US EPA

3452634 

Journal Article 

Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice 

Carratt, SA; Morin, D; Buckpitt, AR; Edwards, PC; Van Winkle, LS 

2016 

1 

Toxicology Letters
ISSN: 0378-4274
EISSN: 1879-3169 

246 

35-41 

English 

26840748 

10.1016/j.toxlet.2016.01.019 

WOS:000370525300005 

http://://WOS:000370525300005
Exit
 

Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. 1,2-Dihydro-1,2-dihydroxynaphthalene (NA-dihydrodiol) is a major metabolite of NA generated by microsomal epoxide hydrolase (mEH). To investigate the role of the NA-dihydrodiol and subsequent metabolites (i.e. 1,2-naphthoquinone) in cytotoxicity, we exposed both male and female wild type (WT) and mEH null mice (KO) to NA by inhalation (5, 10, 20 ppm for 4h). NA-dihydrodiol was ablated in the KO mice. High-resolution histopathology was used to study site-specific cytotoxicity, and formation of naphthalene metabolites was measured by HPLC in microdissected airways. Swollen and vacuolated airway epithelial cells were observed in the intra- and extrapulmonary airways of all mice at and below the current OSHA standard (10 ppm). Female mice may be more susceptible to this acute cytotoxicity. In the extrapulmonary airways, WT mice were more susceptible to damage than KO mice, indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site. The level of cytotoxicity in the mEH KO mice at all airway levels suggests that non-mEH metabolites are contributing to NA cellular damage in the lung. Our results indicate that the apparent contribution of mEH-dependent metabolites to toxicity differs by location in the lung. These studies suggest that metabolites generated through the mEH pathway may be of minor importance in distal airway toxicity and subsequent carcinogenesis from NA exposure. 

Toxicology Abstracts; P450 cytochrome P450; GSH glutathione; GST glutathione transferase; KO knockout; mEH microsomal epoxide hydrolase; NA naphthalene; NQ naphthoquinone; OSHA Occupational Safety and Health Administration; WT wild type; Cytochrome P450; Cell injury/cell death; Carcinogen metabolism; Microsomal epoxide hydrolase; Lung/pulmonary/olfactory; Toxicology; Epithelial cells; Toxicity; Cytotoxicity; High-performance liquid chromatography; Carcinogenesis; Epoxide hydrolase; Inhalation; Respiratory tract; Naphthalene; Metabolites; Pollutants; X 24350:Industrial Chemicals