Global DNA methylation in a population with aflatoxin B1 exposure

Hui-Chen Wu,Qiao Wang,Hwai-I Yang,Wei-Yann Tsai,Chien-Jen Chen,Regina M Santella

doi:10.4161/epi.25696

Abstract

We previously reported that global DNA hypomethylation, measured as Sat2 methylation in white blood cells (WBC), and aflatoxin B1 (AFB1) exposure were associated with increased hepatocellular carcinoma risk. In this study, we assessed the association between AFB1 exposure and global DNA methylation. We measured LINE-1 and Sat2 methylation in WBC DNA samples from 1140 cancer free participants of the Cancer Screening Program (CSP) cohort. Blood and urine samples were used to determine the level of AFB1-albumin (AFB1-Alb) adducts and urinary AFB1 metabolites. In continuous models, we found reverse associations of urinary AFB1 with LINE-1 and Sat2 methylation. The odds ratio (OR) per 1 unit decrease were 1.12 (95%CI = 1.03–1.22) for LINE-1 and 1.48 (95%CI = 1.10–2.00) for Sat2 methylation. When compared with subjects in the highest quartile of LINE-1, we found that individuals in the 2nd and 3rd quartiles were less likely to have detectable AFB1-Alb adducts, with ORs (95%CI) of 0.61 (0.40–0.93), 0.61 (0.40-.94), and 1.09 (0.69–1.72), respectively. The OR for detectable AFB1-Alb was 1.81 (95%CI = 1.15–2.85) for subjects in the lowest quartile of Sat2 methylation. The OR for detection of urinary AFB1 for those with LINE-1 methylation in the lowest quartile compared with those in the highest quartile was 1.87 (95%CI = 1.15–3.04). The corresponding OR was 1.75 (95%CI = 1.08–2.82) for subjects in the lowest quartile of Sat2 methylation. The association between AFB1 exposure and global DNA methylation may have implications for the epigenetic effect of AFB1 on hepatocellular carcinoma development and also suggests that changes in DNA methylation may represent an epigenetic biomarker of dietary AFB1 exposure.

Highlights

Aflatoxins are naturally occurring mycotoxins produced by only a few Aspergillus species of which A. flavus and A. parasiticus are the most important; they live in hot and humid conditions
We previously reported that global DNA hypomethylation in white blood cells (WBC) DNA was significantly associated with increased hepatocellular carcinoma (HCC) risk later in life.[29]
We found that decreased LINE-1 or Sat[2] methylation was associated with dietary exposed to Aflatoxin B1 (AFB1)

Summary

Introduction

Aflatoxins are naturally occurring mycotoxins produced by only a few Aspergillus species of which A. flavus and A. parasiticus are the most important; they live in hot and humid conditions. Aflatoxin B1 (AFB1), the most potent hepatocarcinogen, can induce principally G→T mutations, including a p53 codon 249 hotspot mutation.[1,2,3] Once ingested, AFB1 is metabolized by the cytochrome P-450 system at the 8,9-vinyl bond to produce an unstable reactive intermediate, AFB1-8,9-epoxide.[4] This intermediate can bind covalently to DNA,[5] forming AFB1guanine adducts, and to protein, forming AFB1-albumin and other protein adducts.[6,7] Much epidemiological evidence suggests that dietary exposure to AFB1 is an important contributor to the high incidence of hepatocellular carcinoma (HCC) in Eastern and South-Eastern Asia, including Taiwan This intermediate can bind covalently to DNA,[5] forming AFB1guanine adducts, and to protein, forming AFB1-albumin and other protein adducts.[6,7] Much epidemiological evidence suggests that dietary exposure to AFB1 is an important contributor to the high incidence of hepatocellular carcinoma (HCC) in Eastern and South-Eastern Asia, including Taiwan (reviewed in ref. 8)

Methods

Results

Conclusion