Perinatally administered bisphenol a as a potential mammary gland carcinogen in rats

Abstract

Background: Environmental exposure to bisphenol A (BPA) affects mammary gland development in rodents and primates. Prenatal exposure to environmentally relevant doses of BPA increased the number of intraductal hyperplasias and ductal carcinomas in situ by 50 days of age in Wistar-Furth rats.

Objective: We aimed to determine whether BPA exposure of dams during gestation only or throughout lactation affects the incidence of mammary gland neoplasia in female offspring.

Methods: We treated pregnant Sprague-Dawley rats with BPA at 0, 0.25, 2.5, 25, or 250 μg BPA/kg BW/day from gestational day (GD) 9 to birth and from GD9 to postnatal day (PND) 21. Mammary glands from BPA-exposed offspring were examined at four time points for preneoplastic and neoplastic lesions. To assess circulating BPA levels, we exposed pregnant rats to vehicle or 250 μg BPA/kg BW/day during gestation only or during gestation/lactation and analyzed sera from dams, fetuses, and nursing pups for total and unconjugated BPA.

Results: Total and unconjugated BPA were detected in sera from 100% of dams and fetuses and 33% of pups exposed to 250 μg BPA/kg BW/day. Unconjugated BPA levels in exposed dams and fetuses (gestational) and in exposed dams and pups (gestational/lactational) were within levels found in humans. Preneoplastic lesions developed in BPA-exposed female offspring across all doses as early as PND50. Unexpectedly, mammary gland adenocarcinomas developed in BPA-exposed offspring by PND90.

Conclusions: Our findings suggest that developmental exposure to environmentally relevant levels of BPA during gestation and lactation induces mammary gland neoplasms in the absence of any additional carcinogenic treatment. Thus, BPA may act as a complete mammary gland carcinogen.

Figure 1

Representative photomicrographs of preneoplastic and neoplastic lesions observed in PND50 mammary glands from BPA-exposed rats. (A) UDH (usual intra­ductal hyperplasia) from rat after gestational/lactational exposure to BPA25. (B,C) ADH (atypical ductal hyperplasia) from rats after gestational/lactational exposure to BPA25 and BPA2.5, respectively. (D) DCIS from rat after gestational/lactational exposure to BPA25. Bar = 50 μm.

Figure 2

Representative photomicrographs of presumptive lesions detected in mammary gland whole mounts from PND90 and PND140 females. (A) Lesion (diameter, 1.7 mm) from rat at PND90 after gestational exposure to BPA250. (B) Lesion (diameter, 6.3 mm) from rat at PND90 after gestational/lactational exposure to BPA25. (C) Lesion (diameter, 5.8 mm) from rat at PND140 after gestational/lactational exposure to BPA0.25. Lesions were excised, sectioned, and H&E stained for diagnosis; bar = 1 mm. (D,E,F) Representative histological sections of (A), (B), and (C), respectively. Lobular alveolar hyperplasia was characterized by infiltration of mammary fat pad with glandular acini (D) and/or by focal, irregular proliferation of alveolar epithelium (E,F) with secretory activity (arrowheads). Bar = 50 μm.

Figure 3

Photomicrographs of H&E-stained tumors from BPA-treated rats at time of sacrifice at PND90 (A,D), 140 (B,E), and 200 (C,F) in gestationally and gestationally/lactationally exposed females. (A,B,D,E) Papillary adenocarcinoma from rats exposed gestationally to BPA250 (A) or BPA2.5 (D), or gestationallly/lactationally to BPA2.5 (B) or BPA25 (E). (C) Ulcerative adenocarcinoma from rat exposed gestationally to BPA0.25. (F) Fibroadenoma from rat exposed gestationally/lactationally to BPA2.5. Bar = 500 μm. Insets: Magnification at 10× base image to show detail of tumor morphology.