Aflatoxin B[subscript 1]-DNA adduct formation and mutagenicity in livers of neonatal female B6C3F1 mice

Abstract

Exposure to genotoxic chemicals at a young age increases cancer incidence later in life. Aflatoxin B[subscript 1] (AFB[subscript 1]) is a potent genotoxin that induces hepatocellular carcinoma (HCC) in many animal species and in humans. Whereas adult mice are insensitive to aflatoxin-induced carcinogenesis, mice treated with AFB[subscript 1] shortly after birth develop a high incidence of HCC in 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 AFB[subscript 1] produced similar levels of DNA damage and mutations in the liver of newborn male and female gpt delta B6C3F1 mice. Twenty-four hours after dosing with AFB[subscript 1] (6 mg/kg), the highly mutagenic AFB1-FAPY adduct was present at twice the level of AFB[subscript 1]-N[superscript 7]-guanine in liver DNA of males and females. A multiple dose regimen (3 × 2 mg/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 AFB[subscript 1]-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 show that infant male and female B6C3F1 mice experience similar amounts of DNA damage and mutation from AFB[subscript 1] 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.