Skip to main content
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2003 Jun;111(8):1020–1036. doi: 10.1289/ehp.6023

A critical review of methods for comparing estrogenic activity of endogenous and exogenous chemicals in human milk and infant formula.

Christopher J Borgert 1, Judy S LaKind 1, Raphael J Witorsch 1
PMCID: PMC1241552  PMID: 12826475

Abstract

The two primary sources of nutrition for infants are human milk and infant formula. Both contain an array of endogenous and exogenous chemicals that may act through many separate hormonal mechanisms. The safety of infant nutrition sources has been questioned based on the possibility that exogenous chemicals may exert adverse effects on nursing or formula-fed infants through estrogen-mediated mechanisms. In response to these and other concerns, the National Research Council recommended assessing the estrogenic potency of natural and anthropogenic hormonally active agents. Furthermore, the Endocrine Disruptor Screening and Testing Advisory Committee of the U.S. Environmental Protection Agency specifically recommended testing chemicals present in human milk as a representative mixture to which large segments of the population are exposed. To date, no clinical or epidemiologic evidence demonstrates that levels of chemicals currently found in human milk or infant formulas cause adverse effects in infants. Nonetheless, the question is sufficiently important to warrant a consideration of how best to evaluate potential estrogenic risks. We reviewed the types of data available for measuring estrogenic potency as well as methods for estimating health risks from mixtures of chemicals in infant nutrition sources that act via estrogenic mechanisms. We conclude that the science is insufficiently developed at this time to allow a credible assessment of health risks to infants based on estimates of estrogenic potency or on an understanding of toxicologic effects mediated by estrogenic mechanisms. However, clinical and epidemiologic data for infant nutrition sources may provide insights about risks of such substances in human milk and infant formulas.

Full Text

The Full Text of this article is available as a PDF (203.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen H. R., Andersson A. M., Arnold S. F., Autrup H., Barfoed M., Beresford N. A., Bjerregaard P., Christiansen L. B., Gissel B., Hummel R. Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals. Environ Health Perspect. 1999 Feb;107 (Suppl 1):89–108. doi: 10.1289/ehp.99107s189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnold S. F., Vonier P. M., Collins B. M., Klotz D. M., Guillette L. J., Jr, McLachlan J. A. In vitro synergistic interaction of alligator and human estrogen receptors with combinations of environmental chemicals. Environ Health Perspect. 1997 Apr;105 (Suppl 3):615–618. doi: 10.1289/ehp.97105s3615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baird D. D., Umbach D. M., Lansdell L., Hughes C. L., Setchell K. D., Weinberg C. R., Haney A. F., Wilcox A. J., Mclachlan J. A. Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. J Clin Endocrinol Metab. 1995 May;80(5):1685–1690. doi: 10.1210/jcem.80.5.7745019. [DOI] [PubMed] [Google Scholar]
  4. Baker M. E. Steroid receptor phylogeny and vertebrate origins. Mol Cell Endocrinol. 1997 Dec 12;135(2):101–107. doi: 10.1016/s0303-7207(97)00207-4. [DOI] [PubMed] [Google Scholar]
