Gonadal vs. Genomic Influences on Xenobiotic Metabolism

性腺与基因组对异生物质代谢的影响

• 批准号: 7005829
• 负责人: Laura S Van Winkle
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-06 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005829
• 关键词: adduct; cancer risk; chemical carcinogen; confocal scanning microscopy; enzyme activity; estradiol; gender difference; gene expression; gene expression profiling; genetic susceptibility; glutathione; glutathione transferase; hormone regulation /control mechanism; immunologic assay /test; laboratory mouse; liver metabolism; lung injury; lung neoplasms; male castration; naphthalenes; ovariectomy; progesterone; respiratory epithelium; respiratory function; tissue /cell culture; toxin metabolism

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.

描述（由申请人提供）：代谢是消除体内异种生物的关键步骤。 尽管代谢在确定污染物和致癌物的效力方面的基本重要性，但对关键代谢途径的性别特定差异知之甚少。性别之间的差异可能是由于类固醇激素（性腺）相互作用或基因含量（基因组相互作用）的差异。 我们建议研究性腺与基因组相互作用对一类无处不在的环境污染物的代谢（多环芳烃，PAHS，PAHS）的代谢的影响，用于化学癌变，肺。 该模型化合物将是萘，这是环境烟草烟雾中的主要PAH和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可能的人致癌。 萘毒性在女性人群中引起了3个原因：1）女性与男性相比，妇女患肺癌和少量吸烟后患有肺癌，2）萘导致雌性（但不是雄性）小鼠的肺肿瘤，而3个数据显示，雌性小鼠比雄性小鼠对萘苯乙烯肺部肺毒性更敏感。 该提案将研究对肺中萘的新陈代谢和萘排毒的影响。 这些系统中的改变可能会预见女性的肺部，以增加气道上皮损伤，并根据发生暴露的生殖周期阶段进行重塑。 中心假设是，女性对代谢活化化合物（例如萘）的易感性升高，主要受性腺激素的影响。 中心假设是通过两个具体目标解决的。 这些将确定：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。 我们将使用一种多学科方法，该方法结合了形态学，特异性定量基因表达，酶活性测量和蛋白质组学方法来定义性别和类固醇激素对萘的生物活化的影响。 拟议的研究与与肺癌和PAH激活相关的疾病（例如肺癌）有关。