The goal of this work is to determine whether bisphenol A (BPA) perturbs epigenetic gene regulation during early mammalian development. BPA is one of the most highly produced chemicals worldwide used in the production of polycarbonate plastics, food and beverage packaging, resin-based products and dental sealant. Humans are ubiquitously exposed to BPA;fetuses and neonates are most vulnerable due to their inability to metabolize BPA efficiently. These observations are alarming as low dose exposure during fetal and early postnatal development in laboratory animals has been associated with various health abnormalities. Although BPA-induced effects are thought to arise from its estrogen-like properties and ability to bind to estrogen receptors, the exact molecular mechanisms are unclear. Recently, BPA exposure has been shown to cause epigenetic changes in the mouse through alteration in DNA methylation, although the work is preliminary and requires further investigation. The proposed research will initially focus on imprinted genes, as these genes are epigenetically regulated. Imprinted genes, as well as appropriate imprinted gene expression patterns, are essential for normal growth and development in mammals. Aberrant expression and regulation of imprinted genes is associated with a number of human diseases, including Beckwith-Wiedemann Syndrome, Prader-Willi Syndrome, Angelman Syndrome and Silver-Russell Syndrome. Preliminary experiments have also demonstrated that BPA exposure results in misregulated imprinted gene expression and reduced DNA methylation at a subset of loci. This proposal will further examine the effect of exposure on imprinted gene expression and methylation in mouse fetuses and newborns of pregnant mice exposed to BPA at various doses and during different developmental windows. Additionally, the genome-wide consequences of BPA exposure will be investigated through global promoter methylation and gene expression studies. To address the question of whether estrogen receptors mediate BPA-induced effects, mice lacking functional genes for the estrogen receptor alpha and beta will be exposed to BPA and the effects on epigenetic gene regulation will be assessed. In addition to providing general mechanistic insights into BPA actions, the proposed work will specifically elucidate the potential etiology of imprinting diseases with underlying environmental causes.
The proposed research will investigate whether exposure to the environmentally relevant chemical bisphenol A (BPA) disrupts the epigenetic regulation of imprinted genes that are critical for normal mammalian growth and development. The mouse system will be used to elucidate molecular mechanisms related to BPA-induced health abnormalities and to determine the potential etiology of human diseases with underlying environmental causes.
|Susiarjo, Martha; Sasson, Isaac; Mesaros, Clementina et al. (2013) Bisphenol a exposure disrupts genomic imprinting in the mouse. PLoS Genet 9:e1003401|