  5. Balaguer P., François F., Comunale F., Fenet H., Boussioux A. M., Pons M., Nicolas J. C., Casellas C. Reporter cell lines to study the estrogenic effects of xenoestrogens. Sci Total Environ. 1999 Aug 15;233(1-3):47–56. doi: 10.1016/s0048-9697(99)00178-3. [DOI] [PubMed] [Google Scholar]
  6. Barrett Julia R. Soy and children's health: a formula for trouble. Environ Health Perspect. 2002 Jun;110(6):A294–A296. doi: 10.1289/ehp.110-a294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bayer T., Colnot T., Dekant W. Disposition and biotransformation of the estrogenic isoflavone daidzein in rats. Toxicol Sci. 2001 Aug;62(2):205–211. doi: 10.1093/toxsci/62.2.205. [DOI] [PubMed] [Google Scholar]
  8. Beato M., Chávez S., Truss M. Transcriptional regulation by steroid hormones. Steroids. 1996 Apr;61(4):240–251. doi: 10.1016/0039-128x(96)00030-x. [DOI] [PubMed] [Google Scholar]
  9. Behnisch P. A., Fujii K., Shiozaki K., Kawakami I., Sakai S. Estrogenic and dioxin-like potency in each step of a controlled landfill leachate treatment plant in Japan. Chemosphere. 2001 May-Jun;43(4-7):977–984. doi: 10.1016/s0045-6535(00)00458-6. [DOI] [PubMed] [Google Scholar]
  10. Berenbaum M. C. What is synergy? Pharmacol Rev. 1989 Jun;41(2):93–141. [PubMed] [Google Scholar]
  11. Bergeron J. M., Crews D., McLachlan J. A. PCBs as environmental estrogens: turtle sex determination as a biomarker of environmental contamination. Environ Health Perspect. 1994 Sep;102(9):780–781. doi: 10.1289/ehp.94102780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bernt K. M., Walker W. A. Human milk as a carrier of biochemical messages. Acta Paediatr Suppl. 1999 Aug;88(430):27–41. doi: 10.1111/j.1651-2227.1999.tb01298.x. [DOI] [PubMed] [Google Scholar]
  13. Blair R. M., Fang H., Branham W. S., Hass B. S., Dial S. L., Moland C. L., Tong W., Shi L., Perkins R., Sheehan D. M. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000 Mar;54(1):138–153. doi: 10.1093/toxsci/54.1.138. [DOI] [PubMed] [Google Scholar]
  14. Bonefeld-Jørgensen E. C., Andersen H. R., Rasmussen T. H., Vinggaard A. M. Effect of highly bioaccumulated polychlorinated biphenyl congeners on estrogen and androgen receptor activity. Toxicology. 2001 Feb 14;158(3):141–153. doi: 10.1016/s0300-483x(00)00368-1. [DOI] [PubMed] [Google Scholar]
  15. Britton J. R., Kastin A. J. Biologically active polypeptides in milk. Am J Med Sci. 1991 Feb;301(2):124–132. doi: 10.1097/00000441-199102000-00007. [DOI] [PubMed] [Google Scholar]
  16. Carlson D. B., Williams D. E. 4-hydroxy-2',4',6'-trichlorobiphenyl and 4-hydroxy-2',3',4',5'-tetrachlorobiphenyl are estrogenic in rainbow trout. Environ Toxicol Chem. 2001 Feb;20(2):351–358. [PubMed] [Google Scholar]
  17. Chang W. Y., Prins G. S. Estrogen receptor-beta: implications for the prostate gland. Prostate. 1999 Jul 1;40(2):115–124. doi: 10.1002/(sici)1097-0045(19990701)40:2<115::aid-pros7>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  18. Charles G. D., Bartels M. J., Zacharewski T. R., Gollapudi B. B., Freshour N. L., Carney E. W. Activity of benzo[a]pyrene and its hydroxylated metabolites in an estrogen receptor-alpha reporter gene assay. Toxicol Sci. 2000 Jun;55(2):320–326. doi: 10.1093/toxsci/55.2.320. [DOI] [PubMed] [Google Scholar]
  19. Chen C. W., Hurd C., Vorojeikina D. P., Arnold S. F., Notides A. C. Transcriptional activation of the human estrogen receptor by DDT isomers and metabolites in yeast and MCF-7 cells. Biochem Pharmacol. 1997 Apr 25;53(8):1161–1172. doi: 10.1016/s0006-2952(97)00097-x. [DOI] [PubMed] [Google Scholar]
  20. Chorazy P. A., Himelhoch S., Hopwood N. J., Greger N. G., Postellon D. C. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics. 1995 Jul;96(1 Pt 1):148–150. [PubMed] [Google Scholar]
