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

Roongtiwa Wattanawaraporn, Leslie L. Woo, Crystal Belanger, Shiou Chi Chang, Jillian E. Adams, Laura J. Trudel, Jason T. Bouhenguel, Patricia A. Egner, John D. Groopman, Robert G. Croy, John M. Essigmann, Gerald N. Wogan

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)326-333
Number of pages8
JournalToxicological Sciences
Volume128
Issue number2
DOIs
StatePublished - Aug 2012

Keywords

  • Aflatoxin B1
  • Hepatocellular carcinoma;
  • Infant mouse.
  • Mutation

ASJC Scopus subject areas

  • Toxicology

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