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Neonatal Exposure to the Phytoestrogen Genistein Alters Mammary Gland Growth and Developmental Programming of Hormone Receptor Levels

Developmental Endocrinology and Endocrine Disruptor Section, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Retha R. Newbold, P.O. Box 12233, National Institute of Environmental Health Sciences, Mail Drop E4-02, Research Triangle Park, North Carolina 27709. E-mail: newbold1{at}niehs.nih.gov.

Developmental effects of genistein (Gen) on the mammary gland were investigated using outbred female CD-1 mice treated neonatally on d 1–5 by sc injections at doses of 0.5, 5, or 50 mg/kg·d. Examination of mammary gland whole mounts (no. 4) before puberty (4 wk) revealed no morphological differences in development after Gen treatment. However, mice treated with Gen-50 had stunted development characterized by less branching at 5 wk and decreased numbers of terminal end buds at 5 and 6 wk. Conversely, at 6 wk, Gen-0.5-treated mice exhibited advanced development with increased ductal elongation compared with controls. Measurements of hormone receptor levels showed increased levels of progesterone receptor protein and estrogen receptor-ß mRNA in Gen-0.5-treated mice compared with controls; ER expression was decreased after all doses of Gen treatment. Lactation ability, measured by pup weight gain and survival, was not affected after neonatal Gen-0.5 and Gen-5. Mice treated with Gen-50 did not deliver live pups; therefore, lactation ability could not be determined. Evaluation of mammary glands in aged mice (9 months) showed no differences between Gen-0.5-treated mice and controls but mice treated with Gen-5 and Gen-50 exhibited altered morphology including reduced lobular alveolar development, dilated ducts, and focal areas of "beaded" ducts lined with hyperplastic ductal epithelium. In summary, neonatal Gen exposure altered mammary gland growth and development as well as hormone receptor levels at all doses examined; higher doses of Gen led to permanent long-lasting morphological changes.