Gonadal vs. Genomic Influences on Xenobiotic Metabolism

描述（由申请人提供）：代谢是消除体内外来生物的关键步骤。尽管代谢在决定污染物和致癌物的效力方面具有根本的重要性，但对关键代谢途径的性别特异性差异知之甚少。两性之间的差异可能是由于类固醇激素（性腺）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——肺中的代谢的影响。模型化合物将是萘，它是环境烟草烟雾中主要的多环芳烃，也是化石燃料燃烧的副产品。人类接触萘是一个问题，因为萘最近被宣布为一种可能的人类致癌物。女性人群对萘毒性的兴趣有三个原因：1)女性患肺癌的时间比男性早，吸烟后接触香烟的时间也比男性少；2)萘在雌性（而不是雄性）小鼠中引起肺部肿瘤；3)数据显示雌性小鼠比雄性小鼠对萘肺毒性更敏感。性别对肺内萘代谢和解毒的影响将在本提案中进行研究。这些系统的改变可能使女性肺部预先受到气道上皮损伤的增加和随后的重塑，这取决于暴露发生的生殖周期阶段。核心假设是，女性对代谢激活化合物（如萘）的敏感性升高主要受性腺激素的影响。中心假设是通过两个具体目标来解决的。这些将决定：1)女性性腺激素是否调节萘的肺代谢；2)女性特异性基因表达是否调节萘的肺代谢。我们将采用多学科方法，结合形态学、位点特异性定量基因表达、酶活性测量和蛋白质组学方法来确定性别和类固醇激素对萘生物活性的影响。提出的研究与肺重塑和多环芳烃活化相关的疾病，如肺癌有关。

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.