Transcriptional regulation of polycyclic aromatic hydrocarbon metabolism

描述（由申请人提供）：多环芳烃（PAH）是一类已知会导致人类毒性和癌症的环境化学品。暴露于PAH诱导的分子变化由芳烃受体（AHR）介导。特别是，AHR介导I相和II相异生物质代谢酶的上调，这些酶可引起PAH的生物活化和解毒。事实上，在直接受AHR依赖性信号影响的化学致癌物的生物活化和解毒之间存在良好的平衡。新出现的证据表明，PPAR？/？可以调节皮肤/角质形成细胞中的AHR活性，并且这种相互作用将显著改变生物活化和解毒之间的平衡，导致对化学诱导的毒性的易感性的差异。对于具体目标1，我们将确定的机制，通过它的过氧化物酶体增殖物激活受体/？可以调节AHR活性，重点是受体异源二聚体易位和关键转录事件，这些事件是增加PAH生物活化和解毒所必需的外源性代谢表达所必需的。对于特定目标2，我们将确定是否有PPAR？/？可以在功能上改变由AHR介导的PAH诱导的皮肤致癌作用。从这些研究的结果将阐明新的调节机制AHR依赖的信号是中央介导的毒性和致癌作用所造成的暴露于环境PAH。重要的是，这些研究的结果可能有助于解释人类AHR依赖性功能的显著变化，因为尚未发现AHR的功能多态性。 公共卫生相关性：暴露于多环芳烃等环境化学品会导致人类中毒和癌症，每年相关成本超过1 000亿美元。化学品引起的毒性和癌症的原因还不清楚。因此，必须确定化学诱导毒性和致癌作用的机制。虽然人们普遍认为，芳香烃受体是介导细胞变化所必需的，这种变化既可以引起（生物活化），也可以防止（解毒），但新出现的证据表明，其他蛋白质也可能影响AHR活性。在这些研究中，我们将检查可能与AHR信号相互作用的新蛋白质，并确定可能调节化学诱导的毒性和癌症的新途径。

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAH) are a class of environmental chemicals that are known to cause toxicity and cancers in humans. The molecular changes induced by exposure to PAH are mediated by the aryl hydrocarbon receptor (AHR). In particular, the AHR mediates up-regulation of phase I and phase II xenobiotic metabolizing enzymes that can cause both bioactivation and detoxification of PAH. Indeed, there is a fine balance between bioactivation and detoxification of chemical carcinogens that are directly influenced by AHR-dependent signaling. Emerging evidence indicates that PPAR?/? may modulate AHR activity in skin/keratinocytes, and that this interaction will significantly alter the balance between bioactivation and detoxification leading to differences in the susceptibility to chemically-induced toxicity. For Specific Aim 1, we will determine the mechanisms by which PPAR?/? can modulate AHR activity with an emphasis on receptor heterodimer translocation and critical transcriptional events necessary for increasing expression of xenobiotic metabolism that are necessary for bioactivation and detoxification of PAH. For Specific Aim 2, we will determine if PPAR?/? can functionally alter PAH-induced skin carcinogenesis mediated by AHR. Results from these studies will elucidate novel regulatory mechanisms of AHR-dependent signaling that are central in mediating the toxic and carcinogenic effects caused by exposure to environmental PAH. Importantly, results from these studies might help explain the significant variation in AHR-dependent function in humans, since no functional polymorphisms in the Ahr have been identified. PUBLIC HEALTH RELEVANCE: Exposure to environmental chemicals such as polycyclic aromatic hydrocarbons can cause toxicity and cancers in humans, with associated costs exceeding $100 billion annually. The causes of chemically-induced toxicity and cancer are very unclear. Thus, it is essential to determine the mechanisms underlying chemically-induced toxicity and carcinogenesis. While it is well accepted that the aryl hydrocarbon receptor is required to mediate cellular changes that can both cause (bioactivation) and prevent (detoxification), emerging evidence suggests that other proteins may also affect AHR activity. In these studies, we will examine new proteins that may interact with AHR signaling and identify novel pathways that may modulate chemically- induced toxicity and cancers.