title: Increased frequencies of micronucleated reticulocytes and T-cell receptor mutation in Aldh2 knockout mice exposed to acetaldehyde.
abstract: Aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde produced from ethanol into acetate and plays a major role in the oxidation of acetaldehyde in vivo. About half of all Japanese people have inactive ALDH2. We generated homozygous Aldh2 null (Aldh2-/-) mice by gene targeting knockout as a model of ALDH2-deficient humans. To investigate the mutagenicity of acetaldehyde, a micronucleus assay and a T-cell receptor (TCR) gene mutation assay were performed in Aldh2-/- mice and wild-type (Aldh2 +/+) mice exposed to acetaldehyde. The mice were continuously exposed to 125 and 500 ppm of acetaldehyde vapor for 2 weeks. Another group was orally administered 100 mg/kg once a day for 2 weeks continuously. The mice were killed after 2 weeks of exposure to acetaldehyde, and the frequency of micronucleated reticulocytes was measured by flow cytometry. We also observed the incidence of TCR gene mutations in T-lymphocytes by measuring the variant CD3(-CD4+) expression by flow cytometry. The frequency of micronucleated reticulocytes induced by acetaldehyde was significantly increased in Aldh2 -/- mice, but not in Aldh2 +/+ mice. TCR mutant frequency was also associated with acetaldehyde exposure in Aldh2-/ - mice, especially after oral administration; however, it was not associated with acetaldehyde exposure in Aldh2 +/+ mice. In conclusion, Aldh2 -/- mice showed high sensitivity in the micronuclei and TCR mutation assays compared with Aldh2 +/+ mice after exposure to acetaldehyde.
authors.affiliation: Department of Health Information Science, School of Health Sciences, University of Occupational and Environmental Health, Iseigaoka, Kitakyushu, Japan. kunugita@med.uoeh-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Kunugita
authors.forename: Toyohi
authors.initials: T
authors.lastname: Isse
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Oyama
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Ogawa
authors.forename: Tetsunosuke
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kinaga
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
mesh_terms: D000079:Acetaldehyde / Q000633:toxicity*; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012156:Reticulocytes / Q000187:drug effects* / Q000473:pathology; D013154:Spleen / Q000166:cytology
chemical_list: D011948:Receptors, Antigen, T-Cell; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde