Aldh2 Knockout Mice Research Articles

Susceptibility to inhalation toxicity of acetaldehyde in Aldh2 knockout mice

In this study, we evaluated the inhalation toxicity of acetaldehyde in Aldh2 KO (Aldh -/-) mice, using pathological method. Male C57BL/6 (Aldh2 +/+) mice and Aldh -/- mice were exposed to atmospheres containing acetaldehyde at levels of 0, 125, and 500 ppm for 24 h/day during 14 days. Although the average blood acetaldehyde concentration of Aldh -/- mice was higher than that of Aldh2 +/+ mice in the acetaldehyde exposure group, observable effects by the acetaldehyde exposure on the lung and liver were not different between wild type and ALDH2 null mice. In Aldh2 -/- mice, the levels of 1) erosion of respiratory epithelium and the subepithelial hemorrhage in nose, 2) hemorrhage in nasal cavity, 3) degeneration of respiratory epithelium in larynx, pharynx and trachea, and 4) degeneration of dorsal skin were higher compared with Aldh2 +/+ mice, indicating that Aldh2 -/- mice are more acetaldehyde-sensitive than Aldh2 +/+ mice. This is the first example for studying pathological effects of Aldh2 deficiency using Aldh -/- mice exposed to a low level of acetaldehyde.

A comparison of covalent binding of ethanol metabolites to DNA according to Aldh2 genotype

In order to clarify the effects of ALDH2 polymorphism on the carcinogenicity and organ damage caused by ethanol consumption, labeled ethanol was administered to wild-type (C57BL/6, Aldh2+/+) and Aldh2 knock-out ( Aldh2−/−) mice, and DNA adduct levels of organs were compared according to Aldh2 genotype. Aldh2−/− mice, which have the same genetic background as C57BL/6 mice except in the Aldh2 gene, were used as a model of lack of ALDH2 activity in humans. The DNA adduct levels in liver, stomach, and kidney and radioactivity in liver, stomach, kidney, and serum were measured by liquid scintillation counting 6, 12, and 24 h after administration. Though radioactivity levels in all organs decreased over time, there were no significant differences in radioactivity between Aldh2+/+ and Aldh2−/− mice. On the other hand, the DNA radioactivity in each organ tested differed significantly between Aldh2+/+ and Aldh2−/− mice 24 h after administration. These findings show that ethanol consumption affects DNA in Aldh2−/− mice much more strongly than in Aldh2+/+ mice. According to the IARC document, ethanol consumption is carcinogenic to humans (Group 1). Moreover, several studies have shown that ALDH2-deficient humans who habitually consume ethanol have higher rates of cancer than humans with ALDH2. Our results support these findings of epidemiological studies.

The role of mitochondrial aldehyde dehydrognase (ALDH-2) for bioactivation of organic nitrates: “Proof of concept” through investigations in ALDH-2 knockout mice

the role of mitochondrial aldehyde dehydrognase (ALDH-2) for bioactivation of organic nitrates: “Proof of concept” through investigations in ALDH-2 knockout mice

E312 Aldh2ノックアウトマウスにおけるアセトアルデヒド曝露による小核誘発(生物学的モニタリング・バイオマーカー,一般演題:口演,地方の時代の産業保健,第79回日本産業衛生学会)

E312 Aldh2ノックアウトマウスにおけるアセトアルデヒド曝露による小核誘発(生物学的モニタリング・バイオマーカー,一般演題:口演,地方の時代の産業保健,第79回日本産業衛生学会)

Urinary 8-Hydoxydeoxyguanosine (8-OHdG) and Plasma Malondialdehyde (MDA) Levels in Aldh2 Knock-Out Mice under Acetaldehyde Exposure

To clarify the carcinogenicity of acetaldehyde when associated with ALDH (aldehyde dehydrogenase) 2 polymorphism, Aldh2 knock-out (Aldh2-/-) mice and their wild type (Aldh2+/+) mice were exposed to two different concentrations of acetaldehyde (125 ppm and 500 ppm) for two weeks. Aldh2-/- mice, which have the same genetic background as C57BL/6J (wild mice) except for the Aldh2 gene, were used as models of humans who lack ALDH2 activity. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) levels were measured as indicators of oxidative DNA damage and lipid peroxidation, respectively. At 125 ppm acetaldehyde exposure for 12 d, urinary 8-OHdG levels in Aldh2+/+ mice did not increase. However, urinary 8-OHdG levels in Aldh2-/- mice were slightly increased by the end of the exposure. On the other hand, plasma MDA levels did not increase in either Aldh2-/- orAldh2+/+ mice. At 500 ppm, urinary 8-OHdG levels in both Aldh2-/- and Aldh2+/+ mice significantly increased after 6 and 12 d, but there was no genetic difference. On the other hand, plasma MDA levels in Aldh2+/+ and Aldh2-/- mice did not increase at either 125 ppm or 500 ppm after two weeks of exposure. In conclusion, it is suspected that DNA was damaged by acetaldehyde inhalation, and that susceptibility to acetaldehyde varies according to Aldh2 genotype.

Aldehyde dehydrogenase (ALDH) 2 associates with oxidation of methoxyacetaldehyde; in vitro analysis with liver subcellular fraction derived from human and Aldh2 gene targeting mouse

A principal pathway of 2-methoxyethanol (ME) metabolism is to the toxic oxidative product, methoxyacetaldehyde (MALD). To assess the role of aldehyde dehydrogenase (ALDH) in MALD metabolism, in vitro MALD oxidation was examined with liver subcellular fractions from Japanese subjects who carried three different ALDH2 genotypes and Aldh2 knockout mice, which were generated in this study. The activity was distributed in mitochondrial fractions of ALDH2*1/*1 and wild type ( Aldh2+/+) mice but not ALDH2*1/*2, *2/*2 subjects or Aldh2 homozygous mutant ( Aldh2−/−) mice. These data suggest that ALDH2 is a key enzyme for MALD oxidation and ME susceptibility may be influenced by the ALDH2 genotype.