Overlapping but distinct effects of genistein and ethinyl estradiol (EE2) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies

Reproductive Toxicology

Volumn 27, Issue 2, 2009, Pages 117-132

  Delclos, K Barry ^a   Weis, Constance C ^a   Bucci, Thomas J ^b   Olson, Greg ^b   Mellick, Paul ^b   Sadovova, Natalya ^b   Latendresse, John R ^b   Thorn, Brett ^a   Newbold, Retha R ^c  

^a NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH   (United States)

^b Pathology Associates International   (United States)

^c NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

Author keywords

Estrous cycle; Ethinyl estradiol; Genistein; Multigenerational; Puberty acceleration; Rat; Reproductive senescence; Reproductive toxicity; Soy free diet

Indexed keywords

ETHINYLESTRADIOL; GENISTEIN; PHYTOESTROGEN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY WEIGHT; CHRONIC TOXICITY; CONTROLLED STUDY; DIETARY INTAKE; ENDOMETRIUM HYPERPLASIA; ESTRUS CYCLE; FEMALE; FEMALE GENITAL SYSTEM; HISTOPATHOLOGY; LITTER SIZE; MATING; NEOPLASM; NONHUMAN; PERINATAL DEVELOPMENT; PREGNANCY; RAT; REPRODUCTIVE TOXICITY; SPRAGUE DAWLEY RAT; SQUAMOUS CELL METAPLASIA; VAGINA;

ANIMALS; BODY WEIGHT; DOSE-RESPONSE RELATIONSHIP, DRUG; EATING; ENDOCRINE DISRUPTORS; ENDOMETRIAL HYPERPLASIA; ESTRUS; ETHINYL ESTRADIOL; FEMALE; GENISTEIN; LITTER SIZE; METAPLASIA; PREGNANCY; RATS; RATS, SPRAGUE-DAWLEY; REPRODUCTION; SEXUAL BEHAVIOR, ANIMAL; SEXUAL MATURATION; TIME FACTORS; UTERUS; VAGINA;

ANIMALIA; RATTUS;

EID: 62549154476     PISSN: 08906238     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.reprotox.2008.12.005     Document Type: Article

References (136)

