Exploring Environmental Chemicals and Risk of Breast Cancer during the Menopausal Transition

Abstract

Teasing out the biologic mechanisms of endocrine-disrupting chemicals (EDCs) in epidemiologic studies is complicated given their heterogeneity, and assessing the effects of exposures in vitro assays and in vivo animal studies may not reflect what happens in human populations. Therefore, using a transdisciplinary approach with a population-based epidemiologic study, in vitro assays, and in vivo mouse models, offers a targeted opportunity to evaluate the role of EDCs in promoting breast cancer during the menopausal transition. We are specifically investigating the effects of three polybrominated diphenyl ethers (BDE-47, BDE-100, and BDE-153). Using blood samples collected during the menopausal transition from women in the prospective California Teachers Study (CTS) cohort, we are assessing the effects of PBDE levels on the epigenome through miRNA and global and gene methylation assays, on total estrogenic activity, and on risk of developing breast cancer. In in vitro experiments in breast cell lines, we are measuring the effects of PBDEs at a range of levels, including at the CTS serum levels, to assess their effects on the activity of the estrogen and progesterone receptors and aromatase, as well as on the epigenome, transcriptome, and cell proliferation. Initial results suggest that BDE-47 acts as a mild ER-α agonist and BDE-100 and BDE-153 act as weak antagonists. In in vivo mouse models, we are testing whether combined effects of PBDEs at the levels seen in serum of the CTS samples cause mammary gland lesions. We first are studying ovariectomized mice, which have minimal estrogenic activity in their bodies, and then will use an ovarian-failure mouse model to represent the menopausal transition. Definitive changes in uterus weight and gene expression profiles have been observed in mice following 1-week feeding of PBDE-containing diet.