Modulation of AhR-dependent signaling by PPARb/d

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The aryl hydrocarbon receptor (AhR) mediates increased expression of phase I and II xenobiotic metabolizing enzymes in response to exposure to chemical carcinogens including polycyclic aromatic hydrocarbons (PAH). We have discovered that peroxisome proliferator-activated receptor-β (PPARβ-also referred to as PPARδ) may also alter AhR-dependent signaling by modulating cytochrome P450 (CYP) expression. In the absence of PPARβ/δ expression, increased expression of CYP1B1 and CYP1A1 and some phase II enzymes does not occur after application of PAHs. Since there is a balance between bio-activation (phase I) and detoxification (phase II) of carcinogens that is mediated by AhR-dependent pathways, this suggests that PPARβ/δ could significantly alter this balance. The central hypothesis of this proposal is that the PPARβ/δ modulates the metabolic fate of PAH. We will determine the functional significance of PPARβ/δ-dependent modulation of AhR-mediated signaling by testing the hypothesis that PPARβ/δ modulates the balance between AhRdependent bio-activation and detoxification of PAH by examining the metabolic fate of PAH as well as oxidative DNA damage in mouse skin, primary keratinocytes; and verifying these changes in human keratinocytes.