1. Bern H.A. The fragile fetus. In: Colborn T., and Clement C. (Eds). Advances in modern environmental toxicology. Vol. XXI. Chemically-induced alterations in sexual and functional development: the wildlife/human connection (1992), Princeton Scientific Publishing Co., Princeton, NJ 9-15
2. Newbold R. Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect 103 Suppl. 7 (1995) 83-87
3. Newbold R.R., Padilla-Banks E., and Jefferson W.N. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology 147 6 Suppl. (2006) S11-S17
4. NIH. DES research update: current knowledge, future directions (1999), National Institutes of Health, Bethesda
5. In: Colborn T., and Clement C. (Eds). Chemically-induced alterations in sexual and functional development: the wildlife/human connection (1992), Princeton Scientific Publishing Company, Inc., Princeton, NJ
6. NRC. Hormonally active agents in the environment (1999), National Academy Press, Washington, DC
7. CFSAN. Redbook 2000-toxicological principles for the safety assessment of food ingredients (2006), U.S. Food and Drug Administration, Rockville, MD
8. OECD. Draft guidance document on reproductive toxicity testing and assessment. Publication no. 43 (2004), Organization for Economic Cooperation and Development, Paris, France
9. Setchell K.D., Zimmer-Nechemias L., Cai J., and Heubi J.E. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350 (1997) 23-27
10. Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncol 3 6 (2002) 364-373
11. Messina M., Kucuk O., and Lampe J.W. An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J AOAC Int 89 4 (2006) 1121-1134
12. Sacks F.M., Lichtenstein A., Van Horn L., Harris W., Kris-Etherton P., and Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation 113 7 (2006) 1034-1044
13. Trock B.J., Hilakivi-Clarke L., and Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98 7 (2006) 459-471
14. Messina M.J., and Wood C.E. Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary. Nutr J 7 1 (2008) 17
15. Williamson-Hughes P.S., Flickinger B.D., Messina M.J., and Empie M.W. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: a critical review of published studies. Menopause 13 5 (2006) 831-839
16. Duffy C., Perez K., and Partridge A. Implications of phytoestrogen intake for breast cancer. CA Cancer J Clin 57 5 (2007) 260-277
17. Cederroth C.R., Vinciguerra M., Gjinovci A., Kuhne F., Klein M., Cederroth M., et al. Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism. Diabetes 57 5 (2008) 1176-1185
18. Orgaard A., and Jensen L. The effects of soy isoflavones on obesity. Exp Biol Med 233 9 (2008) 1066-1080
19. Thigpen J.E., Haseman J.K., Saunders H., Locklear J., Caviness G., Grant M., et al. Dietary factors affecting uterine weights of immature CD-1 mice used in uterotrophic bioassays. Cancer Detect Prev 26 5 (2002) 381-393
20. Dang Z.C., Audinot V., Papapoulos S.E., Boutin J.A., and Lowik C.W. Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 278 2 (2003) 962-967
21. Mezei O., Banz W.J., Steger R.W., Peluso M.R., Winters T.A., and Shay N. Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese zucker rats and murine RAW 264.7. Cells J Nutr 133 5 (2003) 1238-1243
22. Takahashi Y., Lavigne J.A., Hursting S.D., Chandramouli G.V., Perkins S.N., Barrett J.C., et al. Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog 41 2 (2004) 108-119
23. Kim S., Sohn I., and Lee Y.S. Hepatic gene expression profiles are altered by genistein supplementation in mice with diet-induced obesity. J Nutr 135 1 (2005) 33-41
24. Henley D.V., and Korach K.S. Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function. Endocrinology 147 6 Suppl. (2006) S25-S32
25. Chang E.C., Charn T.H., Park S.H., Helferich W.G., Komm B., Katzenellenbogen J.A., et al. Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol 22 5 (2008) 1032-1043
26. Kanno J., Onyon L., Peddada S., Ashby J., Jacob E., and Owens W. The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies. Environ Health Perspect 111 12 (2003) 1530-1549