  21. Connor K., Ramamoorthy K., Moore M., Mustain M., Chen I., Safe S., Zacharewski T., Gillesby B., Joyeux A., Balaguer P. Hydroxylated polychlorinated biphenyls (PCBs) as estrogens and antiestrogens: structure-activity relationships. Toxicol Appl Pharmacol. 1997 Jul;145(1):111–123. doi: 10.1006/taap.1997.8169. [DOI] [PubMed] [Google Scholar]
  22. Cummings A. M., Laws S. C. Assessment of estrogenicity by using the delayed implanting rat model and examples. Reprod Toxicol. 2000 Mar-Apr;14(2):111–117. doi: 10.1016/s0890-6238(00)00062-9. [DOI] [PubMed] [Google Scholar]
  23. Danzo B. J. Environmental xenobiotics may disrupt normal endocrine function by interfering with the binding of physiological ligands to steroid receptors and binding proteins. Environ Health Perspect. 1997 Mar;105(3):294–301. doi: 10.1289/ehp.97105294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Degen G. H., Bolt H. M. Endocrine disruptors: update on xenoestrogens. Int Arch Occup Environ Health. 2000 Sep;73(7):433–441. doi: 10.1007/s004200000163. [DOI] [PubMed] [Google Scholar]
  25. Diel P., Schulz T., Smolnikar K., Strunck E., Vollmer G., Michna H. Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity. J Steroid Biochem Mol Biol. 2000 May;73(1-2):1–10. doi: 10.1016/s0960-0760(00)00051-0. [DOI] [PubMed] [Google Scholar]
  26. DuMond J. W., Jr, Singh K. P., Roy D. Regulation of the growth of mouse Leydig cells by the inactive stereoisomer, 17alpha-estradiol: Lack of correlation between the elevated expression of ERalpha and difference in sensitivity to estradiol isomers. Oncol Rep. 2001 Jul-Aug;8(4):899–902. [PubMed] [Google Scholar]
  27. Ebrahim G. J. Breastmilk endocrinology. J Trop Pediatr. 1996 Feb;42(1):2–4. doi: 10.1093/tropej/42.1.2. [DOI] [PubMed] [Google Scholar]
  28. Elsby R., Ashby J., Sumpter J. P., Brooks A. N., Pennie W. D., Maggs J. L., Lefevre P. A., Odum J., Beresford N., Paton D. Obstacles to the prediction of estrogenicity from chemical structure: assay-mediated metabolic transformation and the apparent promiscuous nature of the estrogen receptor. Biochem Pharmacol. 2000 Nov 15;60(10):1519–1530. doi: 10.1016/s0006-2952(00)00466-4. [DOI] [PubMed] [Google Scholar]
  29. Elsby R., Maggs J. L., Ashby J., Park B. K. Comparison of the modulatory effects of human and rat liver microsomal metabolism on the estrogenicity of bisphenol A: implications for extrapolation to humans. J Pharmacol Exp Ther. 2001 Apr;297(1):103–113. [PubMed] [Google Scholar]
  30. Elsby R., Maggs J. L., Ashby J., Paton D., Sumpter J. P., Park B. K. Assessment of the effects of metabolism on the estrogenic activity of xenoestrogens: a two-stage approach coupling human liver microsomes and a yeast estrogenicity assay. J Pharmacol Exp Ther. 2001 Feb;296(2):329–337. [PubMed] [Google Scholar]
  31. Eroschenko V. P., Johnson T. J., Rourke A. W. Estradiol and pesticide methoxychlor do not exhibit additivity or synergism in the reproductive tract of adult ovariectomized mice. J Toxicol Environ Health A. 2000 Jul 28;60(6):407–421. doi: 10.1080/00984100050033485. [DOI] [PubMed] [Google Scholar]
