Mechanisms of Hormone Action

Adverse Effects on Female Development and Reproduction in CD-1 Mice Following Neonatal Exposure to the Phytoestrogen Genistein at Environmentally Relevant Doses

Abstract
Outbred female CD-1 mice were treated with genistein (Gen), the primary phytoestrogen in soy, by subcutaneous injections on neonatal days 1-5 at doses of 0.5, 5 or 50 mg/kg/day (Gen-0.5, Gen-5 and Gen-50). Day of vaginal opening was observed in mice treated with Gen and compared to controls and although there were some differences, they were not statistically significant. Gen-treated mice had prolonged estrous cycles with a dose and age related increase in severity of abnormal cycles. Females treated with Gen-0.5 or Gen-5 bred to control males at 2, 4 and 6 months showed statistically significant decreases in the number of live pups over time with increasing dose; at 6 months, 60% of the females in the Gen-0.5 group and 40% in the Gen-5 group delivered live pups compared to 100% of controls. Mice treated with Gen-50 did not deliver live pups. Interestingly, at 2 months, >60% of the mice treated with Gen-50 were fertile as determined by uterine implantation sites but pregnancy was not maintained; pregnancy loss was characterized by fewer, smaller implantation sites and increased reabsorptions. Mice treated with lower doses of Gen had increased numbers of corpora lutea compared to controls while mice treated with the highest dose had decreased numbers; however, superovulation with eCG/hCG yielded similar numbers of oocytes as controls. Serum levels of progesterone, estradiol and testosterone were similar between Gen-treated and control mice when measured prior to puberty and during pregnancy. In summary, neonatal treatment with Gen caused abnormal estrous cycles, altered ovarian function, early reproductive senescence, and subfertility/infertility at environmentally relevant doses.

Key words: Female Reproductive Tract • Mechanisms of Hormone Action • Ovary • Developmental biology

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