Early life aflatoxin B1 exposure and epigenetic programming in Nigerian Newborns

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Project Summary Aflatoxin B1 (AFB1) is a major cause of hepatocellular carcinoma (HCC) in Sub Saharan Africa, where aflatoxin contamination is common. In these areas, exposure to AFB1 starts early in life through maternal routes during pregnancy. Populations in these countries experience early onset of HCC, and in utero AFB1 exposure may be a contributing factor to the onset of the disease. Exposures to nutrients, toxic chemicals and biological agents during gestation and early childhood play a critical role in determining susceptibility to diseases later in life. The mechanism of early onset of carcinogenesis may include epigenetic changes in tumor suppressor genes (TSGs). Our previous rodent study showed that in utero AFB1 exposure can alter DNA methylation of TSGs. It is necessary to investigate the impact of in utero AFB1 exposure on methylation and expression of TSGs in humans. The overall hypothesis is that in utero AFB1 exposure will differentially methylate TSGs, and this methylation will inversely correlate with the expression of the TSGs. The overall objective of this project is to establish a pre-birth cohort and study the association between in utero exposure to AFB1 and DNA methylation changes in TSGs of newborns in Nigeria. To achieve this, we will recruit pregnant women in the first trimester from two Nigerian hospitals serving a rural and an urban area. We hypothesize that Nigerian women will have a range of AFB1 exposure levels detectable in plasma. We hypothesize that in utero AFB1 exposure will be associated with differential methylation and expression of TSGs in cord blood samples. The specific aims of this project are to 1) determine the levels of AFB1 in the plasma of pregnant women, using HPLC, collected during the first and third trimesters of pregnancy, and newborns (cord blood), 2) assess the DNA methylation of TSGs in the cord blood via pyrosequencing and to determine if AFB1 concentration is associated with the levels of DNA methylation, 3) determine the expression of TSGs in the cord blood using real-time quantitative PCR and determine if gene expression is inversely correlated with methylation changes in the TSGs. The findings of this study will provide data on AFB1 exposure among pregnant women in Nigeria and its subsequent effect on the epigenome of newborns. This data will provide direction for future research developing epigenetic biomarkers of AFB1 exposure as well as investigating epigenetic mechanisms associated with prenatal exposure to AFB1 and the risk of developing liver cancer in Africa. This research direction may provide insight into reducing the incidence of this cancer in sub-Saharan Africa, especially in countries such as Nigeria, where AFB1 exposure is highly prevalent. Through this research, the PI will become a leader in environmental epigenetics, studying how early-life exposure to environmental contaminants of Public Health concerns in Africa contributes to the development of non- communicable diseases later in life.