  32. Escriva H., Safi R., Hänni C., Langlois M. C., Saumitou-Laprade P., Stehelin D., Capron A., Pierce R., Laudet V. Ligand binding was acquired during evolution of nuclear receptors. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6803–6808. doi: 10.1073/pnas.94.13.6803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Essex C. Phytoestrogens and soy based infant formula. BMJ. 1996 Aug 31;313(7056):507–508. doi: 10.1136/bmj.313.7056.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Feron V. J., Groten J. P., van Bladeren P. J. Exposure of humans to complex chemical mixtures: hazard identification and risk assessment. Arch Toxicol Suppl. 1998;20:363–373. doi: 10.1007/978-3-642-46856-8_32. [DOI] [PubMed] [Google Scholar]
  35. Fertuck K. C., Matthews J. B., Zacharewski T. R. Hydroxylated benzo[a]pyrene metabolites are responsible for in vitro estrogen receptor-mediated gene expression induced by benzo[a]pyrene, but do not elicit uterotrophic effects in vivo. Toxicol Sci. 2001 Feb;59(2):231–240. doi: 10.1093/toxsci/59.2.231. [DOI] [PubMed] [Google Scholar]
  36. Fielden M. R., Chen I., Chittim B., Safe S. H., Zacharewski T. R. Examination of the estrogenicity of 2,4,6,2',6'-pentachlorobiphenyl (PCB 104), its hydroxylated metabolite 2,4,6,2',6'-pentachloro-4-biphenylol (HO-PCB 104), and a further chlorinated derivative, 2,4,6,2',4',6'-hexachlorobiphenyl (PCB 155). Environ Health Perspect. 1997 Nov;105(11):1238–1248. doi: 10.1289/ehp.971051238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Fort P., Moses N., Fasano M., Goldberg T., Lifshitz F. Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children. J Am Coll Nutr. 1990 Apr;9(2):164–167. doi: 10.1080/07315724.1990.10720366. [DOI] [PubMed] [Google Scholar]
  38. Franke A. A., Custer L. J. Daidzein and genistein concentrations in human milk after soy consumption. Clin Chem. 1996 Jun;42(6 Pt 1):955–964. [PubMed] [Google Scholar]
  39. Freni-Titulaer L. W., Cordero J. F., Haddock L., Lebrón G., Martínez R., Mills J. L. Premature thelarche in Puerto Rico. A search for environmental factors. Am J Dis Child. 1986 Dec;140(12):1263–1267. doi: 10.1001/archpedi.1986.02140260065028. [DOI] [PubMed] [Google Scholar]
  40. Garner C. E., Jefferson W. N., Burka L. T., Matthews H. B., Newbold R. R. In vitro estrogenicity of the catechol metabolites of selected polychlorinated biphenyls. Toxicol Appl Pharmacol. 1999 Jan 15;154(2):188–197. doi: 10.1006/taap.1998.8560. [DOI] [PubMed] [Google Scholar]
  41. Gierthy J. F., Arcaro K. F., Floyd M. Assessment of PCB estrogenicity in a human breast cancer cell line. Chemosphere. 1997 Mar-Apr;34(5-7):1495–1505. doi: 10.1016/s0045-6535(97)00446-3. [DOI] [PubMed] [Google Scholar]
  42. Greco W. R., Bravo G., Parsons J. C. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995 Jun;47(2):331–385. [PubMed] [Google Scholar]
  43. Grosvenor C. E., Picciano M. F., Baumrucker C. R. Hormones and growth factors in milk. Endocr Rev. 1993 Dec;14(6):710–728. doi: 10.1210/edrv-14-6-710. [DOI] [PubMed] [Google Scholar]
  44. Gustafsson J. A. An update on estrogen receptors. Semin Perinatol. 2000 Feb;24(1):66–69. doi: 10.1016/s0146-0005(00)80059-2. [DOI] [PubMed] [Google Scholar]
  45. Hall J. M., Couse J. F., Korach K. S. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001 Jul 17;276(40):36869–36872. doi: 10.1074/jbc.R100029200. [DOI] [PubMed] [Google Scholar]
  46. Hamosh M. Bioactive factors in human milk. Pediatr Clin North Am. 2001 Feb;48(1):69–86. doi: 10.1016/s0031-3955(05)70286-8. [DOI] [PubMed] [Google Scholar]
  47. Hany J., Lilienthal H., Sarasin A., Roth-Härer A., Fastabend A., Dunemann L., Lichtensteiger W., Winneke G. Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior. Toxicol Appl Pharmacol. 1999 Aug 1;158(3):231–243. doi: 10.1006/taap.1999.8710. [DOI] [PubMed] [Google Scholar]
