Authors: Sarah A Carratt, Nataliia Kovalchuk, Xinxin Ding, Laura S Van Winkle

Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are thought to be related because the target sites for both are similar. To understand susceptibility of the developing lung to cytotoxicity of inhaled NA, we exposed neonatal (7 days), juvenile (3 weeks), and adult mice to 5 or 10 ppm NA vapor for 4 h. We measured vacuolated airway epithelium morphometrically, quantified NA and NA-glutathione levels in plasma and lung, and quantified gene expression in microdissected airways. NA inhalation caused airway epithelial cytotoxicity at all ages, in both sexes. Contrary to a previous study that showed the greatest airway epithelial cytotoxicity in neonatal mice following intraperitoneal NA injection, we observed the most extensive airway epithelial toxicity in older, juvenile, animals exposed to NA by inhalation. Juvenile female animals were the most susceptible. Furthermore, NA inhalation in juvenile animals resulted in damage to conducting airway Club cells that was greater in proximal versus distal airways. We also found NA tissue burden and metabolism differed by age. Gene expression pathway analysis was consistent with the premise that female juvenile mice are more predisposed to damage; DNA damage and cancer pathways were upregulated. Our data demonstrate special susceptibility of young, juvenile mice to NA inhalation-induced cytotoxicity, highlight the importance of route of exposure and airway location in toxicity of chemicals in the developing lung, and provide metabolic and molecular insights for further identification of mechanisms underlying age and sex differences in NA toxicity.

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