Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice

• Published in: Toxicology (Amsterdam) Vol. 311; no. 3; pp. 107 - 114
• Main Authors: Weng, Zuquan, Suda, Megumi, Ohtani, Katsumi, Mei, Nan, Kawamoto, Toshihiro, Nakajima, Tamie, Wang, Rui-Sheng
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.09.2013
• Subjects: acetaldehyde; Acetaldehyde - blood; Administration, Inhalation; alcohols; aldehyde dehydrogenase; Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase, Mitochondrial; Aldh2; Animals; biofuels; blood; carcinogens; Comet Assay; DNA Damage; Emergency; enzyme activity; Ethyl Ethers - blood; Ethyl Ethers - pharmacokinetics; Ethyl Ethers - toxicity; Ethyl tertiary butyl ether; Female; females; gender differences; genes; Genetic damage; genotoxicity; inhalation exposure; Kinetics; Knockout mice; Male; metabolism; metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Micronucleus Tests; Propylene Glycols - blood; Sex Factors; subchronic exposure; tert-Butyl Alcohol - blood; Toxicity Tests, Subchronic; toxicology; Japan; MPD; 2-methyl-1,2-propanediol; MN-NCE; MN-RETs; ethyl tertiary butyl ether; aldehyde dehydrogenase2; tert-butyl alcohol; MTBE; Genetic damage; ETBE; TBA; ALDH2; hOGG1; micronuclei in the mature normochromatic erythrocyte; acetaldehyde; WT; micronucleated reticulocytes; AA; knockout; Knockout mice; KO; methyl tertiary butyl ether; IARC; International Agency for Research on Cancer; 8-hydroxyguanine DNA-glycosylase; Kinetics; wild-type; Ethyl tertiary butyl ether
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2013.06.005

Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500ppm ETBE for 1–6h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000ppm ETBE for 6h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females.