  48. Harper N., Wang X., Liu H., Safe S. Inhibition of estrogen-induced progesterone receptor in MCF-7 human breast cancer cells by aryl hydrocarbon (Ah) receptor agonists. Mol Cell Endocrinol. 1994 Aug;104(1):47–55. doi: 10.1016/0303-7207(94)90050-7. [DOI] [PubMed] [Google Scholar]
  49. Hodgert Jury H., Zacharewski T. R., Hammond G. L. Interactions between human plasma sex hormone-binding globulin and xenobiotic ligands. J Steroid Biochem Mol Biol. 2000 Dec 15;75(2-3):167–176. doi: 10.1016/s0960-0760(00)00168-0. [DOI] [PubMed] [Google Scholar]
  50. Hopert A. C., Beyer A., Frank K., Strunck E., Wünsche W., Vollmer G. Characterization of estrogenicity of phytoestrogens in an endometrial-derived experimental model. Environ Health Perspect. 1998 Sep;106(9):581–586. doi: 10.1289/ehp.98106581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Jansen H. T., Cooke P. S., Porcelli J., Liu T. C., Hansen L. G. Estrogenic and antiestrogenic actions of PCBs in the female rat: in vitro and in vivo studies. Reprod Toxicol. 1993 May-Jun;7(3):237–248. doi: 10.1016/0890-6238(93)90230-5. [DOI] [PubMed] [Google Scholar]
  52. Katsuda S., Yoshida M., Watanabe G., Taya K., Maekawa A. Irreversible effects of neonatal exposure to p-tert-octylphenol on the reproductive tract in female rats. Toxicol Appl Pharmacol. 2000 Jun 15;165(3):217–226. doi: 10.1006/taap.2000.8940. [DOI] [PubMed] [Google Scholar]
  53. Koldovský O. Hormones in milk. Vitam Horm. 1995;50:77–149. doi: 10.1016/s0083-6729(08)60655-x. [DOI] [PubMed] [Google Scholar]
  54. Kolpin Dana W., Furlong Edward T., Meyer Michael T., Thurman E. Michael, Zaugg Steven D., Barber Larry B., Buxton Herbert T. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: a national reconnaissance. Environ Sci Technol. 2002 Mar 15;36(6):1202–1211. doi: 10.1021/es011055j. [DOI] [PubMed] [Google Scholar]
  55. Korach K. S., McLachlan J. A. Techniques for detection of estrogenicity. Environ Health Perspect. 1995 Oct;103 (Suppl 7):5–8. doi: 10.1289/ehp.95103s75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Korach K. S., Sarver P., Chae K., McLachlan J. A., McKinney J. D. Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes. Mol Pharmacol. 1988 Jan;33(1):120–126. [PubMed] [Google Scholar]
  57. Kuiper G. G., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J. A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5925–5930. doi: 10.1073/pnas.93.12.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Kuiper G. G., Lemmen J. G., Carlsson B., Corton J. C., Safe S. H., van der Saag P. T., van der Burg B., Gustafsson J. A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998 Oct;139(10):4252–4263. doi: 10.1210/endo.139.10.6216. [DOI] [PubMed] [Google Scholar]
  59. LAUG E. P., KUNZE F. M., PRICKETT C. S. Occurrence of DDT in human fat and milk. AMA Arch Ind Hyg Occup Med. 1951 Mar;3(3):245–246. [PubMed] [Google Scholar]
  60. LaKind J. S., Berlin C. M., Naiman D. Q. Infant exposure to chemicals in breast milk in the United States: what we need to learn from a breast milk monitoring program. Environ Health Perspect. 2001 Jan;109(1):75–88. doi: 10.1289/ehp.0110975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. LaKind Judy S., Berlin Cheston M., Jr Technical workshop on human milk surveillance and research on environmental chemicals in the United States: an overview. J Toxicol Environ Health A. 2002 Nov 22;65(22):1829–1837. doi: 10.1080/00984100290071739. [DOI] [PubMed] [Google Scholar]
  62. Laudet V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J Mol Endocrinol. 1997 Dec;19(3):207–226. doi: 10.1677/jme.0.0190207. [DOI] [PubMed] [Google Scholar]
