Abstract
Bisphenol A (BPA) is the most common environmental endocrine disrupting chemical. Studies suggest a link between perinatal BPA exposure and increased breast cancer risk, but the underlying mechanisms remain unclear. This study aims to investigate the effects of in utero BPA exposure on mammary tumorigenesis in MMTV-erbB2 transgenic mice. Pregnant mice were subcutaneously injected with BPA (0, 50, 500 ng/kg and 250 µg/kg BW) daily between gestational days 11–19. Female offspring were examined for mammary tumorigenesis, puberty onset, mammary morphogenesis, and signaling in ER and erbB2 pathways. In utero exposure to low dose BPA (500 ng/kg) induced mammary tumorigenesis, earlier puberty onset, increased terminal end buds, and prolonged estrus phase, which was accompanied by proliferative mammary morphogenesis. CD24/49f-based FACS analysis showed that in utero exposure to 500 ng/kg BPA induced expansion of luminal and basal/myoepithelial cell subpopulations at PND 35. Molecular analysis of mammary tissues at PND 70 showed that in utero exposure to low doses of BPA induced upregulation of ERα, p-ERα, cyclin D1, and c-myc, concurrent activation of erbB2, EGFR, erbB-3, Erk1/2, and Akt, and upregulation of growth factors/ligands. Our results demonstrate that in utero exposure to low dose BPA promotes mammary tumorigenesis in MMTV-erbB2 mice through induction of ER-erbB2 crosstalk and mammary epithelial reprogramming, which advance our understanding of the mechanism associated with in utero exposure to BPA-induced breast cancer risk. The studies also support using MMTV-erbB2 mouse model for relevant studies.
Highlights
Environmental exposure to endocrine disrupting compounds (EDCs) plays a critical role in breast cancer etiology
We investigated in utero exposure to Bisphenol A (BPA)-associated mammary tumor development in MMTV-erbB2 transgenic mice
We found that prenatal exposure to low doses of BPA
Summary
Environmental exposure to endocrine disrupting compounds (EDCs) plays a critical role in breast cancer etiology. Recent studies suggest that the in utero stage is vulnerable to environmental factors and in utero exposure to EDCs may significantly modify breast cancer risk later in life [1,2,3]. A well-known example is maternal exposure to diethylstilbestrol (DES)-associated breast cancer risk [4]. BPA exposure has been associated with increased risk for reproductive abnormalities, obesity, neurobehavioral problems, diabetes, and cancers [12,13,14,15,16,17,18]. BPA exposure-associated breast cancer risk is a major health concern [19,20,21]
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