Perinatal xenoestrogen exposure: epigenesis and neoplasia

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DESCRIPTION (provided by applicant): The increased incidence of uterine leiomyoma, testicular and breast cancer observed in European and US populations during the last 50 years prompted scientists to hypothesize that prenatal exposure to environmental estrogens may be the underlying cause of these neoplasms. Epidemiological studies suggest that fluctuating estrogen levels in the fetal environment have long-term consequences regarding the risk of developing breast cancer during adult life. This is supported by laboratory rodent studies showing that perinatal exposure to pharmacological doses of diethylstilbestrol (DES) increases the incidence and decreases the latency period of mammary cancer. Among the xenoestrogens, bisphenol-A was chosen for these studies because of its widespread use and because it is found in 95% of the urine samples analyzed in a recent CDC study. Perinatal exposure to environmentally relevant doses of the xenoestrogen bisphenol A (BPA) alters the development of the rodent mammary gland and results in outcomes such as increased sensitivity to estrogens at puberty, increased ductal density in adulthood, and an increase in the number of structures where cancer arises. Using a rat mammary carcinogenesis model a pilot experiment was performed that revealed that perinatal exposure to low BPA doses induces intraductal hyperplasias. When challenged with a subcarcinogenic dose of nitrosomethylurea, only the BPA exposed animals developed neoplasias. Thus it is hypothesized that BPA administered perinatally will permanently alter tissue-specific patterns of gene expression by altering the methylation pattern of specific genes. These alterations will, in turn, affect development beyond the period of exposure to BPA, leading to an increase in susceptibility to breast cancer. Specific Aim 1 will compare the global pattern of DNA methylation in the mammary glands of vehicle and BPA-exposed animals and to construct a chromosomal methylation idiogram. The three components of Specific Aim 2 are to: 1) Determine the mRNA expression profiles of the BPA-treated mammary glands by DNA microarray analysis and to map the loci of differentially expressed genes on the rat chromosomal ideogram; 2) Identify candidate genes that are differentially expressed according to the mRNA microarray analysis that map onto the BPA-methylated or demethylated chromosomal regions; and 3) Narrow the set of candidate genes by bioinformatics techniques (molecular pathway and ontology analysis). The most promising candidate(s) will be probed in detail using bisulfite mapping of the methylated CpG dinucleotides. If a causal link is found between perinatal BPA exposure and alterations in gene methylation, this work will provide testable hypotheses connecting BPA-induced gene marking and propensity to develop mammary gland neoplasia. If the hypothesis is consistent with the result, this will constitute a major shift in emphasis from adult exposures to in utero exposures. This will also have a great impact on the way we study risk factors and conduct epidemiological studies; it may even influence public policy about breast cancer prevention.