  63. Le Guevel R., Pakdel F. Assessment of oestrogenic potency of chemicals used as growth promoter by in-vitro methods. Hum Reprod. 2001 May;16(5):1030–1036. doi: 10.1093/humrep/16.5.1030. [DOI] [PubMed] [Google Scholar]
  64. Lemini C., Silva G., Timossi C., Luque D., Valverde A., González-Martínez M., Hernández A., Rubio-Póo C., Chávez Lara B., Valenzuela F. Estrogenic effects of p-hydroxybenzoic acid in CD1 mice. Environ Res. 1997 Nov;75(2):130–134. doi: 10.1006/enrs.1997.3782. [DOI] [PubMed] [Google Scholar]
  65. Li M., Rhine C., Hansen L. G. Hepatic enzyme induction and acute endocrine effects of 2,3,3',4',6-pentachlorobiphenyl in prepubertal female rats. Arch Environ Contam Toxicol. 1998 Jul;35(1):97–103. doi: 10.1007/s002449900355. [DOI] [PubMed] [Google Scholar]
  66. Lieberman S. Are the differences between estradiol and other estrogens, naturally occurring or synthetic, merely semantical? J Clin Endocrinol Metab. 1996 Feb;81(2):850–851. doi: 10.1210/jcem.81.2.8636315. [DOI] [PubMed] [Google Scholar]
  67. Madhavapeddi R., Ramachandran P. Side effects of oral contraceptive use in lactating women--enlargement of breast in a breast-fed child. Contraception. 1985 Nov;32(5):437–443. doi: 10.1016/0010-7824(85)90014-9. [DOI] [PubMed] [Google Scholar]
  68. Madigou T., Le Goff P., Salbert G., Cravedi J. P., Segner H., Pakdel F., Valotaire Y. Effects of nonylphenol on estrogen receptor conformation, transcriptional activity and sexual reversion in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol. 2001 Aug;53(3-4):173–186. doi: 10.1016/s0166-445x(01)00164-3. [DOI] [PubMed] [Google Scholar]
  69. Maness S. C., McDonnell D. P., Gaido K. W. Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells. Toxicol Appl Pharmacol. 1998 Jul;151(1):135–142. doi: 10.1006/taap.1998.8431. [DOI] [PubMed] [Google Scholar]
  70. Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835–839. doi: 10.1016/0092-8674(95)90199-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Matthews J., Celius T., Halgren R., Zacharewski T. Differential estrogen receptor binding of estrogenic substances: a species comparison. J Steroid Biochem Mol Biol. 2000 Nov 15;74(4):223–234. doi: 10.1016/s0960-0760(00)00126-6. [DOI] [PubMed] [Google Scholar]
  72. McKenna N. J., Lanz R. B., O'Malley B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999 Jun;20(3):321–344. doi: 10.1210/edrv.20.3.0366. [DOI] [PubMed] [Google Scholar]
  73. McKenna N. J., Xu J., Nawaz Z., Tsai S. Y., Tsai M. J., O'Malley B. W. Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):3–12. doi: 10.1016/s0960-0760(98)00144-7. [DOI] [PubMed] [Google Scholar]
  74. McMurry C. S., Dickerson R. L. Effects of binary mixtures of six xenobiotics on hormone concentrations and morphometric endpoints of northern bobwhite quail (Colinus virginianus). Chemosphere. 2001 May-Jun;43(4-7):829–837. doi: 10.1016/s0045-6535(00)00441-0. [DOI] [PubMed] [Google Scholar]
  75. Metcalfe C. D., Metcalfe T. L., Kiparissis Y., Koenig B. G., Khan C., Hughes R. J., Croley T. R., March R. E., 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] [Google Scholar]
  76. Moras D., Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol. 1998 Jun;10(3):384–391. doi: 10.1016/s0955-0674(98)80015-x. [DOI] [PubMed] [Google Scholar]
  77. Mäkelä S., Strauss L., Kuiper G., Valve E., Salmi S., Santti R., Gustafsson J. A. Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract. Mol Cell Endocrinol. 2000 Jun;164(1-2):109–116. doi: 10.1016/s0303-7207(00)00233-1. [DOI] [PubMed] [Google Scholar]
