Metabolomics of Lung Microdissections Reveals Region- and Sex-Specific Metabolic Effects of Acute Naphthalene Exposure in Mice.
Nathanial C StevensPatricia C EdwardsLisa M TranXinxin DingLaura S Van WinkleOliver FiehnPublished in: Toxicological sciences : an official journal of the Society of Toxicology (2022)
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.
Keyphrases
- mass spectrometry
- dna damage
- oxidative stress
- liquid chromatography
- high fat diet induced
- cystic fibrosis
- high resolution
- combination therapy
- high throughput
- amino acid
- adipose tissue
- human health
- cell proliferation
- air pollution
- hepatitis b virus
- single cell
- dna repair
- intensive care unit
- insulin resistance
- big data
- cell cycle arrest
- wild type
- capillary electrophoresis
- wastewater treatment
- water quality
- simultaneous determination