Toxicity and mitigation of Versicolorin A, a new fungal mycotoxin – VersiTox
Toxicity and mitigation of Versicolorin A, a new fungal mycotoxin
Versicolorin (VerA) is the precursor in the biosynthesis of the toxin Aflatoxin B1 (AFB1). Both molecules are produced in food commodities colonized by fungal species from the Aspergillus genera and so usually co-contaminate food. Whereas AFB1 is a known dangerous toxin for which regulations exist, little is known on the toxicity of VerA. The results of this project are essential for the assessment of the danger associated with the presence of VerA in food.
Deciphering the toxicity of Versicolorin A
Mycotoxins are widespread secondary fungal metabolites, which can contaminate crops either in the field or during storage. They have multiple toxic effects and thus represent a serious threat for human and animal health. As their presence in food and feed is unavoidable, they are strictly regulated, especially in the European Union. Unfortunately, 25% of the world’s harvested crops are contaminated with mycotoxins each year. Aflatoxins (AFs) are a highly dangerous mycotoxins family, of which the most occurring and toxic member is AFB1. AFB1 is the strongest known natural liver carcinogen, but it also exert its effect in other organs, including the intestine. VerA is a precursor in the biosynthesis of the AFB1. Both molecules have a double bond in the 12-13-position of the terminal furan ring, known to be essential for the toxic action of AFB1 (Figure 1). The similarity in the chemical structure suggest a similar mechanism of toxicity. Whereas the toxic activity of AFB1 has been widely documented, very little information on the toxicity of VerA is available. Despite some evidence of the toxicity of VerA reported decades ago, no further research had been performed until very recently. New data produced in our laboratory indicate that VerA shows a high in-vitro cytotoxic, genotoxic and clastogenic power. Our preliminary data have shown that VerA is more toxic than AFB1 in intestinal and liver cells. In order to characterize the hazard associated with the presence of VerA in food, a global picture of the toxic effect of VerA is needed, especially on two organs: (1) the small intestine: the organ representing the first barrier in contact with food contaminants:, and (2) the liver: the potential target organ of VerA due to similarity with AFB1.
The project proposes a systematic workflow that will study the effect of VerA from the cell to the tissue, at the physiological, structural and molecular level; this will provide a complete overview of the toxicity of VerA. The effect of Versicolorin A in several cell functions will be evaluated using in vitro intestinal and liver cell models, based in the known toxic effect of Aflatoxin B1. Then, in order to discover toxic effects of mechanisms of toxicity not foreseen by literature, -omics techniques (transcriptomics, proteomics, metabolomics) will be applied in intestinal and livel models. Results will be combined in order to understand the toxic effect. The combined effect of VerA and AFB1 will be evaluated using the newly discovered toxicity endpoints. Finally, a remediation strategy based in the use of probiotics will be investigated.
The expected deliverables of VersiTox are: - Determination of the minimal concentrations of VerA having a significant cytotoxic and genotoxic effect relative to that of AFB1 in the intestine and in the liver, as well as affecting the intestinal barrier funcion. - Description of the global effect of VerA in the intestine and liver, based on changes at the morphological, transcriptional, proteomic and metabolic level. - Evaluation of the danger associated with the co-exposure to AFB1 and VerA. - Development of a mitigation strategy to counteract the VerA intestinal toxicity using probiotics. As a side effect, our project will also provide with a battery of molecular/systems biology tools to investigate the effect of xenobiotics using porcine tissues.
VersiTox is an ambitious project whose first objective is to define for the first time the hazard associated with the presence of VerA in food and feed. The project proposes a systematic workflow that will study the effect of VerA from the cell to the tissue, at the physiological, structural and molecular level; this will provide a complete overview of the toxicity of VerA. Our technical approach is quite original in toxicology. Indeed, the use of -omics has been recently reported as the most adequate approach to study the effect of toxicants with pleiotropic actions such as mycotoxins. We propose to provide with a broad overview of the toxic effect of VerA in the intestine and the liver by combining hypothesis-driven and hypothesis- producing analysis. Likewise, the assessment of the danger associated with the combined presence of AFB1 and VerA will be established for the first time. The results of VersiTox will be essential to help move further steps in understanding the VerA toxicology in order to provide a sufficiently informed scenario for risk assessment. The latter are the basis for the adoption of regulations to limit the overall mycotoxin dietary exposure. Last, but not least, the attenuation of the toxic effects or VerA (as defined throughout the project) based in the use of probiotics will be tested. In consequence, we expect to provide with a novel solution to the danger linked with the presence of VerA in food.
i) Some of the analysis of VersiTox might lead to the discovery and characterization of biomarkers/molecular signatures of VerA/AFB1 effect. These could be susceptible of intellectual protection. The managing plan of the project will include punctual contacts with the INRA Transfert office in order to identify critical data that would need to be protected. The project coordinator acts as a correspondent for the Carnot Institute, and so is very well-place for the dissemination of the objectives and outcome of VersiTox to technical actors /potential commercial stakeholders.
ii) Special attention will be paid to outreach activities. These will be specially developed to reinforce the visibility of science and the role of ANR in society. Together with the PhD student to be hired, an outreach plan based in the assistance to general dissemination activities, development of devoted profiles in social networks and eventual press releases describing the achievement of VersiTox milestones will be sought.
iii) The diffusion of the data of VersiTox to regulatory stakeholders in food safety at the national and the European levels will be sought.
Versicolorin (VerA) is the precursor in the biosynthesis of the toxin Aflatoxin B1 (AFB1). Both molecules are produced in food commodities by fungal species from the Aspergillus genera and so usually co-contaminate food. Whereas AFB1 is a known dangerous toxin for which regulations exist, little is known on the toxicity of VerA, although its genotoxicity and cytotoxicity has been reported. VersiTox objectives are (1) to characterize the toxic effects of VerA on the small intestine and the liver, (2) to study the combined effect of VerA and AFB1 to determine if the exposure to both toxins result in a synergistic effect, and (3) to demonstrate that the co-incubation of VerA with a lactic acid bacteria such as Lactobacillus can decrease the intestinal toxicity of VerA.
Project coordination
Laura Soler Vasco (Toxicologie Alimentaire)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
INRA TOXALIM BTM Toxicologie Alimentaire
Help of the ANR 342,580 euros
Beginning and duration of the scientific project:
March 2019
- 48 Months