27. Hsieh C.Y., Santell R.C., Haslam S.Z., and Helferich W.G. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo [published erratum appears in Cancer Res 1999;59(March(6)):1388]. Cancer Res 58 17 (1998) 3833-3838
28. Allred C.D., Allred K.F., Ju Y.H., Clausen L.M., Doerge D.R., Schantz S.L., et al. Dietary genistein results in larger MNU-induced, estrogen-dependent mammary tumors following ovariectomy of Sprague-Dawley rats. Carcinogenesis 25 2 (2004) 211-218
29. Allred C.D., Allred K.F., Ju Y.H., Virant S.M., and Helferich W.G. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res 61 13 (2001) 5045-5050
30. Naciff J.M., Jump M.L., Torontali S.M., Carr G.J., Tiesman J.P., Overmann G.J., et al. Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicol Sci 68 1 (2002) 184-199
31. Naciff J.M., Torontali S.M., Overmann G.I., Carr G.J., Tiesman J.P., and Daston G.P. Evaluation of the gene expression changes induced by 17-alpha-ethynyl estradiol in the immature uterus/ovaries of the rat using high density oligonucleotide arrays. Birth Defects Res B Dev Reprod Toxicol 74 2 (2005) 164-184
32. Setchell K.D., Gosselin S.J., Welsh M.B., Johnston J.O., Balistreri W.F., Kramer L.W., et al. Dietary estrogens-a probable cause of infertility and liver disease in captive cheetahs. Gastroenterology 93 2 (1987) 225-233
33. East J. The effect of genistein on the fertility of mice. J Endocrinol 13 (1955) 94-100
34. Stob M. Naturally occurring food toxicants: estrogens. In: Rechcigl Jr. M. (Ed). Handbook of naturally occurring food toxicants: estrogens (1983), CRC Press, Boca Raton, FL 81-100
35. Price K.R., and Fenwick G.R. Naturally occurring oestrogens in foods-a review. Food Additives Contam 2 2 (1985) 73-106
36. Jefferson W.N., Couse J.F., Padilla-Banks E., Korach K.S., and Newbold R.R. Neonatal exposure to genistein induces estrogen receptor (ER)alpha expression and multioocyte follicles in the maturing mouse ovary: evidence for ERbeta-mediated and nonestrogenic actions. Biol Reprod 67 4 (2002) 1285-1296
37. Jefferson W.N., Padilla-Banks E., and Newbold R.R. Adverse effects on female development and reproduction in CD-1 mice following neonatal exposure to the phytoestrogen genistein at environmentally relevant doses. Biol Reprod 73 4 (2005) 798-806
38. Jefferson W.N., Padilla-Banks E., and Newbold R.R. Disruption of the developing female reproductive system by phytoestrogens: genistein as an example. Mol Nutr Food Res 51 7 (2007) 832-844
39. Newbold R.R., Banks E.P., Bullock B., and Jefferson W.N. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res 61 11 (2001) 4325-4328
40. Li D.K., Daling J.R., Mueller B.A., Hickok D.E., Fantel A.G., and Weiss N.S. Oral contraceptive use after conception in relation to the risk of congenital urinary tract anomalies. Teratology 51 1 (1995) 30-36
41. Potter L.S. How effective are contraceptives? The determination and measurement of pregnancy rates. Obstet Gynecol 88 3 Suppl. (1996) 13S-23S
42. USFDA. Guidance for industry: labeling for combined oral contraceptives (2004), U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD
43. WHO. Medical eligibility criteria for contraceptive use. 3rd ed. (2004), Reproductive Health and Research, World Health Organization, Geneva, Switzerland
44. Kidd K.A., Blanchfield P.J., Mills K.H., Palace V.P., Evans R.E., Lazorchak J.M., et al. Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci USA 104 21 (2007) 8897-8901
45. Barkhem T., Carlsson B., Nilsson Y., Enmark E., Gustafsson J., and Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 54 1 (1998) 105-112
46. Gutendorf B., and Westendorf J. Comparison of an array of in vitro assays for the assessment of the estrogenic potential of natural and synthetic estrogens, phytoestrogens and xenoestrogens. Toxicology 166 1-2 (2001) 79-89
47. Masutomi N., Shibutani M., Takagi H., Uneyama C., and Hirose M. Dietary influence on the impact of ethinylestradiol-induced alterations in the endocrine/reproductive system with perinatal maternal exposure. Reprod Toxicol 18 1 (2004) 23-33
