title: Prenatal exposure of mice to the human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change.
abstract: It has become axiomatic that critical windows of susceptibility to genotoxins exist and that genetic damage in utero may be a trigger for later life cancers. Data supporting this critical window hypothesis are remarkably few. This study provides a quantitative bridge between DNA damage by the liver carcinogen aflatoxin B1 (AFB1 ) during prenatal development and the risk of later life genetic disease. AFB1 was given to pregnant C57BL/6J mice, carrying F1 gestation day 14 (GD14) embryos of the B6C3F1 genotype. Ultra-high performance liquid chromatography and mass spectrometry (UPLC-MS) using aflatoxin-(15) N5 -guanine adduct standards afforded measurement of the AFB1 -N(7) -Gua and AFB1 -FAPY adducts 6-hr post dosing in liver DNA of mothers and embryos. A parallel cohort gave birth and the livers of the F1 were analyzed for mutations in the gpt gene at 3 and 10 weeks of age. The data revealed mutational spectra dominated by G:C to T:A mutations in both the mother and offspring that are characteristic of AFB1 and distinct from background. It was shown that adducts in GD14 embryos were 20-fold more potent inducers of mutagenesis than adducts in parallel-dosed adults. This sensitivity enhancement correlated with Ki67 staining of the liver, reflecting the proliferative potential of the tissue. Taken together, these data provide insight into the relative genetic risks of prenatal and adult exposures to AFB1 . Early life exposure, especially during the embryonic period, is strikingly more mutagenic than treatment later in life. Moreover the data provide a baseline against which risk prevention strategies can be evaluated.
authors: Departments of Biological Engineering and Chemistry, and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Graduate Program in Environmental Toxicology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
authors: Supawadee
authors: S
authors: Chawanthayatham
authors: Apinya
authors: A
authors: Thiantanawat
authors: Patricia A
authors: PA
authors: Egner
authors: John D
authors: JD
authors: Groopman
authors: Gerald N
authors: GN
authors: Wogan
authors: Robert G
authors: RG
authors: Croy
authors: John M
authors: JM
authors: Essigmann
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D016604:Aflatoxin B1
keywords: Aflatoxin B1; DNA adducts; mutagenesis; prenatal exposure