Differential mutagenicity of aflatoxin B1 in the liver of neonatal and adult mice.
Children are generally more sensitive to toxicants than adults, including an increased sensitivity to genotoxic carcinogens. We previously demonstrated that neonatal mice are also more sensitive to the mutagenic effects of the direct alkylating agents N-ethyl-N-nitrosoamine and the arylamine 4-aminobiphenyl than adult mice. In this study, we have evaluated the effect of age on the mutagenicity of the fungal toxin and liver carcinogen aflatoxin B(1) (AFB(1)). Neonatal Big Blue transgenic mice were treated with 6 mg/kg AFB(1), a treatment that produces liver tumors, while adult mice were treated with 6 and 60 mg/kg AFB(1), treatments that do not result in tumors. The cII liver mutant frequency (MF) in mice treated with AFB(1) as neonates was 22-fold higher than in control neonatal mice, whereas the treatment of adult mice with either dose of AFB(1) did not significantly increase the liver MF over the controls. In AFB(1)-treated neonatal mice, the frequency of G:C --> T:A transversion, a major type of mutation induced by AFB(1), was about 82-fold higher than for the control and 31-fold higher than for adult mice treated with 60 mg/kg AFB(1). Our mutagenicity findings parallel the relative carcinogenicity of AFB(1) in neonatal and adult mice, and are consistent with previous observations of the lower level of hepatic glutathione S-transferase and higher level of hepatic AFB(1)-DNA adduction in neonatal mice compared to adult mice.
Chen
Tao
T
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA. tao.chen@fda.hhs.gov
Heflich
Robert H
RH
Moore
Martha M
MM
Mei
Nan
N
D016604:Aflatoxin B1 / Q000008:administration & dosage / Q000633:toxicity*; D000375:Aging; D000818:Animals; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D016678:Genome / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests; D017354:Point Mutation; D011042:Poisons / Q000008:administration & dosage / Q000633:toxicity*; D014157:Transcription Factors / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics
D011042:Poisons; D014157:Transcription Factors; D014764:Viral Proteins; C039000:cII protein, bacteriophage lambda; D016604:Aflatoxin B1