Gonadal vs. Genomic Influences on Xenobiotic Metabolism

描述（由申请人提供）：代谢是从体内消除外源性物质的关键步骤。 尽管代谢在确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。性别之间的差异可能是由于类固醇激素（性腺）的相互作用或基因内容的差异（基因组相互作用）。 我们建议调查性腺与基因组相互作用对一类普遍存在的环境污染物（多环芳烃，多环芳烃）在化学致癌的主要靶器官，肺代谢的影响。 模型化合物将是萘，环境烟草烟雾中主要的PAH和化石燃料燃烧的副产品。 由于萘最近被宣布为可能的人类致癌物，因此人类接触萘是一个令人关注的问题。 萘毒性在雌性群体中引起关注，原因有3个：1）女性比男性更早发生肺癌，并且在吸烟暴露较少后发生肺癌，2）萘在雌性（但不是雄性）小鼠中引起肺肿瘤，3）数据显示雌性小鼠比雄性小鼠对萘肺毒性更敏感。 在这项建议中，性别特异性的影响萘在肺中的代谢和解毒将进行调查。 这些系统的改变可能使女性的肺易于增加气道上皮损伤和随后的重塑，这取决于暴露发生的生殖周期阶段。 核心假设是，女性对代谢活化化合物（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的目标。 这些将决定：1）雌性性腺激素调节萘的肺代谢和2）雌性特异性基因表达调节萘的肺代谢。 我们将使用一个多学科的方法，结合形态学，位点特异性定量基因表达，酶活性的措施和蛋白质组学的方法来定义性和类固醇激素对萘的生物活化的影响。 拟议的研究与肺重塑和PAH激活相关的疾病（如肺癌）相关。

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.