Abstract A27: Bisphenol S induces proestrogenic effect in vitro and modifies mammary development dynamics after in utero exposure

Due to the growing health concern of bisphenol A (BPA), a popular endocrine-disrupting compound (EDC), the FDA has banned its use in the production of baby bottles. Bisphenol S (BPS) is a substitute of BPA and was believed to be less estrogenic/toxic, which has been widely used in the production of many household products. However, recent studies suggest that BPS exhibits proestrogenic/proliferative effects similar to BPA. Whether/how BPS exposure impacts human health at various stages, especially in children/adolescents, is emerging as a new public health concern. In this study, we investigated the in vitro and in vivo effect of BPS on breast cancer cell proliferation and signaling and mouse mammary development. Results from MTT and clonogenic assays using MCF-7 and T47D cells, two ER+ breast cancer cell lines, indicated that BPS at 0.5–5 μM promoted cell proliferation. Cell cycle analysis showed that BPS at 1 and 5 μM significantly increased the percentage of cells in S phase and decreased cells in G0/G1 phase. Luciferase reporter assays also indicated that BPS potently activated estrogen response element (ERE)-mediated transcription. Analysis of signal transduction demonstrated that PBS induced the upregulation and activation/phosphorylation of ERα, erbB3, Akt, and Erk/12. Examination of the mRNA levels of key regulators in ER signaling and growth regulation showed that BPS induced significant upregulation of AREG, MYC, IGF1R/2R, and CCND1. We also demonstrated that BPS at 1 μM attenuated tamoxifen-mediated growth inhibition of MCF-7 and T47D cells. These data demonstrate that BPS is a potent endocrine disruptor. To test the in vivo effect of in utero exposure to BPS on pubertal mammary development, MMTV-erbB2 transgenic mice were exposed to BPS via drinking water at doses of 0, 15, and 30 μM BPS/L between gestation day 10 to day 19. Mammary glands of female offspring at week 5 and week 10 of age were analyzed for morphogenesis, colony formation cell (CFC) assay, and mammary epithelial subpopulations. BPS-treated mammary tissues at 5 weeks of age displayed decreased ductal elongation and CFC numbers. At 10s week of age, mammary tissues with 30 μM BPS/L exposure displayed more complex ductal trees, CFC numbers, and increased CD24high/CD49fhigh and CD61high/CD49fmid cells, which are enriched with putative mammary stem/progenitor subpopulations. Overall, we demonstrated that BPS has a proestrogenic effect that may promote the growth of ER+ breast cancer cells. In vivo results demonstrated that in utero exposure to BPS modifies the dynamics of mammary development. The health impact of BPS exposure on mammary development warrants further investigation. Citation Format: Qingxia Zhao, Amanda B. Parris, Zhikun Ma, Xiaohe Yang. Bisphenol S induces proestrogenic effect in vitro and modifies mammary development dynamics after in utero exposure [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A27.