Versicolorin A enhances the genotoxicity of aflatoxin B1 in human liver cells by inducing the transactivation of the Ah-receptor

Clémence Budin,Hai-Yen Man,Carine Al-Ayoubi,Sylvie Puel,Barbara M.A Van Vugt-Lussenburg,Abraham Brouwer,Isabelle P Oswald,Bart Van Der Burg,Laura Soler

doi:10.1016/j.fct.2021.112258

Abstract

Aflatoxins are a group of mycotoxins that have major adverse effects on human health. Aflatoxin B1 (AFB1) is the most important aflatoxin and a potent carcinogen once converted into a DNA-reactive form by cytochrome P450 enzymes (CYP450). AFB1 biosynthesis involves the formation of Versicolorin A (VerA) which shares structural similarities with AFB1 and can be found in contaminated commodities, often co-occurring with AFB1. This study investigated and compared the toxicity of VerA and AFB1, alone or in combination, in HepG2 human liver cells. Our results show that both toxins have similar cytotoxic effects and are genotoxic although, unlike AFB1, the main genotoxic mechanism of VerA does not involve the formation of DNA double-strand breaks. Additionally, we show that VerA activates the aryl hydrocarbon receptor (AhR) and significantly induce the expression of the CYP450-1A1 (CYP1A1) while AFB1 did not induce AhR-dependent CYP1A1 activation. Combination of VerA with AFB1 resulted in enhanced genotoxic effects, suggesting that AhR-activation by VerA influences AFB1 genotoxicity by promoting its bioactivation by CYP450s to a highly DNA-reactive metabolite. Our results emphasize the need for expanding the toxicological knowledge regarding mycotoxin biosynthetic precursors to identify those who may pose, directly or indirectly, a threat to human health.

Highlights

Mycotoxins are toxic secondary metabolites produced by moulds that may contaminate food commodities
Results pre sented in Fig. 1 show that, for both Aflatoxin B1 (AFB1) and Versicolorin A (VerA), the percentage of viable cells at 48 h decreased at concentrations higher than 1 μM in a doseresponse manner
The cytotoxicity we report for VerA after 48h of incubation is in line with what have been reported by Gauthier et al (2020) in human intestinal HCT116 and Caco-2 cell lines using the same method

Summary

Introduction

Mycotoxins are toxic secondary metabolites produced by moulds that may contaminate food commodities. Aflatoxins are a group of mycotoxins synthesized mainly by moulds from Aspergillus flavus and A. parasiticus species which can contaminate crops such as maize, rice and nuts, typically in tropical and sub-tropical areas (Schrenk et al, 2020). The health issues related to the presence of AFB1 in food commodities are major and include carcinogenicity, impaired development, immunotoxicity, and even death in case of severe acute exposure (Meissonnier et al, 2008; Schrenk et al, 2020). In Europe for example, safe levels of AFB1 in food vary depending on the matrix and range from 0.1 μg/kg in processed cereal-based foods and baby foods to 8 μg/kg in groundnuts to be subjected to physical treatment, before human consumption or use as an ingredient in foodstuffs (Commission Regulation (EC) No 1881/2006)

Methods

Results

Conclusion