Aldehyde dehydrogenase 2 deficiency significantly exacerbates tert-butyl alcohol-induced toxicity in mice
| Autor: | Jisheng Nie, Yukie Yanagiba, Megumi Suda, Rui-Sheng Wang, Yuehan Zhang, Zuquan Weng, Chenlan Xu, Liping Lin, Tamie Nakajima |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Genotype tert-Butyl Alcohol Metabolite Aldehyde dehydrogenase 010501 environmental sciences Ethyl tert-butyl ether Toxicology 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Internal medicine Toxicity Tests medicine Animals 030304 developmental biology 0105 earth and related environmental sciences ALDH2 Mice Knockout 0303 health sciences Inhalation Exposure Ethanol biology Aldehyde Dehydrogenase Mitochondrial Acetaldehyde Genetic Variation Glutathione Endocrinology chemistry Toxicity Models Animal biology.protein Chemical and Drug Induced Liver Injury Deficiency Diseases |
| Zdroj: | Journal of applied toxicology : JATREFERENCES. 40(7) |
| ISSN: | 1099-1263 |
| Popis: | Owing to the use of ethyl tert-butyl ether (ETBE) as a fuel additive, the possible adverse effects of ETBE exposure have become a public concern. Our previous study showed that ETBE-induced toxicity in aldehyde dehydrogenase 2 (Aldh2) gene knockout (KO) mice was caused by its primary metabolite acetaldehyde, which was toxic. However, it is unclear whether tert-butyl alcohol (TBA), another main metabolite of ETBE, plays a role in ETBE-induced toxicity. To investigate this relationship, we analyzed the changes of TBA concentrations in tissues after ETBE exposure, and then evaluated the toxicity after direct TBA treatment in both KO and wild-type (WT) mice. An exposure to 500 ppm ETBE via inhalation resulted in the formation of its three metabolites, TBA, 2-methyl-1,2-propanediol and ethanol, whose concentrations in the liver, brain, fat and testis of male KO mice were significantly higher than the corresponding concentrations observed in male WT mice. Direct treatment to TBA (20 mg/mL of drinking water) caused significant changes in relative organ weights and histopathology, and increased levels of genetic damages in both types of mice. These toxic effects were also seen in KO mice exposed to a lower concentration of TBA (5 mg/mL), which was associated with increased oxidative stress in serum (reduced glutathione and reduced glutathione/oxidized glutathione ratio decreased). Our findings indicate that ALDH2 is involved in the metabolism of ETBE and TBA, and ALDH2 deficiency could greatly increase the sensitivity to TBA-induced toxicity. |
| Databáze: | OpenAIRE |
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