;224(2):61–68. [PubMed]
  • Gupta C. The role of estrogen receptor, androgen receptor and growth factors in diethylstilbestrol-induced programming of prostate differentiation. Urol Res. 2000 Aug;28(4):223–229. [PubMed]
  • Putz O, Schwartz CB, Kim S, LeBlanc GA, Cooper RL, Prins GS. Neonatal low- and high-dose exposure to estradiol benzoate in the male rat: I. Effects on the prostate gland. Biol Reprod. 2001 Nov;65(5):1496–1505. [PubMed]
  • Prins GS, Birch L. The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology. 1995 Mar;136(3):1303–1314. [PubMed]
  • Santti R, Newbold RR, Mäkelä S, Pylkkänen L, McLachlan JA. Developmental estrogenization and prostatic neoplasia. Prostate. 1994;24(2):67–78. [PubMed]
  • Martikainen PM, Mäkelä SI, Santti RS, Härkönen PL, Suominen JJ. Interaction of male and female sex hormones in cultured rat prostate. Prostate. 1987;11(4):291–303. [PubMed]
  • Bigazzi M, Brandi ML, Bani G, Sacchi TB. Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer. 1992 Aug 1;70(3):639–643. [PubMed]
  • Welshons WV, Engler KS, Taylor JA, Grady LH, Curran EM. Lithium-stimulated proliferation and alteration of phosphoinositide metabolites in MCF-7 human breast cancer cells. J Cell Physiol. 1995 Oct;165(1):134–144. [PubMed]
  • Taylor JA, Grady LH, Engler KS, Welshons WV. Relationship of growth stimulated by lithium, estradiol, and EGF to phospholipase C activity in MCF-7 human breast cancer cells. Breast Cancer Res Treat. 1995 Jun;34(3):265–277. [PubMed]
  • Somjen D, Kohen F, Jaffe A, Amir-Zaltsman Y, Knoll E, Stern N. Effects of gonadal steroids and their antagonists on DNA synthesis in human vascular cells. Hypertension. 1998 Jul;32(1):39–45. [PubMed]
  • Moosmann B, Behl C. The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8867–8872. [PMC free article] [PubMed]
  • Davis JM, Svendsgaard DJ. U-shaped dose-response curves: their occurrence and implications for risk assessment. J Toxicol Environ Health. 1990 Jun;30(2):71–83. [PubMed]
  • Medlock KL, Lyttle CR, Kelepouris N, Newman ED, Sheehan DM. Estradiol down-regulation of the rat uterine estrogen receptor. Proc Soc Exp Biol Med. 1991 Mar;196(3):293–300. [PubMed]
  • vom Saal FS, Nagel SC, Palanza P, Boechler M, Parmigiani S, Welshons WV. Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during fetal life on subsequent territorial behaviour in male mice. Toxicol Lett. 1995 May;77(1-3):343–350. [PubMed]
  • Shelby MD, Newbold RR, Tully DB, Chae K, Davis VL. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. Environ Health Perspect. 1996 Dec;104(12):1296–1300. [PMC free article] [PubMed]
  • Oberdörster E, Rittschof D, LeBlanc GA. Alteration of [14C]-testosterone metabolism after chronic exposure of Daphnia magna to tributyltin. Arch Environ Contam Toxicol. 1998 Jan;34(1):21–25. [PubMed]
  • Alworth LC, Howdeshell KL, Ruhlen RL, Day JK, Lubahn DB, Huang THM, Besch-Williford CL, vom Saal FS. 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. Toxicol Appl Pharmacol. 2002 Aug 15;183(1):10–22. [PubMed]
  • Soule HD, Vazguez J, Long A, Albert S, Brennan M. A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 1973 Nov;51(5):1409–1416. [PubMed]
  • Lippman ME, Bolan G. Oestrogen-responsive human breast cancer in long term tissue culture. Nature. 1975 Aug 14;256(5518):592–593. [PubMed]
  • Lippman M, Bolan G, Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res. 1976 Dec;36(12):4595–4601. [PubMed]
  • Welshons WV, Murphy CS, Koch R, Calaf G, Jordan VC. Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol. Breast Cancer Res Treat. 1987 Nov;10(2):169–175. [PubMed]
  • Oesterreich S, Zhang P, Guler RL, Sun X, Curran EM, Welshons WV, Osborne CK, Lee AV. 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. Cancer Res. 2001 Aug 1;61(15):5771–5777. [PubMed]
  • Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496–2500. [PMC free article] [PubMed]
  • Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumor agents. Endocr Rev. 1990 Nov;11(4):578–610. [PubMed]
  • Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev. 1984 Dec;36(4):245–276. [PubMed]
  • Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. Exposure to bisphenol A advances puberty. Nature. 1999 Oct 21;401(6755):763–764. [PubMed]
