Gonadal vs. Genomic Influences on Xenobiotic Metabolism

描述(申请人提供)：新陈代谢是从体内清除外源物质的关键步骤。尽管新陈代谢在确定污染物和致癌物的效力方面具有基本的重要性，但人们对关键新陈代谢途径中的性别差异知之甚少。性别之间的差异可能是由于类固醇激素(性腺)的相互作用或基因含量的差异(基因组相互作用)。我们建议研究性腺和基因组的相互作用对一类普遍存在的环境污染物(多环芳烃，PAHs)在化学致癌的主要靶器官肺中代谢的影响。模型化合物将是萘，这是环境烟草烟雾中的主要多环芳烃，也是化石燃料燃烧的副产品。人类接触到萘是一个令人担忧的问题，因为最近宣布萘可能是人类致癌物质。有3个原因引起了女性群体的兴趣：1)女性比男性更早地患上肺癌，并且在吸烟后的暴露时间比男性更少；2)女性(而不是男性)会导致肺癌；3)数据显示，雌性小鼠比雄性小鼠对萘的肺部毒性更敏感。在这项提案中，将研究不同性别对肺中萘的代谢和解毒的影响。这些系统的改变可能使女性的肺预先发生呼吸道上皮损伤增加和随后的重塑，这取决于暴露发生的生殖周期阶段。中心假设是，女性对新陈代谢活性化合物(如萘)的敏感性增加，主要受性腺激素的影响。中心假说通过两个具体的目标来阐述。这些结果将决定：1)女性性腺激素是否调节肺内萘的代谢；2)女性特有的基因表达是否调节肺内的萘代谢。我们将使用一种多学科的方法，结合形态学、特定部位的定量基因表达、酶活性测量和蛋白质组学方法来确定性激素和类固醇激素对萘生物活性的影响。拟议的研究与与肺重塑和PAH激活相关的疾病有关，如肺癌。

DESCRIPTION (provided by applicant): Metabolism is a key step in eliminating xenobiotics from the body. Despite the fundamental importance of metabolism in determining the potency of contaminants and carcinogens, little is known about sex-specific differences in critical metabolic pathways. Differences between the sexes can be due to steroid hormone (gonadal) interactions or to differences in gene content (genomic interactions). We propose to investigate the effect of gonadal vs. genomic interactions on metabolism of a class of ubiquitous environmental contaminants (polycyclic aromatic hydrocarbons, PAHs) in a primary target organ for chemical carcinogenesis, the lung. The model compound will be naphthalene, the predominant PAH in environmental tobacco smoke and a byproduct of fossil fuel combustion. Human exposure to naphthalene is a concern as naphthalene was recently declared a likely human carcinogen. Naphthalene toxicity is of interest in the female population for 3 reasons: 1) women develop lung cancer earlier and after less cigarette exposure than men, 2) naphthalene causes lung tumors in female (but not male) mice and 3) data shows that female mice are more sensitive than male mice to naphthalene pulmonary toxicity. Sex-specific effects on metabolism and detoxification of naphthalene in the lung will be investigated in this proposal. Alterations in these systems may pre-dispose the lungs of females to increased airway epithelial injury and subsequent remodeling dependent on the stage of the reproductive cycle at which exposure occurs. The central hypothesis is that elevated susceptibility of females to metabolically activated compounds, such as naphthalene, is influenced primarily by gonadal hormones. The central hypothesis is addressed through two specific aims. These will determine if: 1) Female gonadal hormones regulate pulmonary metabolism of naphthalene and 2) Female-specific gene expression regulates pulmonary metabolism of naphthalene. We will use a multidisciplinary approach that combines morphology, site-specific quantitative gene expression, enzyme activity measures and proteomic approaches to define the effect of sex and steroid hormones on bioactivation of naphthalene. The proposed studies are relevant to diseases associated with pulmonary remodeling and PAH activation, such as lung cancer.