Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells.
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.
Weng
Yu-I
YI
Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA.
Hsu
Pei-Yin
PY
Liyanarachchi
Sandya
S
Liu
Joseph
J
Deatherage
Daniel E
DE
Huang
Yi-Wen
YW
Zuo
Tao
T
Rodriguez
Benjamin
B
Lin
Ching-Hung
CH
Cheng
Ann-Lii
AL
Huang
Tim H-M
TH
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds; D001940:Breast / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000187:drug effects; D010636:Phenols / Q000633:toxicity*; D055815:Young Adult; D059666:Lysosomal-Associated Membrane Protein 3; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D051907:Lysosomal Membrane Proteins; D009363:Neoplasm Proteins; D019913:Nuclear Localization Signals; D010636:Phenols; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3; C006780:bisphenol A; D000098826:Bisphenol A Compounds