Arsenite and Epigenetic Regulation of Gene Expression
Mary B. Martin, Ph.D.
Endocrine disrupters are thought to be an underlying risk factor for the high incidence of hormone related diseases such as early puberty onset and breast cancer. Estrogens play a central role both in the onset of puberty and the etiology of breast cancer. Because estrogen receptor-alpha (ER-a) mediates many of the effects of estrogens, molecules that can bind to and activate ER-a can potentially advance the onset of puberty and increase the risk of breast cancer. Published studies from this laboratory demonstrate that the metalloid arsenite activates ER-a through a high affinity interaction (KI = 10-10 M) with hormone binding domain of the receptor involving amino acids C381, C447, H524, K529 and/or K531, and N532. More importantly, it has been shown that an environmentally relevant dose of arsenite mimics the effects of estradiol on the growth and expression of genes in MCF-7 breast cancer cells. Preliminary data presented in this application demonstrate that environmentally relevant doses of arsenite also mimic the effects of estrogens in vivo. In ovariectomized animals, arsenite increases uterine wet weight and induces estrogen regulated genes. In intact animals, prepubertal exposure to arsenite accelerates the development of the mammary gland and increases the incidence of mammary tumors in animals challenged with the chemical carcinogen dimethylbenzanthracene, consistent with an estrogen like effect on mammary tumorigenesis. Based on these observations, this application will test the hypothesis that early life exposure to environmentally relevant amounts of arsenite imprints or reprograms gene expression in the mammary gland leading to early onset of puberty and increased susceptibility to mammary tumorigenesis. Specific Aim 1 will identify genes altered by prepubertal exposure to arsenite and determine whether their expression is altered through epigenetic mechanisms. Specific Aim 2 will determine whether in utero exposure to arsenite alters gene expression.