Abstract
The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/-::gpt and nrf2-/-::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2-/-) mice than nrf2 heterozygous (nrf2+/-) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2-/- and nrf2+/- mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/- and nrf2-/- mice, respectively, compared with BaP-untreated nrf2+/- mice, showing that nrf2-/- mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/- mice was substantially different from that in BaP-untreated nrf2-/- mice. In nrf2-/- mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations.
Highlights
Nrf2 is an essential transcription factor for inducible and constitutive expression of several phase II detoxification enzymes, including glutathione S-transferase-a (GST-a) and GST-k and UDPglucuronosyl transferase 1A6 [1]
In Nrf2-deficient mice, which have attenuated basal and inducible expression of these enzymes [7]: (a) DNA adduct formation is accelerated after diesel exhaust exposure [8]; (b) hepatotoxicity is enhanced after acetaminophen administration [9]; and (c) benzo(a)pyrene (BaP)–induced DNA adduct and neoplasm formation in forestomach is more prevalent than in wild-type mice [10, 11]
The frequency of spontaneous mutations in the lung, liver, and testis was compared among gpt delta mice, heterozygous mice, and homozygous mice
Summary
Nrf is an essential transcription factor for inducible and constitutive expression of several phase II detoxification enzymes, including glutathione S-transferase-a (GST-a) and GST-k and UDPglucuronosyl transferase 1A6 [1]. Nrf2-mediated induction of cytoprotective enzymes plays an important role in mitigating the adverse effects of mutagens and oxidants. In Nrf2-deficient mice, which have attenuated basal and inducible expression of these enzymes [7]: (a) DNA adduct formation is accelerated after diesel exhaust exposure [8]; (b) hepatotoxicity is enhanced after acetaminophen administration [9]; and (c) benzo(a)pyrene (BaP)–induced DNA adduct and neoplasm formation in forestomach is more prevalent than in wild-type mice [10, 11]. Nrf attenuation or malfunction may be an important aspect of diseases caused by environmental mutagens or oxidants, the mechanism linking Nrf deficiency and mutation frequency is not well understood
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