Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells

Abstract

Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ERα signaling pathway and global gene expression profiles. Compared to control cells, nuclear internalization of ERα was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ERα-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ERα-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells.

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

“…An increase in DNA methylation in the promoter regions of lysosomal‐associated membrane protein 3 (LAMP3) was observed both in human primary epithelial cells and breast cancer cells after exposure to low‐dose BPA, indicating that epigenetic regulation is a crucial mechanism of BPA's carcinogenic effects 140. Moreover, it was suggested that BPA‐induced changes in expression levels of microRNAs (a mode of epigenetic regulation) in placental cells might account for abnormal mammary gland architecture following fetal exposure to BPA 141.…”

Effect of bisphenol A on the EGFR-STAT3 pathway in MCF-7 breast cancer cells

“…A stock solution of AG1478 was produced in DMSO at 20 mM/l and then diluted with phenol red-free 1640 medium to a final working solution at 10 µM. MCF-7 cells were seeded in 6-well plates at 1x10 6 cells/well and 96-well plates at 5000 cells/well. BPA and AG1478 were added at the working concentrations, respectively, to 96-well plates with five repeats for each group.…”

“…Neonatal exposure to BPA is associated with higher body weight, increased breast and prostate cancer incidence and altered reproductive function (5). Experimental evidence indicates that exposure to BPA during childhood increases the risk of breast cancer in the adult female (6). As a consequence of this widespread opportunity for exposure, 95% of Americans carry detectable levels of BPA (7), which is currently one of the highest volume chemicals produced in the world (8).…”

Impact of Environmental Contaminants on Breast Cancer / Wpływ Zanieczyszczenia Środowiska Na Raka Piersi

“…In examination of epigenetic changes in breast epithelial cells treated with low-dose BPA and the effect of BPA on the ER-α signalling pathway and global gene expression profiles, 170 genes with similar expression changes in response to BPA were identified, and the gene suppression by BPA was mediated in part through an ER-α dependent pathway [134]. Administration of BPA to mice confirmed that DNA adducts are formed in target mammary cells (4.7-fold higher than in controls) [135].…”