UC Davis Genome Center, University of California Davis, Davis, California 95616, USA.
Center for Health and the Environment, University of California Davis, Davis, California, USA.
Toxicol Sci. 2021 Nov 24;184(2):214-222. doi: 10.1093/toxsci/kfab110.
Naphthalene is a ubiquitous environmental contaminant produced by combustion of fossil fuels and is a primary constituent of both mainstream and side stream tobacco smoke. Naphthalene elicits region-specific toxicity in airway club cells through cytochrome P450 (P450)-mediated bioactivation, resulting in depletion of glutathione and subsequent cytotoxicity. Although effects of naphthalene in mice have been extensively studied, few experiments have characterized global metabolomic changes in the lung. In individual lung regions, we found metabolomic changes in microdissected mouse lung conducting airways and parenchyma obtained from animals sacrificed at 3 timepoints following naphthalene treatment. Data on 577 unique identified metabolites were acquired by accurate mass spectrometry-based assays focusing on lipidomics and nontargeted metabolomics of hydrophilic compounds. Statistical analyses revealed distinct metabolite profiles between the 2 lung regions. Additionally, the number and magnitude of statistically significant exposure-induced changes in metabolite abundance were different between airways and parenchyma for unsaturated lysophosphatidylcholines, dipeptides, purines, pyrimidines, and amino acids. Importantly, temporal changes were found to be highly distinct for male and female mice with males exhibiting predominant treatment-specific changes only at 2 h postexposure. In females, metabolomic changes persisted until 6 h postnaphthalene treatment, which may explain the previously characterized higher susceptibility of female mice to naphthalene toxicity. In both males and females, treatment-specific changes corresponding to lung remodeling, oxidative stress response, and DNA damage were observed. Overall, this study provides insights into potential mechanisms contributing to naphthalene toxicity and presents a novel approach for lung metabolomic analysis that distinguishes responses of major lung regions.
萘是一种普遍存在的环境污染物，由化石燃料燃烧产生，是主流和侧流烟草烟雾的主要成分。萘通过细胞色素 P450（P450）介导的生物活化，在气道细胞中引起特定区域的毒性，导致谷胱甘肽耗竭，随后产生细胞毒性。尽管已经对小鼠中的萘进行了广泛的研究，但很少有实验对肺部的全局代谢组学变化进行了表征。在个别肺区域中，我们在暴露于萘后 3 个时间点处死的动物的微解剖小鼠肺传导气道和实质中发现了代谢组学变化。通过基于精确质量的质谱法测定法，针对亲水性化合物的脂质组学和非靶向代谢组学，获得了 577 个独特鉴定代谢物的数据。统计分析显示，2 个肺区域之间的代谢物图谱存在明显差异。此外，在气道和实质之间，未饱和溶血磷脂酰胆碱、二肽、嘌呤、嘧啶和氨基酸的丰度的暴露诱导变化的数量和幅度也不同。重要的是，雄性和雌性小鼠的时间变化高度不同，雄性仅在暴露后 2 小时表现出主要的特定于处理的变化。在雌性中，代谢组学变化一直持续到萘处理后 6 小时，这可能解释了先前描述的雌性小鼠对萘毒性的更高易感性。在雄性和雌性中，观察到与肺重塑、氧化应激反应和 DNA 损伤对应的特定于处理的变化。总体而言，这项研究提供了对萘毒性的潜在机制的深入了解，并提出了一种用于区分主要肺区域反应的新型肺部代谢组学分析方法。
