Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust

Yasunobu Aoki, Hiromi Sato, Noriko Nishimura, Satoru Takahashi, Ken Itoh, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

258 Citations (Scopus)

Abstract

Diesel exhaust (DE) has been recognized as a noxious mutagen and/or carcinogen, because its components can form DNA adducts. Mechanisms governing the susceptibility to DE and the efficiency of such DNA adduct formation require clarification. The transcription factor Nrf2 is essential for inducible and/or constitutive expression of a group of detoxification and antioxidant enzymes, and we hypothesized that the nrf2 gene knockout mouse might serve as an excellent model system for analyzing DE toxicity. To address this hypothesis, lungs from nrf2(-/-) and nrf2(+/-) mice were examined for the production of xenobiotic-DNA adducts after exposure to DE (3 mg/m3 suspended particulate matter) for 4 weeks. Whereas the relative adduct levels (RAL) were significantly increased in the lungs of both nrf2(+/-) and nrf2(-/-) mice upon exposure to DE, the increase of RAL in the lungs from nrf2(-/-) mice exposed to DE were approximately 2.3-fold higher than that of nrf2(+/-) mice exposed to DE. In contrast, cytochrome P4501A1 mRNA levels in the nrf2(-/-) mouse lungs were similar to those in the nrf2(+/-) mouse lungs even after exposure to DE, suggesting that suppressed activity of phase II drug-metabolizing enzymes is important in giving rise to the increased level of DNA adducts in the Nrf2-null mutant mouse subjected to DE. Importantly, severe hyperplasia and accumulation of the oxidative DNA adduct 8-hydroxydeoxyguanosine were observed in the bronchial epidermis of nrf2(-/-) mice following DE exposure. These results demonstrate the increased susceptibility of the nrf2 germ line mutant mouse to DE exposure and indicate the nrf2 gene knockout mouse may represent a valuable model for the assessment of respiratory DE toxicity.

Original languageEnglish
Pages (from-to)154-160
Number of pages7
JournalToxicology and Applied Pharmacology
Volume173
Issue number3
DOIs
Publication statusPublished - 2001 Jun 15
Externally publishedYes

Keywords

  • 8-hydroxydeoxyguanosine
  • Bronchial epithelial cells
  • DNA adduct
  • Diesel exhaust
  • Knockout mouse
  • Lung
  • Nrf2
  • Oxidative stress
  • Phase II enzyme
  • Polyaromatic hydrocarbon

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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