Benzo(a)pyrene (BaP) is a ligand for the aryl hydrocarbon receptor (Ahr) and a potent genotoxic carcinogen. Environmental exposure to BaP has been associated with tumorigenesis, atherosclerosis and developmental deficits in several organ systems. The Ramos laboratory has recently shown that treatment of metanephric cultures with BaP is associated with Ahr-dependent disruption of nephrogenesis, as evidenced by inhibition of glomerulogenesis and branching morphogenesis. Nephrogenesis is characterized by mesenchymal-to-epithelial transition and this process is regulated by the Wilm's tumor suppressor gene (Wt-1). Disruption of nephrogenesis by BaP involves interference with Wt-1 splicing and reductions in Wt-1 protein. Studies are proposed in this application to test the hypothesis that ligands of Ahr disrupt nephrogenesis in vivo by altering Wt-1 mRNA splicing.
Aim 1 examines the impact of in utero BaP exposure on nephrogenesis and Wt-1 mRNA splicing.
Aim 2 will determine the kinetic profiles of BaP-induced inhibition of nephrogenesis and altered Wt-1 splice variant expression.
Aim 3 will characterize the mouse mesonephric M15 cell line as a model to evaluate downstream effects of increased -KTS/+KTS mRNA ratios. ? ?
