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.
Highlights
Factors including rapid cell division and unique developmental changes during the prenatal period create a remarkable window of susceptibility to the numerous toxic effects of environmental agents
Mutagenic aflatoxin B1 (AFB1)-DNA adducts form in both fetal and maternal liver DNA adducts formed by AFB1 are potent inducers of G:C to T:A mutations,[14, 31] which is among the most frequent mutations found in human hepatocellular carcinoma (HCC).[14]
To determine whether the developing fetus is at risk of genetic damage from maternal exposures to AFB1, pregnant gpt delta C57BL/6J mice at gestation day 14 were treated with the toxin and the levels of AFB1DNA adducts in both maternal and B6C3F1 fetal livers were quantified six hr after administration of AFB1 via i.p. injection, providing a snapshot of adduct density at a time when it is reasonable to assume that carcinogenesis is initiated
Summary
Factors including rapid cell division and unique developmental changes during the prenatal period create a remarkable window of susceptibility to the numerous toxic effects of environmental agents. Maternal exposures to environmental factors during pregnancy influence the risk of many chronic adult-onset diseases in the offspring, including cancer.[1,2,3] Early life including in utero exposures can result in growth impairment, behavioral defects and teratogenesis.[4,5]. It is a potent genotoxin that induces hepatocellular carcinoma (HCC) in most animal species, including humans.[6] In sub-Saharan Africa and many parts of Asia where 80% of HCC cases occur, there is growing evidence that AFB1 exposure disproportionately affects childhood health in these regions.[7]
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