Role of epigenetic alterations in aflatoxin-induced hepatocellular carcinoma

Abstract

Aflatoxins are produced by Aspergillus flavus and Aspergillus parasiticus and are toxic carcinogens. These ‘fungal molds’ grow on corn, groundnuts, cereals and other grains. Of all the aflatoxins, Aflatoxin-B1 (AFB1) is considered the most toxic. Long-term exposure of AFB1 forms DNA adducts causing many genetic mutations and epigenetic alterations, ultimately leading to hepatocellular carcinoma (HCC). The liver is the major site of Aflatoxin detoxification; wherein cytochrome P-450 (CYP450) enzymes process the AFB1 into its epoxide AFB1-Exo-8,9-Epoxy (ABFO) and other less toxic metabolites. ABFO, in turn, reacts with DNA, RNA and protein molecules forming AFB adducts. The AFB1-DNA adducts in turn will induce various mutations, mainly mediated by G→T transversions. Aflatoxins are also known to cause HCC cell proliferation, growth, and invasion as well as angiogenesis by various epigenetic mechanisms including DNA methylation, histone post-translational modifications and non-coding RNA deregulation, etc. In this review, we will be emphasizing on epigenetic mechanisms by which aflatoxins induce hepatocarcinogenesis. In the last section, we will also discuss various methodologies to control aflatoxin contamination and detoxification of aflatoxin adducts using natural substances that are potentially anti-aflatoxins.