  78. Nadal A., Díaz M., Valverde M. A. The estrogen trinity: membrane, cytosolic, and nuclear effects. News Physiol Sci. 2001 Dec;16:251–255. doi: 10.1152/physiologyonline.2001.16.6.251. [DOI] [PubMed] [Google Scholar]
  79. Nagel S. C., vom Saal F. S., Thayer K. A., Dhar M. G., Boechler M., Welshons W. V. 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. doi: 10.1289/ehp.9710570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Nagel S. C., vom Saal F. S., Welshons W. V. 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. doi: 10.3181/00379727-217-44236. [DOI] [PubMed] [Google Scholar]
  81. Nakagawa Yoshio, Suzuki Toshinari. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem Biol Interact. 2002 Feb 20;139(2):115–128. doi: 10.1016/s0009-2797(01)00293-9. [DOI] [PubMed] [Google Scholar]
  82. Nikov G. N., Hopkins N. E., Boue S., Alworth W. L. Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. Environ Health Perspect. 2000 Sep;108(9):867–872. doi: 10.1289/ehp.00108867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Nilsson R. Endocrine modulators in the food chain and environment. Toxicol Pathol. 2000 May-Jun;28(3):420–431. doi: 10.1177/019262330002800311. [DOI] [PubMed] [Google Scholar]
  84. Payne J., Scholze M., Kortenkamp A. Mixtures of four organochlorines enhance human breast cancer cell proliferation. Environ Health Perspect. 2001 Apr;109(4):391–397. doi: 10.1289/ehp.01109391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Petroff B. K., Gao X., Rozman K. K., Terranova P. F. Interaction of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in an ovulation model: evidence for systemic potentiation and local ovarian effects. Reprod Toxicol. 2000 May-Jun;14(3):247–255. doi: 10.1016/s0890-6238(00)00075-7. [DOI] [PubMed] [Google Scholar]
  86. Potischman N., Troisi R. In-utero and early life exposures in relation to risk of breast cancer. Cancer Causes Control. 1999 Dec;10(6):561–573. doi: 10.1023/a:1008955110868. [DOI] [PubMed] [Google Scholar]
  87. Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol. 1990;21(1):51–88. doi: 10.3109/10408449009089873. [DOI] [PubMed] [Google Scholar]
  88. Safe S., Wang F., Porter W., Duan R., McDougal A. Ah receptor agonists as endocrine disruptors: antiestrogenic activity and mechanisms. Toxicol Lett. 1998 Dec 28;102-103:343–347. doi: 10.1016/s0378-4274(98)00331-2. [DOI] [PubMed] [Google Scholar]
  89. Santell R. C., Chang Y. C., Nair M. G., Helferich W. G. Dietary genistein exerts estrogenic effects upon the uterus, mammary gland and the hypothalamic/pituitary axis in rats. J Nutr. 1997 Feb;127(2):263–269. doi: 10.1093/jn/127.2.263. [DOI] [PubMed] [Google Scholar]
  90. Schell J. D., Jr, Budinsky R. A., Wernke M. J. PCBs and neurodevelopmental effects in Michigan children: an evaluation of exposure and dose characterization. Regul Toxicol Pharmacol. 2001 Jun;33(3):300–312. doi: 10.1006/rtph.2001.1475. [DOI] [PubMed] [Google Scholar]
  91. Setchell K. D., Zimmer-Nechemias L., Cai J., Heubi J. E. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997 Jul 5;350(9070):23–27. doi: 10.1016/S0140-6736(96)09480-9. [DOI] [PubMed] [Google Scholar]
  92. Sheehan D. M. Herbal medicines, phytoestrogens and toxicity: risk:benefit considerations. Proc Soc Exp Biol Med. 1998 Mar;217(3):379–385. doi: 10.3181/00379727-217-44248. [DOI] [PubMed] [Google Scholar]
