A single neonatal exposure to aflatoxin B₁ induces prolonged genetic damage in two loci of mouse liver

Aflatoxin B₁ (AFB₁) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB₁-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks, the spectrum at a second locus, the red/gam genes of the mouse λEG10 transgene. Whereas the gpt locus is typically used to define local base changes, the red/gam genes, via the Spi^- assay, often are used to detect more global mutations such as large deletions and rearrangements. Three weeks after dosing with AFB₁, there was a 10-fold increase over the control in the Spi^- mutant fraction (MF) in liver DNA; after 10 weeks, a further increase was observed. The MF in the gpt gene was also increased at 10 weeks compared with the MF at 3 weeks. No gender-specific differences were found in the Spi^- or gpt MFs. Whereas Spi^- mutations often signal large genetic changes, they did not in this specific case. The Spi^- spectrum was dominated by GC to TA transversions, with one exceptionally strong hotspot at position 314. Using two genetic loci, the data show a strong preference for the induction of GC to TA mutations in mice, which is the dominant mutation seen in people exposed to aflatoxin.