48. Takagi H., Shibutani M., Lee K.Y., Lee H.C., Nishihara M., Uneyama C., et al. Lack of modifying effects of genistein on disruption of the reproductive system by perinatal dietary exposure to ethinylestradiol in rats. Reprod Toxicol 18 5 (2004) 687-700
49. Timms B.G., Howdeshell K.L., Barton L., Bradley S., Richter C.A., and vom Saal F.S. Estrogenic chemicals in plastic and oral contraceptives disrupt development of the fetal mouse prostate and urethra. Proc Natl Acad Sci USA 102 19 (2005) 7014-7019
50. Yasuda Y., Kihara T., and Nishimura H. Effect of prenatal treatment with ethinyl estradiol on the mouse uterus and ovary. Am J Obstet Gynecol 127 8 (1977) 832-836
51. Yasuda Y., Kihara T., and Nishimura H. Effect of ethinyl estradiol on development of mouse fetuses. Teratology 23 2 (1981) 233-239
52. Yasuda Y., Kihara T., and Nishimura H. Transplacental effect of ethinyl estradiol on mouse vaginal epithelium. Dev Growth Differ 19 (1977) 241-247
53. Yasuda Y., Kihara T., and Tanimura T. Effect of ethinyl estradiol on the differentiation of mouse fetal testis. Teratology 32 1 (1985) 113-118
54. Yasuda Y., Kihara T., Tanimura T., and Nishimura H. Gonadal dysgenesis induced by prenatal exposure to ethinyl estradiol in mice. Teratology 32 2 (1985) 219-227
55. Yasuda Y., Konish H., and Tanimura T. Ovarian follicular cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol. Teratology 36 1 (1987) 35-43
56. Yasuda Y., Konishi H., Matuso T., and Tanimura T. Accelerated differentiation in seminiferous tubules of fetal mice prenatally exposed to ethinyl estradiol. Anat Embryol 174 3 (1986) 289-299
57. Yasuda Y., Konishi H., and Tanimura T. Leydig cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol. Teratology 33 3 (1986) 281-288
58. Yasuda Y., Ohara I., Konishi H., and Tanimura T. Long-term effects on male reproductive organs of prenatal exposure to ethinyl estradiol. Am J Obstet Gynecol 159 5 (1988) 1246-1250
59. Delclos K.B., Bucci T.J., Lomax L.G., Latendresse J.R., Warbritton A., Weis C.C., et al. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reprod Toxicol 15 (2001) 1-17
60. NTP. NTP technical report on the reproductive dose range-finding toxicity study of genistein (CAS no. 446-72-0) administered in feed to Sprague-Dawley rats (feed study). Toxicity report series no. 79. NIH publication no. 07-4477. Research Triangle Park, NC: National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services; 2007.
61. NTP. Multigenerational reproductive toxicology study of ethinyl estradiol (CAS no. 57-63-6) in Sprague-Dawley rats (feed study). Report no. 547, NIH publication no. 07-5888. Research Triangle Park, NC: National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services; 2007.
62. NTP. Toxicology and carcinogenesis study of ethinyl estradiol (CAS no. 57-63-6) in Sprague-Dawley rats (feed study). Report no. 548, NIH publication no. 07-5889. Research Triangle Park, NC: National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services; 2007.
63. NTP. Multigenerational reproductive toxicology study of genistein (cas no. 446-72-0) in Sprague-Dawley rats (feed study). Report no. 548, NIH publication no. 07-5889. Research Triangle Park, NC: National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services; 2007.
64. NTP. Toxicology and carcinogenesis study of genistein (cas no. 446-72-0) in Sprague-Dawley rats (feed study). Report no. 545, NIH publication 07-4430. Research Triangle Park, NC: National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services; 2007.
65. Doerge D.R., Chang H.C., Churchwell M.I., and Holder C.L. Analysis of soy isoflavone conjugation in vitro and in human blood using liquid chromatography-mass spectrometry. Drug Metab Dispos 28 3 (2000) 298-307
66. Thigpen J.E., Setchell K.D., Ahlmark K.B., Locklear J., Spahr T., Caviness G.F., et al. Phytoestrogen content of purified, open- and closed-formula laboratory animal diets. Lab Anim Sci 49 5 (1999) 530-536
67. Dunnett C.W. A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 50 (1955) 1096-1121
68. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat 6 (1979) 65-70
