Abstract
BackgroundSeveral environmental agents termed “endocrine disrupting compounds” or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells.Methodology/Principal FindingsTo investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive. Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1. Interestingly, a differential increase in expression of Jun and Fas by BPA but not DDT or estrogen was observed. In addition to ER responsive mRNAs, we investigated the ability of DDT and BPA to alter the miRNA profiles in MCF-7 cells. While the EDCs and estrogen similarly altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and BPA compared to estrogen.Conclusions/SignificanceWe have shown, for the first time, that BPA and DDT, two well known EDCs, alter the expression profiles of microRNA in MCF-7 breast cancer cells. A better understanding of the molecular mechanisms of these compounds could provide important insight into the role of EDCs in human disease, including breast cancer.
Highlights
Organochlorine pesticides and plasticizing agents are ubiquitous environmental endocrine disrupting compounds with the potential to negatively impact human health [1]
While the endocrine disrupting compounds (EDCs) and estrogen altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and bisphenol A (BPA) compared to estrogen
Jun and Fas were increased by approximately 1.8 and 1.5 fold by BPA but were relatively unchanged by E2 and DDT (Table 1). These subtle changes in gene expression mediated by the individual compounds prompted us to investigate whether EDC’s might alter the microRNA expression profile in MCF-7 breast cancer cells in a manner distinct from that seen by estrogen
Summary
Organochlorine pesticides and plasticizing agents are ubiquitous environmental endocrine disrupting compounds with the potential to negatively impact human health [1]. The majority of NHR- functional effects are mediated by changes in mRNA transcription, recent studies have demonstrated regulation of microRNA expression as an important mechanism in transcriptome networks. An important role for microRNAs in hormone signaling has recently been described [14], including estrogen regulation of microRNA expression in the hormone responsive MCF-7 breast cancer cells [15,16,17], and these studies further demonstrate that direct targets of ERa include miR-206, miR-155, miR-125b, miR-145 and miR-21. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently noncoding RNAs (ncRNAs). Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells
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