title: Differential genotoxic effects of subchronic exposure to ethyl tertiary butyl ether in the livers of Aldh2 knockout and wild-type mice.
abstract: Ethyl tertiary butyl ether (ETBE) is used as an additive to gasoline to reduce carbon monoxide emissions in some developed countries. So far, ETBE was not found with positive results in many genotoxic assays. This study is undertaken to investigate the modifying effects of deficiency of aldehyde dehydrogenase 2 (ALDH2) on the toxicity of ETBE in the livers of mice. Eight-week-old wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice of both sexes were exposed to 0, 500, 1,750, and 5,000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Histopathology assessments and measurements of genetic effects in the livers were performed. Significantly increased accidences of centrilobular hypertrophy were observed in the livers of WT and KO mice of both sexes in 5,000 ppm group; there was a sex difference in centrilobular hypertrophy between male and female KO mice, with more severe damage in the males. In addition, DNA strand breaks, 8-hydroxyguanine DNA-glycosylase (hOGG1)-modified oxidative base modification, and 8-hydroxydeoxyguanosine as genetic damage endpoints were significantly increased in three exposure groups in KO male mice, while these genotoxic effects were only found in 5,000 ppm group of KO female mice. In WT mice, significant DNA damage was seen in 5,000 ppm group of male mice, but not in females. Thus, sex differences in DNA damage were found not only in KO mice, but also in WT mice. These results suggest that ALDH2 polymorphisms and sex should be taken into considerations in predicting human health effects of ETBE exposure.
authors.affiliation: Division of Health Effects Research, Japan National Institute of Occupational Safety and Health, 6-21-1 Nagao, Kawasaki 214-8585, Japan.
authors.forename: Zuquan
authors.initials: Z
authors.lastname: Weng
authors.forename: Megumi
authors.initials: M
authors.lastname: Suda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Nan
authors.initials: N
authors.lastname: Mei
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
authors.forename: Rui-Sheng
authors.initials: RS
authors.lastname: Wang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D049108:Cell Enlargement / Q000187:drug effects; D053960:DNA Breaks; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D005019:Ethyl Ethers / Q000145:classification / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009152:Mutagenicity Tests; D009153:Mutagens / Q000145:classification / Q000633:toxicity*; D012737:Sex Factors; D013045:Species Specificity
chemical_list: D005019:Ethyl Ethers; D009153:Mutagens; C098546:ethyl tert-butyl ether; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D045647:DNA Glycosylases