  • Timms Barry G, Peterson Richard E, vom Saal Frederick S. 2,3,7,8-tetrachlorodibenzo-p-dioxin interacts with endogenous estradiol to disrupt prostate gland morphogenesis in male rat fetuses. Toxicol Sci. 2002 Jun;67(2):264–274. [PubMed]
  • Boettger-Tong H, Murthy L, Chiappetta C, Kirkland JL, Goodwin B, Adlercreutz H, Stancel GM, Mäkelä S. A case of a laboratory animal feed with high estrogenic activity and its impact on in vivo responses to exogenously administered estrogens. Environ Health Perspect. 1998 Jul;106(7):369–373. [PMC free article] [PubMed]
  • Markaverich Barry, Mani Shaila, Alejandro Mary Ann, Mitchell Andrea, Markaverich David, Brown Trellis, Velez-Trippe Claudia, Murchison Chris, O'Malley Bert, Faith Robert. A novel endocrine-disrupting agent in corn with mitogenic activity in human breast and prostatic cancer cells. Environ Health Perspect. 2002 Feb;110(2):169–177. [PMC free article] [PubMed]
  • Soto AM, Justicia H, Wray JW, Sonnenschein C. p-Nonyl-phenol: an estrogenic xenobiotic released from "modified" polystyrene. Environ Health Perspect. 1991 May;92:167–173. [PMC free article] [PubMed]
  • Krishnan AV, Stathis P, Permuth SF, Tokes L, Feldman D. Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology. 1993 Jun;132(6):2279–2286. [PubMed]
  • Adlercreutz H, Bannwart C, Wähälä K, Mäkelä T, Brunow G, Hase T, Arosemena PJ, Kellis JT, Jr, Vickery LE. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem Mol Biol. 1993 Feb;44(2):147–153. [PubMed]
  • Hoel DG, Portier CJ. Nonlinearity of dose-response functions for carcinogenicity. Environ Health Perspect. 1994 Jan;102 (Suppl 1):109–113. [PMC free article] [PubMed]
  • Zalko Daniel, Soto Ana M, Dolo Laurence, Dorio Céline, Rathahao Estelle, Debrauwer Laurent, Faure Robert, Cravedi Jean-Pierre. Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CD1 mice. Environ Health Perspect. 2003 Mar;111(3):309–319. [PMC free article] [PubMed]
  • Matsumoto Junya, Yokota Hiroshi, Yuasa Akira. Developmental increases in rat hepatic microsomal UDP-glucuronosyltransferase activities toward xenoestrogens and decreases during pregnancy. Environ Health Perspect. 2002 Feb;110(2):193–196. [PMC free article] [PubMed]
  • Brotons JA, Olea-Serrano MF, Villalobos M, Pedraza V, Olea N. Xenoestrogens released from lacquer coatings in food cans. Environ Health Perspect. 1995 Jun;103(6):608–612. [PMC free article] [PubMed]
  • Sonnenschein C, Soto AM, Fernandez MF, Olea N, Olea-Serrano MF, Ruiz-Lopez MD. Development of a marker of estrogenic exposure in human serum. Clin Chem. 1995 Dec;41(12 Pt 2):1888–1895. [PubMed]
  • Olea N, Pulgar R, Pérez P, Olea-Serrano F, Rivas A, Novillo-Fertrell A, Pedraza V, Soto AM, Sonnenschein C. Estrogenicity of resin-based composites and sealants used in dentistry. Environ Health Perspect. 1996 Mar;104(3):298–305. [PMC free article] [PubMed]
  • Steinmetz R, Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N. The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology. 1997 May;138(5):1780–1786. [PubMed]
  • Bolger R, Wiese TE, Ervin K, Nestich S, Checovich W. Rapid screening of environmental chemicals for estrogen receptor binding capacity. Environ Health Perspect. 1998 Sep;106(9):551–557. [PMC free article] [PubMed]
  • Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T, Safe S, McDonnell DP, Gaido KW. Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol. Mol Cell Endocrinol. 1998 Jul 25;142(1-2):203–214. [PubMed]
  • Celius T, Haugen TB, Grotmol T, Walther BT. A sensitive zonagenetic assay for rapid in vitro assessment of estrogenic potency of xenobiotics and mycotoxins. Environ Health Perspect. 1999 Jan;107(1):63–68. [PMC free article] [PubMed]
  • Takahashi O, Oishi S. Disposition of orally administered 2,2-Bis(4-hydroxyphenyl)propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses. Environ Health Perspect. 2000 Oct;108(10):931–935. [PMC free article] [PubMed]
  • Shin Beom Soo, Yoo Sun Dong, Cho Chang Youn, Jung Ji Hoon, Lee Byung Mu, Kim Jung Ha, Lee Kang Choon, Han Soon-Young, Kim Hyung Sik, Park Kui Lea. Maternal-fetal disposition of bisphenol a in pregnant Sprague-Dawley rats. J Toxicol Environ Health A. 2002 Mar;65(5-6):395–406. [PubMed]
  • Ikezuki Yumiko, Tsutsumi Osamu, Takai Yasushi, Kamei Yoshimasa, Taketani Yuji. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod. 2002 Nov;17(11):2839–2841. [PubMed]
  • Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C, Soto AM. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod. 2001 Oct;65(4):1215–1223. [PubMed]
  • Schönfelder G, Flick B, Mayr E, Talsness C, Paul M, Chahoud I. In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina. Neoplasia. 2002 Mar-Apr;4(2):98–102. [PMC free article] [PubMed]
  • Elswick BA, Welsch F, Janszen DB. Effect of different sampling designs on outcome of endocrine disruptor studies. Reprod Toxicol. 2000 Jul-Aug;14(4):359–367. [PubMed]
  • Ramos JG, Varayoud J, Sonnenschein C, Soto AM, Muñoz De Toro M, Luque EH. Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate. Biol Reprod. 2001 Oct;65(4):1271–1277. [PubMed]
  • vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV. 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. Toxicol Ind Health. 1998 Jan-Apr;14(1-2):239–260. [PubMed]
  • Takai Y, Tsutsumi O, Ikezuki Y, Kamei Y, Osuga Y, Yano T, Taketan Y. Preimplantation exposure to bisphenol A advances postnatal development. Reprod Toxicol. 2001 Jan-Feb;15(1):71–74. [PubMed]
  • Takai Y, Tsutsumi O, Ikezuki Y, Hiroi H, Osuga Y, Momoeda M, Yano T, Taketani Y. Estrogen receptor-mediated effects of a xenoestrogen, bisphenol A, on preimplantation mouse embryos. Biochem Biophys Res Commun. 2000 Apr 21;270(3):918–921. [PubMed]
  • Honma Shizuka, Suzuki Atsuko, Buchanan David L, Katsu Yoshinao, Watanabe Hajime, Iguchi Taisen. Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reprod Toxicol. 2002 Mar-Apr;16(2):117–122. [PubMed]
  • Kloas W, Lutz I, Einspanier R. Amphibians as a model to study endocrine disruptors: II. Estrogenic activity of environmental chemicals in vitro and in vivo. Sci Total Environ. 1999 Jan 12;225(1-2):59–68. [PubMed]
  • Haubruge E, Petit F, Gage MJ. Reduced sperm counts in guppies (Poecilia reticulata) following exposure to low levels of tributyltin and bisphenol A. Proc Biol Sci. 2000 Nov 22;267(1459):2333–2337. [PMC free article] [PubMed]
  • Oehlmann J, Schulte-Oehlmann U, Tillmann M, Markert B. Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part I: Bisphenol A and octylphenol as xeno-estrogens. Ecotoxicology. 2000 Dec;9(6):383–397. [PubMed]
  • Metcalfe CD, Metcalfe TL, Kiparissis Y, Koenig BG, Khan C, Hughes RJ, Croley TR, March RE, Potter T. Estrogenic potency of chemicals detected in sewage treatment plant effluents as determined by in vivo assays with Japanese medaka (Oryzias latipes). Environ Toxicol Chem. 2001 Feb;20(2):297–308. [PubMed]
  • Sohoni P, Tyler CR, Hurd K, Caunter J, Hetheridge M, Williams T, Woods C, Evans M, Toy R, Gargas M, et al. Reproductive effects of long-term exposure to Bisphenol A in the fathead minnow (Pimephales promelas). Environ Sci Technol. 2001 Jul 15;35(14):2917–2925. [PubMed]
  • Tabata A, Kashiwada S, Ohnishi Y, Ishikawa H, Miyamoto N, Itoh M, Magara Y. Estrogenic influences of estradiol-17 beta, p-nonylphenol and bis-phenol-A on Japanese medaka (Oryzias latipes) at detected environmental concentrations. Water Sci Technol. 2001;43(2):109–116. [PubMed]
  • Ashby J, Tinwell H, Haseman J. Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero. Regul Toxicol Pharmacol. 1999 Oct;30(2 Pt 1):156–166. [PubMed]
  • Ashby J. Dose levels of 0.01-0.2 microg/kg/day diethylstilbestrol are not suitable for use as a positive control in endocrine toxicity studies. Regul Toxicol Pharmacol. 1999 Jun;29(3):235–237. [PubMed]
  • Thayer KA, Ruhlen RL, Howdeshell KL, Buchanan DL, Cooke PS, Preziosi D, Welshons WV, Haseman J, vom Saal FS. Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17alpha-ethinyl oestradiol. Hum Reprod. 2001 May;16(5):988–996. [PubMed]
  • Rajapakse Nissanka, Silva Elisabete, Kortenkamp Andreas. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect. 2002 Sep;110(9):917–921. [PMC free article] [PubMed]
  • Grady LH, Nonneman DJ, Rottinghaus GE, Welshons WV. pH-dependent cytotoxicity of contaminants of phenol red for MCF-7 breast cancer cells. Endocrinology. 1991 Dec;129(6):3321–3330. [PubMed]
  • Welshons WV, Rottinghaus GE, Nonneman DJ, Dolan-Timpe M, Ross PF. A sensitive bioassay for detection of dietary estrogens in animal feeds. J Vet Diagn Invest. 1990 Oct;2(4):268–273. [PubMed]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...