69. Kruskal W.H., and Wallis W.A. Use of ranks in one-criterion analysis of variance. J Am Stat Assoc 47 (1952) 583-621
70. Wilcoxon F. Individual comparisons by ranking methods. Biometrics 1 (1945) 80-83
71. Cooper R.L., and Goldman J.M. Vaginal cytology. In: Daston G., and Kimmel C. (Eds). An evaluation and interpretation of reproductive endpoints for human health risk assessment (1999), International Life Sciences Institute Press, Washington, DC 42-56
72. Jonckheere A.R. A distribution-free k-sample test against ordered alternatives. Biometrika 41 (1954) 133-145
73. Hollander M., and Wolfe D.A. Nonparametric statistical methods (1973), John Wiley and Sons, New York
74. Myers R.H., Montgomery D.C., and Vining G.G. Generalized linear models: with applications in engineering and sciences (2001), John Wiley and Sons, New York
75. Weibull W. A statistical distribution function of wide applicability. J Appl Mech 18 (1951) 292-297
76. Shirley E. A non-parametric equivalent of Williams' test for contrasting increasing dose levels of a treatment. Biometrics 33 2 (1977) 386-389
77. Williams D.A. A note on Shirley's nonparametric test for comparing several dose levels with a zero-dose control. Biometrics 42 (1986) 183-186
78. Blair R.M., Fang H., Branham W.S., Hass B.S., Dial S.L., Moland C.L., et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 54 1 (2000) 138-153
79. Kuiper G.G., Carlsson B., Grandien K., Enmark E., Haggblad J., Nilsson S., et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138 3 (1997) 863-870
80. Kuiper G.G., Lemmen J.G., Carlsson B., Corton J.C., Safe S.H., van der Saag P.T., et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139 10 (1998) 4252-4263
81. Holder C.L., Churchwell M.I., and Doerge D.R. Quantification of soy isoflavones, genistein and daidzein, and conjugates in rat blood using LC/ES-MS. J Agric Food Chem 47 9 (1999) 3764-3770
82. Chang H.C., Churchwell M.I., Delclos K.B., Newbold R.R., and Doerge D.R. Mass spectrometric determination of genistein tissue distribution in diet-exposed Sprague-Dawley rats. J Nutr 130 8 (2000) 1963-1970
83. Dusterberg B., Kuhne G., and Tauber U. Half-lives in plasma and bioavailability of ethinylestradiol in laboratory animals. Arzneimittelforschung 36 8 (1986) 1187-1190
84. Whitten P.L., and Patisaul H.B. Cross-species and interassay comparisons of phytoestrogen action. Environ Health Perspect 109 Suppl. 1 (2001) 5-20
85. Doerge D.R., Churchwell M.I., Chang H.C., Newbold R.R., and Delclos K.B. Placental transfer of the soy isoflavone genistein following dietary and gavage administration to Sprague Dawley rats. Reprod Toxicol 15 2 (2001) 105-110
86. Doerge D.R., Twaddle N.C., Churchwell M.I., Newbold R.R., and Delclos K.B. Lactational transfer of the soy isoflavone, genistein, in Sprague-Dawley rats consuming dietary genistein. Reprod Toxicol 21 3 (2006) 307-312
87. Pryor J.L., Hughes C., Foster W., Hales B.F., and Robaire B. Critical windows of exposure for children's health: the reproductive system in animals and humans. Environ Health Perspect 108 Suppl. 3 (2000) 491-503
88. Faber K.A., and Hughes Jr. C.L. Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats. Reprod Toxicol 7 1 (1993) 35-39
89. Yang J., Nakagawa H., Tsuta K., and Tsubura A. Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague-Dawley rats. Cancer Lett 149 1-2 (2000) 171-179
90. Nagao T., Yoshimura S., Saito Y., Nakagomi M., Usumi K., and Ono H. Reproductive effects in male and female rats of neonatal exposure to genistein. Reprod Toxicol 15 4 (2001) 399-411
91. Foster W.G., Younglai E.V., Boutross-Tadross O., Hughes C.L., and Wade M.G. Mammary gland morphology in Sprague-Dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein. Toxicol Sci 77 1 (2004) 91-100
92. Erdman Jr. J.W., Badger T.M., Lampe J.W., Setchell K.D., and Messina M. Not all soy products are created equal: caution needed in interpretation of research results. J Nutr 134 5 (2004) S1229-S1233
93. Allred C.D., Allred K.F., Ju Y.H., Goeppinger T.S., Doerge D.R., and Helferich W.G. Soy processing influences growth of estrogen-dependent breast cancer tumors in mice. Carcinogenesis 25 9 (2004) 1649-1657
