Olfactory toxicity of environmental agents

描述（由申请人提供）：长期目标是确定环境毒物对嗅觉系统的影响，以及化学物质暴露在嗅觉缺失和其他与鼻腔有关的疾病（如鼻息肉、慢性鼻炎症、微生物感染和哮喘）病因学中的作用。我们的重点是组织特异性毒性的机制和风险评估的分子方法。先前的体外研究表明，嗅觉粘膜（OM）显性细胞色素P450 （CYP）酶可能在许多化学物质的OM选择性毒性中起重要作用。在目前的资助期内，我们已经成功地制备和初步表征了两种敲除小鼠模型，一种是omm特异性Cyp2gl基因的种系破坏（Cyp2gl-null小鼠），另一种是nadph -细胞色素P450还原酶（Cpr）基因的肝脏特异性缺失（肝脏- pr-null小鼠）。通过这些模型，我们获得了肝脏代谢在对乙酰氨基酚（作为模型毒物）鼻毒性中的作用，以及CYP2A5和/或CYP2G1在对乙酰氨基酚在侧鼻腺（LNG）毒性中的作用的重要初步数据。在拟议的研究中，我们将验证一个一般假设，即靶组织代谢激活对肝外化学毒性至关重要；然而，特定组织对给定化合物的敏感性将取决于许多因素（除了母体化合物的系统清除率之外），例如循环肝脏代谢物的水平和反应性，以及目标组织中内源性底物的稳态。具体目的是：1)确定肝脏代谢和靶组织代谢激活对鼻毒物OM毒性的影响；2)确定cyp2gl缺失小鼠LNG对AP毒性抗性增强的机制；3)建立更多的小鼠模型，用于确定CYP2A5和CYP2G1在OM和LNG靶组织代谢激活和化学毒性中的具体作用。这些研究将对潜在鼻毒性物质的风险评估具有广泛的意义，并可作为研究其他肝外组织化学毒性机制的模型。

DESCRIPTION (provided by applicant): The long-term objective is to determine the impact of environmental toxicants on the olfactory system and the role of chemical exposure in the etiology of anosmia and other diseases concerning the nasal cavity, such as nasal polyps, chronic nasal inflammation, microbial infection, and asthma. Our focus has been on the mechanisms of tissue-specific toxicity and molecular approaches to risk assessment. Previous in vitro studies have suggested that olfactory mucosa (OM)-predominant cytochrome P450 (CYP) enzymes may be important in the OM-selective toxicity of many chemicals. In the current funding period, we have succeeded in the preparation and initial characterization of two knockout mouse models, one with germ-line disruption of the OM-specific Cyp2gl gene (Cyp2gl-null mouse), the other with liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene (liver-Cpr-null mouse). Using these models, we have obtained important preliminary data concerning the role of hepatic metabolism in nasal toxicity of acetaminophen (as a model toxicant), and the role of CYP2A5 and/or CYP2G1 in the toxicity of acetaminophen in the lateral nasal gland (LNG). In the proposed studies, we will test a general hypothesis that target tissue metabolic activation is critical for extrahepatic chemical toxicity; however, the sensitivity of a particular tissue to a given compound will depend on many factors (in addition to the rate of systemic clearance of the parent compound), such as the level and reactivity of circulating hepatic metabolites, and homeostasis of endogenous substrates in the target tissue. The specific aims are: 1) To determine the impact of hepatic metabolism and target tissue metabolic activation on OM toxicity of nasal toxicants; 2) To determine the mechanisms of the increased resistance to AP toxicity in the LNG of the Cyp2gl-null mouse; and 3) To generate additional mouse models that can be used for determining the specific roles of CYP2A5 and CYP2G1 in target tissue metabolic activation and chemical toxicity in the OM and LNG. These studies will have broad implications for risk assessment of potential nasal toxicants, and may serve as a model for studying mechanisms of chemical toxicity in other extrahepatic tissues.