Abstract
Aflatoxin B1 (AFB1) is a widespread contaminant of grains and other agricultural crops and is globally associated with both acute toxicity and carcinogenicity. In the present study, we utilized nuclear magnetic resonance (NMR), and specifically high-resolution magic angle spin (HRMAS) NMR, coupled to the zebrafish (Danio rerio) embryo toxicological model, to characterize metabolic profiles associated with exposure to AFB1. Exposure to AFB1 was associated with dose-dependent acute toxicity (i.e., lethality) and developmental deformities at micromolar (≤ 2 µM) concentrations. Toxicity of AFB1 was stage-dependent and specifically consistent, in this regard, with a role of the liver and phase I enzyme (i.e., cytochrome P450) bioactivation. Metabolic profiles of intact zebrafish embryos exposed to AFB1 were, furthermore, largely consistent with hepatotoxicity previously reported in mammalian systems including metabolites associated with cytotoxicity (i.e., loss of cellular membrane integrity), glutathione-based detoxification, and multiple pathways associated with the liver including amino acid, lipid, and carbohydrate (i.e., energy) metabolism. Taken together, these metabolic alterations enabled the proposal of an integrated model of the hepatotoxicity of AFB1 in the zebrafish embryo system. Interestingly, changes in amino acid neurotransmitters (i.e., Gly, Glu, and GABA), as a key modulator of neural development, supports a role in recently-reported neurobehavioral and neurodevelopmental effects of AFB1 in the zebrafish embryo model. The present study reinforces not only toxicological pathways of AFB1 (i.e., hepatotoxicity, neurotoxicity), but also multiple metabolites as potential biomarkers of exposure and toxicity. More generally, this underscores the capacity of NMR-based approaches, when coupled to animal models, as a powerful toxicometabolomics tool.
Highlights
Aflatoxins are potent mycotoxins produced by the fungal genus Aspergillus, which is endemic to soil organic matter, and among the most common fungal contaminants of food and feed crops including, in particular, grains, nuts/seeds, legumes, and various other staples
Numerous metabolites associated with carbohydrate metabolism, and cellular energetics, were significantly altered by Aflatoxin B1 (AFB1) treatment including: (1) decreases in glucose-1-phosphate (G1P) and glucose-6-phosphate (G6P), as well as glucose (Glc; p < 0.001) itself; (2) highly significant increases in lactate (Lac, p < 0.0001) as the product of lactate dehydrogenase and/or anaerobic glycolysis; and (3) increases in several metabolites associated with cellular energetics including ATP, NADH, and NAD+ (p < 0.05)
Solution-state nuclear magnetic resonance (NMR) techniques have been previously applied ex vivo [20,21,22,23] to metabolomics studies of AFB1 in mammalian systems; the present study represents the first to utilize high-resolution magic angle spin (HRMAS) NMR of an intact organismal model to understand the toxicology of AFB1
Summary
Aflatoxins are potent mycotoxins produced by the fungal genus Aspergillus, which is endemic to soil organic matter, and among the most common fungal contaminants of food and feed crops including, in particular, grains (e.g., rice, corn, wheat), nuts/seeds, legumes, and various other staples (for a current review, see [1]). AFB1 has been linked to other sub-acute health effects including interference with micronutrient adsorption (and consequent malnutrition), growth impairment, and immunosuppression [1,5]. NMR techniques, which has showntotoenable enable both highly quantitative (HRMAS) NMR techniques, which hasbeen beenrecently recently shown both highly quantitative and and qualitative (i.e., metabolite identification) analyses of major metabolites in the developing zebrafish qualitative (i.e., metabolite identification) analyses of major metabolites in the developing zebrafish embryo [15,16,17,18,19] Application of this metabolomics approachtotothe thezebrafish zebrafishembryo embryo model model has, has, in been previously demonstrated with respect to other naturally-occurring toxicants andininthese theseprior been fact, previously demonstrated with respect to other naturally-occurring toxicants and prior studies shown to both facilitate both characterization of toxicological pathways and identification of studies shown to facilitate characterization of toxicological pathways and identification of possible possible biomarkers of toxin exposure [18,19].
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