Aflatoxin B1-DNA adduct formation and mutagenicity in livers of neonatal male and female B6C3F1 mice

Abstract

Exposure to genotoxic chemicals at a young age increases cancer incidence later in life. Aflatoxin B1 (AFB1) is a potent genotoxin that induces hepatocellular carcinoma (HCC) inmany animal species and in humans. Whereas adult mice are insensitive to aflatoxin-induced carcinogenesis, mice treated with AFB1 shortly after birth develop a high incidence of HCCin adulthood. Furthermore, the incidence of HCC in adult male mice treated as infants is much greater than in females, reasons for which are unclear. In this study, treatment with AFB1 produced similar levels of DNA damage and mutations in the liver of newborn male and female gpt delta B6C3F1 mice. Twentyfour hours after dosing with AFB1 (6 mg/kg), the highly mutagenic AFB1-FAPY adduct was present at twice the level of AFB1-N7-guanine in liverDNA ofmales and females. A multiple dose regimen (3 × 2mg/kg), while delivering the same total dose, resulted in lower AFB1 adduct levels. Mutation frequencies in the gpt transgene in liver were increased by 20- to 30-fold. The most prominent mutations in AFB1-treated mice were G:C to T:A transversions and G:C to A:T transitions. At this 21-day time point, no significant differences were found in mutation frequency or types of mutations between males and females. These results showthat infantmale and female B6C3F1 mice experience similar amounts ofDNAdamage andmutation from AFB1 that may initiate the neoplastic process. The gender difference in the subsequent development of HCC highlights the importance of elucidating additional factors that modulate HCC development. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.