94. Twaddle N.C., Churchwell M.I., Newbold R.R., Delclos K.B., and Doerge D.R. Determination using liquid-chromatography-electrospray tandem mass spectroscopy of ethinylestradiol serum pharmacokinetics in adult Sprague-Dawley rats. J Chromatogr B Anal Technol Biomed Life Sci 793 2 (2003) 309-315
95. van den Heuvel M.W., van Bragt A.J., Alnabawy A.K., and Kaptein M.C. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 72 3 (2005) 168-174
96. Slikker Jr. W., Bailey J.R., Newport D., Lipe G.W., and Hill D.E. Placental transfer and metabolism of 17 alpha-ethynylestradiol-17 beta and estradiol-17 beta in the rhesus monkey. J Pharmacol Exp Ther 223 2 (1982) 483-489
97. Thayer K.A., Ruhlen R.L., Howdeshell K.L., Buchanan D.L., Cooke P.S., Preziosi D., et al. Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17alpha-ethinyl oestradiol. Hum Reprod 16 5 (2001) 988-996
98. Nilsson S., Nygren K.G., and Johansson E.D. Ethinyl estradiol in human milk and plasma after oral administration. Contraception 17 2 (1978) 131-139
99. Betrabet S.S., Shikary Z.K., Toddywalla V.S., Patel D., Vaidya P., and Saxena B.N. ICMR Task Force Study on hormonal contraception. Biological activity of ethinyl estradiol present in the breast milk. Contraception 34 2 (1986) 169-175
100. Cargill D.I., Meli A., Giannina T., and Steinetz B.G. Secretion of ethynylestradiol and its 3-cyclopentyl ether in the milk of lactating rats. Proc Soc Exp Biol Med 131 4 (1969) 1362-1365
101. Wade G.N., and Schneider J.E. Metabolic fuels and reproduction in female mammals. Neurosci Biobehav Rev 16 2 (1992) 235-272
102. Toth M.J., Poehlman E.T., Matthews D.E., Tchernof A., and MacCoss M.J. Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats. Am J Physiol Endocrinol Metab 280 3 (2001) E496-501
103. Wallen W.J., Belanger M.P., and Wittnich C. Sex hormones and the selective estrogen receptor modulator tamoxifen modulate weekly body weights and food intakes in adolescent and adult rats. J Nutr 131 9 (2001) 2351-2357
104. Casanova M., You L., Gaido K.W., Archibeque-Engle S., Janszen D.B., and Heck H.A. Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro. Toxicol Sci 51 2 (1999) 236-244
105. Naaz A., Yellayi S., Zakroczymski M.A., Bunick D., Doerge D.R., Lubahn D.B., et al. The soy isoflavone genistein decreases adipose deposition in mice. Endocrinology 144 8 (2003) 3315-3320
106. Kim H.K., Nelson-Dooley C., Della-Fera M.A., Yang J.Y., Zhang W., Duan J., et al. Genistein decreases food intake, body weight, and fat pad weight and causes adipose tissue apoptosis in ovariectomized female mice. J Nutr 136 2 (2006) 409-414
107. Kishida T., Mizushige T., Ohtsu Y., Ishikawa S., Nagamoto M., Izumi T., et al. Dietary soy isoflavone-aglycone lowers food intake in female rats with and without ovariectomy. Obesity (Silver Spring) 16 2 (2008) 290-297
108. Rozman K.K., Bhatia J., Calafat A.M., Chambers C., Culty M., Etzel R.A., et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of genistein. Birth Defects Res B Dev Reprod Toxicol 77 6 (2006) 485-638
109. McClain R.M., Wolz E., Davidovich A., Edwards J., and Bausch J. Reproductive safety studies with genistein in rats. Food Chem Toxicol 45 8 (2007) 1319-1332
110. Fusani L., Della Seta D., Dessi-Fulgheri F., and Farabollini F. Altered reproductive success in rat pairs after environmental-like exposure to xenoestrogen. Proc Biol Sci 274 1618 (2007) 1631-1636
111. Clark R.L. Endpoints of reproductive system development. In: Daston G., and Kimmel C. (Eds). An evaluation and interpretation of reproductive endpoints for human health risk assessment (1999), International Life Sciences Institute Press, Washington, DC 10-27
112. McIntyre B.S., Barlow N.J., and Foster P.M.D. Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. Toxicol Sci 62 2 (2001) 236-249
113. Zehr J.L., Gans S.E., and McClintock M.K. Variation in reproductive traits is associated with short anogenital distance in female rats. Dev Psychobiol 38 4 (2001) 229-238
