The impact of chronic Aflatoxin B1 exposure and p53 genotype on base excision repair in mouse lung and liver.

Aflatoxin B1 (AFB1) is produced by species of Aspergillus, and is a known human carcinogen. AFB1-induced oxidative DNA damage, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG) lesions, has been demonstrated in both animal models and in humans, and is repaired by base excision repair (BER). The tumour suppressor gene p53 is implicated in the regulation of DNA repair, and heterozygous p53 knockouts have an attenuated nucleotide excision repair response to AFB1. Male heterozygous p53 knockout mice and their wild-type controls were exposed to 0, 0.2 or 1.0ppm AFB1 for 26 weeks in their diet. BER activity of lung and liver was assessed with an in vitro assay, using 8-OHdG-damaged plasmid DNA as a substrate. BER activity did not differ between livers or lungs from untreated wild-type versus heterozygous p53 knockout mice. In wild-type mice, repair was 65% lower in liver extracts from mice exposed to 1.0ppm AFB1 than in liver extracts from mice exposed to 0.2ppm AFB1 (p<0.05), but not significantly lower than that in liver extracts from control mice. AFB1 did not affect BER in lung extracts from wild-type mice, or in lung and liver extracts from heterozygous p53 knockout mice. In liver and lung, AFB1 exposure did not alter levels of 8-oxoguanine glycosylase protein, a key enzyme in the repair of 8-OHdG, and did not cause hepatotoxicity, as indicated by plasma alanine aminotransferase levels. In conclusion, chronic exposure to AFB1 did not affect BER in lungs or livers of heterozygous p53 knockout mice. BER activity was lower in livers from p53 wild type mice exposed to 1.0ppm AFB1 versus those exposed to 0.2ppm AFB1, an effect that was not attributable to liver cell death or altered levels of 8-oxoguanine glycosylase.