Timing of gene expression alters susceptibility to aflatoxicosis: a heterogeneous spectrum of disease in response to a single universal agent

Abstract

Abstract Aflatoxins (AFs) and their metabolites are a group of universally abundant organic compounds produced by fungus species of Aspergillus , that are seriously genotoxic and carcinogenic. They were ranked to be the most carcinogenic substances on Earth. AFs-induced disease is not limited to carcinogenicity and genotoxicity, they cause a spectrum of different morbidities to humans and other species, and the clinical spectrum changes with age at exposure. Aspergillus form AFs on grains, cereals, and other crops. They poison through ingestion, inhalation, mucous, or cutaneous routes. In healthy individuals, AFs are detoxified into non-toxic excretable compounds via hepatic phase 1 (CYP1A2, CYP34A, CYP3A5, and CYP3A7) and phase 2 (glutathione S transferase) enzymes and glutathione S-transferase M1 (GSTM1). Normally, gene expression of some family members of CYP family is beyond the first month of life, hence individuals younger than 1 month rely mainly on GSTM1 for detoxification of AFs. Despite contaminating up to 60–80% of crops, not all 60–80% of the population fall sick. The extent of AF-inflicted disease is not only related to the amount of AF and the timing of exposure. The genomics of bioactivation and detoxification capacity of the individual is a major decisive factor for susceptibility to AF-induced disease. At exposure to a sublethal dose of AFs, only those with defective detoxification capacity – The Kotb detoxification defect disease (KDDD)- will fall sick. The collective genomics of detoxification enzymes dictates the clinical phenotype in response to AFs exposure. In the susceptible subject with KDDD, AFs cause direct DNA and tissue injury and initiate a cascade of massive inflammatory response. Aflatoxin (AF)-induced disease ranges from the perinatally acquired aflatoxicosis biliary atresia: the Kotb disease, to massive hepatic necrosis and hepatocellular carcinoma (HCC). They are responsible for 4.6–28.2% of HCC globally. In this short review, we aim to highlight the disease burden inflicted by aflatoxicosis. The review also discusses the factors that affect and modulate the disease intensity and its clinical spectrum.