114. Bowman C.J., Barlow N.J., Turner K.J., Wallace D.G., and Foster P.M. Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicol Sci 74 2 (2003) 393-406
115. Weber K.S., Setchell K.D., and Lephart E.D. Maternal and perinatal brain aromatase: effects of dietary soy phytoestrogens. Brain Res Dev Brain Res 126 2 (2001) 217-221
116. Levy J.R., Faber K.A., Ayyash L., and Hughes C.L. The effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats. Exp Biol Med 208 1 (1995) 60-66
117. 1 offspring maternally exposed to genistein at human intake dose level. Food Chem Toxicol 40 1 (2002) 43-51
118. Lamartiniere C.A., Zhang J.X., and Cotroneo M.S. Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity. Am J Clin Nutr 68 6 Suppl. (1998) 1400-1405
119. Badger T.M., Ronis M.J.J., and Hakkak R. Developmental effects and health aspects of soy protein isolate, casein, and whey in male and female rats. Int J Toxicol 20 (2001) 165-174
120. You L., Casanova M., Bartolucci E.J., Fryczynski M.W., Dorman D.C., Everitt J.I., et al. Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor. Toxicol Sci 66 1 (2002) 91-104
121. Lewis R.W., Brooks N., Milburn G.M., Soames A., Stone S., Hall M., et al. The effects of the phytoestrogen genistein on the postnatal development of the rat. Toxicol Sci 71 1 (2003) 74-83
122. Nikaido Y., Danbara N., Tsujita-Kyutoku M., Yuri T., Uehara N., and Tsubura A. Effects of prepubertal exposure to xenoestrogen on development of estrogen target organs in female CD-1 mice. In Vivo 19 3 (2005) 487-494
123. Nikaido Y., Yoshizawa K., Danbara N., Tsujita-Kyutoku M., Yuri T., Uehara N., et al. Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring. Reprod Toxicol 18 6 (2004) 803-811
124. Lamartiniere C.A., Moore J.B., Brown N.M., Thompson R., Hardin M.J., and Barnes S. Genistein suppresses mammary cancer in rats. Carcinogenesis 16 (1995) 2833-2840
125. Murrill W.B., Brown N.M., Zhang J.X., Manzolillo P.A., Barnes S., and Lamartiniere C.A. Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17 7 (1996) 1451-1457
126. Kouki T., Kishitake M., Okamoto M., Oosuka I., Takebe M., and Yamanouchi K. Effects of neonatal treatment with phytoestrogens, genistein and daidzein, on sex difference in female rat brain function: estrous cycle and lordosis. Horm Behav 44 2 (2003) 140-145
127. Fritz W.A., Coward L., Wang J., and Lamartiniere C.A. Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat. Carcinogenesis 19 12 (1998) 2151-2158
128. Awoniyi C.A., Roberts D., Veeramachaneni D.N., Hurst B.S., Tucker K.E., and Schlaff W.D. Reproductive sequelae in female rats after in utero and neonatal exposure to the phytoestrogen genistein. Fertil Steril 70 3 (1998) 440-447
129. Lamartiniere C.A., Murrill W.B., Manzolillo P.A., Zhang J.X., Barnes S., Zhang X., et al. Genistein alters the ontogeny of mammary gland development and protects against chemically-induced mammary cancer in rats. Proc Soc Exp Biol Med 217 3 (1998) 358-364
130. Doerge D.R., Twaddle N.C., Banks E.P., Jefferson W.N., and Newbold R.R. Pharmacokinetic analysis in serum of genistein administered subcutaneously to neonatal mice. Cancer Lett 184 1 (2002) 21-27
131. Eldridge J.C., Wetzel L.T., and Tyrey L. Estrous cycle patterns of Sprague-Dawley rats during acute and chronic atrazine administration. Reprod Toxicol 13 6 (1999) 491-499
132. Matt D.W., Sarver P.L., and Lu J.K. Relation of parity and estrous cyclicity to the biology of pregnancy in aging female rats. Biol Reprod 37 2 (1987) 421-430
133. LeFevre J., and McClintock M.K. Isolation accelerates reproductive senescence and alters its predictors in female rats. Hormones Behav 25 2 (1991) 258-272
134. Rubin B.S. Hypothalamic alterations and reproductive aging in female rats: evidence of altered luteinizing hormone-releasing hormone neuronal function. Biol Reprod 63 4 (2000) 968-976
135. Wise P.M., Krajnak K.M., and Kashon M.L. Menopause: the aging of multiple pacemakers. Science 273 5271 (1996) 67-70
136. Weiss G., Skurnick J.H., Goldsmith L.T., Santoro N.F., and Park S.J. Menopause and hypothalamic-pituitary sensitivity to estrogen. JAMA 292 24 (2004) 2991-2996