Polycyclic aromatic hydrocarbons (PAHs), derived largely from the combustion of fossil fuels, are widespread environmental contaminants that have been shown to cross the placenta. Therefore, developmental exposure to PAHs has the potential to cause adverse health outcomes. Despite the potential developmental risk posed from individual or mixtures of PAHs, there are substantial information gaps regarding structure-developmental toxicity relationships and, most importantly, the mechanism underlying PAH toxicity remains largely unknown. It is widely believed that toxicity from PAHs is initiated by binding to the aryl hydrocarbon receptor (AHR) and subsequent cytochrome P4501A (CYP1A) induction;however, recent studies have suggested that a subset of PAHs produce developmental toxicity independent of AHR. The difficulty in elucidating mechanisms of developmental toxicity can be largely attributed to the limitations of current vertebrate models. Recent advances in the fields of genomics, chemistry, genetics, bioinformatics and rapid-throughput screening have provided powerful new approaches for the study of complex biological processes. Global transcriptional analysis coupled with comparative bioinformatics now allows for the discovery of gene-gene interactions which are necessary to produce toxicity. Complex biological responses can be dissected with the aid of rapid-throughput phenotypic screens of small molecule libraries. The well-known advantages of the zebrafish embryo have made this model amenable to all of the above approaches. We are just beginning to realize the enormous contribution that zebrafish will make as part of an integrative approach to improve human health. This proposal specifically seeks to use zebrafish to define the mechanism of PAH developmental toxicity. Our underlying hypothesis is that PAHs produce developmental toxicity by AHR-dependent and AHR-independent mechanisms, depending on the structure of the PAH. We will test this hypothesis in three Specific Aims: 1) directly determine the role of the AHR in mediating the developmental toxicity of PAHs;2) define early developmental biomarkers of PAH exposure;3 use chemical genetics to identify cellular targets that modulate PAH developmental toxicity. Successful completion of the proposed experiments will result in the identification of developmental responses to PAHs at the molecular and cellular level, and determination of the role of responsive genes in toxicity. For the first time we will identify pathways that are necessary for PAH developmental toxicity. The identification of these cellular targets has the potential to unravel gene-environmental interactions that will help explain individual susceptibility to PAHs.
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