Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B1 and its dependence on p53 genotype

• Mice are chronically exposed to low doses of the mycotoxin aflatoxin B1 (AFB1).
• The effects of AFB1 and p53 status on nucleotide excision repair are investigated.
• AFB1 increases nucleotide excision repair in wild type mouse lung and liver.
• This increase is attenuated in p53 heterozygous mouse lung and liver.
• Results portray the role of p53 in nucleotide excision repair after AFB1 exposure.

Aflatoxin B1 (AFB1) is biotransformed in vivo into an epoxide metabolite that forms DNA adducts that may induce cancer if not repaired. p53 is a tumor suppressor gene implicated in the regulation of global nucleotide excision repair (NER). Male heterozygous p53 knockout (B6.129-Trp53tm1BrdN5, Taconic) and wild-type mice were exposed to 0, 0.2 or 1.0 ppm AFB1 for 26 weeks. NER activity was assessed with an in vitro assay, using AFB1-epoxide adducted plasmid DNA as a substrate. For wild-type mice, repair of AFB1–N7-Gua adducts was 124% and 96% greater in lung extracts from mice exposed to 0.2 ppm and 1.0 ppm AFB1 respectively, and 224% greater in liver extracts from mice exposed to 0.2 ppm AFB1 (p < 0.05). In heterozygous p53 knockout mice, repair of AFB1–N7-Gua was only 45% greater in lung extracts from mice exposed to 0.2 ppm AFB1 (p < 0.05), and no effect was observed in lung extracts from mice treated with 1.0 ppm AFB1 or in liver extracts from mice treated with either AFB1 concentration. p53 genotype did not affect basal levels of repair. AFB1 exposure did not alter repair of AFB1-derived formamidopyrimidine adducts in lung or liver extracts of either mouse genotype nor did it affect XPA or XPB protein levels. In summary, chronic exposure to AFB1 increased NER activity in wild-type mice, and this response was diminished in heterozygous p53 knockout mice, indicating that loss of one allele of p53 limits the ability of NER to be up-regulated in response to DNA damage.