  93. Shelby M. D., Newbold R. R., Tully D. B., Chae K., Davis V. L. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. Environ Health Perspect. 1996 Dec;104(12):1296–1300. doi: 10.1289/ehp.961041296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Silva Elisabete, Rajapakse Nissanka, Kortenkamp Andreas. Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 2002 Apr 15;36(8):1751–1756. doi: 10.1021/es0101227. [DOI] [PubMed] [Google Scholar]
  95. Smeets J. M., van Holsteijn I., Giesy J. P., Seinen W., van den Berg M. Estrogenic potencies of several environmental pollutants, as determined by vitellogenin induction in a carp hepatocyte assay. Toxicol Sci. 1999 Aug;50(2):206–213. doi: 10.1093/toxsci/50.2.206. [DOI] [PubMed] [Google Scholar]
  96. Strom B. L., Schinnar R., Ziegler E. E., Barnhart K. T., Sammel M. D., Macones G. A., Stallings V. A., Drulis J. M., Nelson S. E., Hanson S. A. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA. 2001 Aug 15;286(7):807–814. doi: 10.1001/jama.286.7.807. [DOI] [PubMed] [Google Scholar]
  97. Sugihara K., Kitamura S., Sanoh S., Ohta S., Fujimoto N., Maruyama S., Ito A. Metabolic activation of the proestrogens trans-stilbene and trans-stilbene oxide by rat liver microsomes. Toxicol Appl Pharmacol. 2000 Aug 15;167(1):46–54. doi: 10.1006/taap.2000.8979. [DOI] [PubMed] [Google Scholar]
  98. Teuschler Linda, Klaunig James, Carney Ed, Chambers Janice, Conolly Rory, Gennings Chris, Giesy John, Hertzberg Richard, Klaassen Curtis, Kodell Ralph. Support of science-based decisions concerning the evaluation of the toxicology of mixtures: a new beginning. Regul Toxicol Pharmacol. 2002 Aug;36(1):34–39. doi: 10.1006/rtph.2002.1570. [DOI] [PubMed] [Google Scholar]
  99. Thornton J. W. 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 1;98(10):5671–5676. doi: 10.1073/pnas.091553298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Thorpe K. L., Hutchinson T. H., Hetheridge M. J., Scholze M., Sumpter J. P., Tyler C. R. Assessing the biological potency of binary mixtures of environmental estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss). Environ Sci Technol. 2001 Jun 15;35(12):2476–2481. doi: 10.1021/es001767u. [DOI] [PubMed] [Google Scholar]
  101. Tsai M. J., O'Malley B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–486. doi: 10.1146/annurev.bi.63.070194.002315. [DOI] [PubMed] [Google Scholar]
  102. Tully D. B., Cox V. T., Mumtaz M. M., Davis V. L., Chapin R. E. Six high-priority organochlorine pesticides, either singly or in combination, are nonestrogenic in transfected HeLa cells. Reprod Toxicol. 2000 Mar-Apr;14(2):95–102. doi: 10.1016/s0890-6238(00)00060-5. [DOI] [PubMed] [Google Scholar]
  103. Weatherman R. V., Fletterick R. J., Scanlan T. S. Nuclear-receptor ligands and ligand-binding domains. Annu Rev Biochem. 1999;68:559–581. doi: 10.1146/annurev.biochem.68.1.559. [DOI] [PubMed] [Google Scholar]
  104. Westphal U. Steroid-protein interactions II. Monogr Endocrinol. 1986;27:1–603. [PubMed] [Google Scholar]
  105. Whitten P. L., Lewis C., Russell E., Naftolin F. Potential adverse effects of phytoestrogens. J Nutr. 1995 Mar;125(3 Suppl):771S–776S. doi: 10.1093/jn/125.3_Suppl.771S. [DOI] [PubMed] [Google Scholar]
  106. Whitten P. L., Naftolin F. Reproductive actions of phytoestrogens. Baillieres Clin Endocrinol Metab. 1998 Dec;12(4):667–690. doi: 10.1016/s0950-351x(98)80010-4. [DOI] [PubMed] [Google Scholar]
  107. Whitten P. L., Patisaul H. B. Cross-species and interassay comparisons of phytoestrogen action. Environ Health Perspect. 2001 Mar;109 (Suppl 1):5–20. doi: 10.1289/ehp.01109s15. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES