Prenatal Bisphenol A Exposure Induces Preneoplastic Lesions in the Mammary Gland in Wistar Rats

Abstract

BackgroundHumans are routinely exposed to bisphenol A (BPA), an estrogenic compound that leaches from dental materials, food and beverage containers, and other consumer products. Prenatal exposure to BPA has produced long-lasting and profound effects on rodent hormone-dependent tissues that are manifested 1–6 months after the end of exposure.ObjectiveThe aim of the present work was to examine whether in utero exposure to BPA alters mammary gland development and increases its susceptibility to the carcinogen N-nitroso-N-methylurea (NMU).MethodsPregnant Wistar rats were exposed to BPA (25 μg/kg body weight per day) or to vehicle. Female offspring were sacrificed on postnatal day (PND) 30, 50, 110, or 180. On PND50 a group of rats received a single subcarcinogenic dose of NMU (25 mg/kg) and they were sacrificed on either PND110 or PND180.ResultsAt puberty, animals exposed prenatally to BPA showed an increased proliferation/apoptosis ratio in both the epithelial and stromal compartments. During adulthood (PND110 and PND180), BPA-exposed animals showed an increased number of hyperplastic ducts and augmented stromal nuclear density. Moreover, the stroma associated with hyperplastic ducts showed signs of desmoplasia and contained an increased number of mast cells, suggesting a heightened risk of neoplastic transformation. Administration of a subcarcinogenic dose of NMU to animals exposed prenatally to BPA increased the percentage of hyperplastic ducts and induced the development of neoplastic lesions.ConclusionsOur results demonstrate that the prenatal exposure to low doses of BPA perturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to a chemical challenge administered 50 days after the end of BPA exposure.

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure

“…The present report as well as the above-mentioned publications show that developmental exposure to BPA enhances the likelihood of developing carcinomas in both the mammary gland and the prostate [47,48]. Further work will be necessary to verify whether the ductal hyperplasias and CIS we have observed in the mammary gland have the ability to generate invasive carcinomas.…”

“…However, the increased propensity of the BPA-exposed animals to develop PINs was revealed when those rats were given a hormonal stimulus (testosterone plus estradiol for 16 weeks) during adulthood. Similarly, Durando et al showed that fetal exposure to 25μg BPA/kg BW/day induced the development of mammary gland neoplasia which was manifested after treatment with NMU during adulthood [48].…”

Low‐Dose Bisphenol A Exposure: A Seemingly Instigating Carcinogenic Effect on Breast Cancer

“…The mammary glands of the rats in these studies also had an increase in tumor multiplicity and the number of tumors, indicating that BPA exposure can increase susceptibility to DMBA‐induced mammary cancer. In another study by Durando and colleagues, Wistar rats exposed in utero to a low dose of BPA (25 µg kg –1 BW day –1 ), who received N ‐nitroso‐ N ‐methylurea (NMU, a chemical carcinogen) at PND50, had significantly more hyperplastic ducts at 110 and 180 days of age and had a higher incidence of NMU‐induced ductal carcinoma in situ at 180 days of age 110. These results together suggest that BPA exposure during early life can sensitize the mammary gland to carcinogenic insults encountered in adulthood.…”

Bisphenol A alters the development of the rhesus monkey mammary gland

“…Furthermore, rats exposed to BPA in utero developed precancerous and cancerous lesions (32). Also, perinatal exposure increased rodents' sensitivity to chemical carcinogens (33)(34)(35)(36). Although a small human study found no association between To whom correspondence should be addressed.…”