Transcriptional regulation of polycyclic aromatic hydrocarbon metabolism

说明书(申请人提供)：多环芳烃(PAH)是一类已知会对人类造成毒性和癌症的环境化学品。多环芳烃引起的分子变化是由芳烃受体(AHR)介导的。特别是，AHR介导了I相和II相异源代谢酶的上调，这些酶可以导致PAH的生物激活和解毒。事实上，在直接受AHR依赖的信号影响的化学致癌物的生物激活和解毒之间存在着微妙的平衡。新的证据表明，PPAR？/？可能调节皮肤/角质形成细胞中的AHR活性，这种相互作用将显著改变生物激活和解毒之间的平衡，从而导致对化学诱导毒性的不同敏感性。对于具体目标1，我们将确定PPAR？/？可以调节AHR的活性，重点是受体异二聚体的移位和关键的转录事件，这是增加外源代谢表达所必需的，这是PAH生物激活和解毒所必需的。对于特定的目标2，我们将确定PPAR？/？能功能性地改变AHR介导的多环芳烃诱导的皮肤癌变。这些研究的结果将阐明AHR依赖的信号的新的调控机制，这些机制在调节环境中多环芳烃引起的毒性和致癌效应中起核心作用。重要的是，这些研究的结果可能有助于解释人类AHR依赖功能的显著差异，因为AHR中没有发现功能多态。 与公共健康相关：暴露在环境化学品中，如多环芳烃，可对人类造成毒性和癌症，相关成本每年超过1000亿美元。化学诱导的毒性和癌症的原因非常不清楚。因此，确定化学诱导毒性和致癌的潜在机制是至关重要的。虽然人们普遍认为芳烃受体是介导细胞变化所必需的，这种变化既可以引起(生物激活)，也可以阻止(解毒)，但新的证据表明，其他蛋白质也可能影响AHR的活性。在这些研究中，我们将研究可能与AHR信号相互作用的新蛋白，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.