BaP-mediated reproductive and developmental toxicity

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DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are a human health concern because they are implicated in human cancers and reproductive and developmental deficits. The overall goal of this project is to determine the molecular mechanisms involved with benzo (a)pyrene (BaP)-mediated inhibition of CYP19A2 expression and the related physiological consequences. Our guiding hypothesis is that BaP deregulates the steroid hormone hypothalamus-pituitary-gonad feedback loop adversely affecting reproductive development and physiology. In our previous research, we have successfully used the fish Fundulus heteroclitus as a model for understanding the molecular mechanisms and pathological consequences of PAH exposure in humans and established BaP-induced effects on CYP19 expression and activity. This proposed project builds on our prior research to further probe the molecular mechanisms associated with these toxicities. In Aim 1 we will further establish BaP-mediated toxicological endpoints including phenotypic (gonad morphology) and molecular consequences (steroid concentrations, LH and FSH expression, and primordial germ cell migration). In Aim 2 we will knockdown CYP19A2 during early development and measure phenotypic and molecular consequences of the inhibition. Successful completion of these aims will provide a greater molecular understanding of the potential for environmentally relevant PAHs to adversely impact reproduction and development. In addition, we will gain additional insights into a critical physiological process (i.e. primordial germ cell migration) that could be adversely affected by BaP exposure while validating the fish model for further investigation of other stressors on these physiological outcomes. PUBLIC HEALTH RELEVANCE: Polycyclic aromatic hydrocarbon (PAH) concentrations in the environment are increasing. These compounds are a human health concern because they are implicated in human cancers and reproductive and developmental deficits. This research will provide a greater understanding of the molecular mechanisms and pathological consequences of PAH exposure.