title: Gestational exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin induces BRCA-1 promoter hypermethylation and reduces BRCA-1 expression in mammary tissue of rat offspring: preventive effects of resveratrol.
abstract: Studies with murine models suggest that maternal exposure to aromatic hydrocarbon receptor (AhR) agonists may impair mammary gland differentiation and increase the susceptibility to mammary carcinogenesis in offspring. However, the molecular mechanisms responsible for these perturbations remain largely unknown. Previously, we reported that the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CpG methylation of the breast cancer-1 (BRCA-1) gene and reduced BRCA-1 expression in breast cancer cell lines. Based on the information both the human and rat BRCA-1 genes harbor xenobiotic responsive elements (XRE = 5'-GCGTG-3'), which are binding targets for the AhR, we extended our studies to the analysis of offspring of pregnant Sprague-Dawley rats treated during gestation with TCDD alone or in combination with the dietary AhR antagonist resveratrol (Res). We report that the in utero exposure to TCDD increased the number of terminal end buds (TEB) and reduced BRCA-1 expression in mammary tissue of offspring. The treatment with TCDD induced occupancy of the BRCA-1 promoter by DNA methyltransferase-1 (DNMT-1), CpG methylation of the BRCA-1 promoter, and expression of cyclin D1 and cyclin-dependent kinase-4 (CDK4). These changes were partially overridden by pre-exposure to Res, which stimulated the expression of the AhR repressor (AhRR) and its recruitment to the BRCA-1 gene. These findings point to maternal exposure to AhR agonists as a risk factor for breast cancer in offspring through epigenetic inhibition of BRCA-1 expression, whereas dietary antagonists of the AhR may exert protective effects.
authors.affiliation: Department of Nutritional Sciences and Arizona Cancer Center, The University of Arizona, Tucson, Arizona.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Papoutsis
authors.forename: Ornella I
authors.initials: OI
authors.lastname: Selmin
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Borg
authors.forename: Donato F
authors.initials: DF
authors.lastname: Romagnolo
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D019398:Genes, BRCA1 / Q000187:drug effects*; D018811:Maternal Exposure / Q000009:adverse effects*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D013723:Teratogens / Q000633:toxicity*
chemical_list: D016588:Anticarcinogenic Agents; D019313:BRCA1 Protein; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D013723:Teratogens; D000077185:Resveratrol
keywords: BRCA-1; aromatic hydrocarbon receptor; epigenetics; mammary carcinogenesis; resveratrol