| Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life Retha R. Newbold, Wendy N. Jefferson, and Elizabeth Padilla-Banks 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, USA Abstract
Background: Exposure to endocrine-disrupting chemicals during critical developmental periods causes adverse consequences later in life ; an example is prenatal exposure to the pharmaceutical diethylstilbestrol (DES) . Bisphenol A (BPA) , an environmental estrogen used in the synthesis of plastics, is of concern because its chemical structure resembles that of DES, and it is a “high-volume production” chemical with widespread human exposure. Objectives: In this study we investigated whether prenatal BPA causes long-term adverse effects in female reproductive tissues in an experimental animal model previously shown useful in studying effects of prenatal DES. Methods: Timed pregnant CD-1 mice were treated on days 9–16 of gestation with BPA (0.1, 1, 10, 100, or 1,000 µg/kg/day) . After delivery, pups were held for 18 months ; reproductive tissues were then evaluated. Results: Ovarian cysts were significantly increased in the 1‑µg/kg BPA group ; ovarian cystadenomas were seen in the other three BPA-treated groups but not in corn-oil controls. We observed increased progressive proliferative lesions of the oviduct after BPA treatment, similar to those described in response to DES. Further, although not statistically different from the controls, prominent mesonephric (Wolffian) remnants and squamous metaplasia of the uterus, as well as vaginal adenosis, were present in BPA-treated mice, similar to lesions reported following DES treatment. More severe pathologies observed in some BPA-treated animals included atypical hyperplasia and stromal polyps of the uterus ; sarcoma of the uterine cervix ; and mammary adenocarcinoma. We did not observe these lesions in controls. Conclusions: These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation. Key words: BPA, carcinogenesis, DES, development, diethylstilbestrol, endocrine disruptors, ovary, reproduction, toxicology, uterus. Environ Health Perspect 117:879–885 (2009) . [Online 15 January 2009]
Address correspondence to R.R. Newbold, National Institute of Environmental Health Sciences, MD K2-15, P.O. Box 12233, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-0738. E-mail: newbold1@niehs.nih.gov We thank G. Kissling (NIEHS) for the statistical analysis of the data and N. Flagler (NIEHS) for the photomicrographs. We also thank B. Bullock (Department of Pathology, Wake Forest University School of Medicine) for consultation in pathology, and K. Thayer and J. Huff (NIEHS) for manuscript review and their helpful comments. This research was supported by the Intramural Research Program of the NIEHS, NIH. The authors declare they have no competing financial interests. Received 25 July 2008 ; accepted 15 January 2009.
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