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BOR - Papers in Press, published online ahead of print June 1, 2005.
Biol Reprod 2005, 10.1095/biolreprod.105.041277
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BIOLOGY OF REPRODUCTION 73, 798–806 (2005)
DOI: 10.1095/biolreprod.105.041277
© 2005 by the Society for the Study of Reproduction, Inc.

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

Wendy N. Jefferson 1, 2,3 , Elizabeth Padilla-Banks 2, and Retha R. Newbold 2

Developmental Endocrinology Section,2 Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 Department of Environmental and Molecular Toxicology,3 North Carolina State University, Raleigh, North Carolina 27605

Outbred female CD-1 mice were treated with genistein (Gen), the primary phytoestrogen in soy, by s.c. injections on Neonatal Days 1–5 at doses of 0.5, 5, or 50 mg/kg per day (Gen-0.5, Gen-5, and Gen-50). The day of vaginal opening was observed in mice treated with Gen and compared with 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 mo showed statistically significant decreases in the number of live pups over time with increasing dose; at 6 mo, 60% of the females in the Gen-0.5 group and 40% in the Gen-5 group delivered live pups compared with 100% of controls. Mice treated with Gen-50 did not deliver live pups. At 2 mo, >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 with 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 before 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.

developmental biology, female reproductive tract, mechanisms of hormone action, ovary

1 Correspondence: Wendy Jefferson, Mail Drop E4-02, NIEHS, 111 Alexander Drive, South Campus, P.O. Box 12233, Research Triangle Park, NC 27709. FAX: 919 541 4634; jeffers1{at}niehs.nih.gov


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