Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain

Acrylamide is a recognized carcinogen that has strong neurotoxic effectseffects in humans and in experimental animals, although the molecular mechanisms underlying these neurotoxic effects are not completely understood. We studied acrylamide neurotoxicity in adult zebrafish using an integrated approach that included biochemical, transcriptomic, proteomic and metabolomic data. Brain samples from exposed and control zebrafish were subjected to proton-NMR for metabolomic analysis, to MALDI-TOF mass spectrometry for proteome analysis, and to high-throughput RNA sequencing for transcriptomic analysis. We detected the formation of acrylamide adducts with thiol groups in the brain metabolome, and the accumulation of acrylamide conjugates and propionamide adducts in Cys residues of proteins. These combined effects resulted in a quasi-complete depletion of glutathione and to the inactivation of different components of the thioredoxin system. Multi-omic functional analyses identified microtubules, thioredoxin-related proteins, transmembrane transport, redox metabolism and catalytic activity, as the cellular functions significantly altered by acrylamide in the fish brain. We propose that the combined loss-of-function of both redox metabolism-related systems configure a perfect storm that explains many acrylamide neurotoxic effects, like the dysregulation of genes related to microtubules, presynaptic vesicle alteration, and behavioral alterations. We further propose an Adverse Outcome Pathway of acrylamide neurotoxicity, connecting the different toxic effects across different levels of organization, from molecular interactions to behavioral changes. Our mechanistical approach may help developing new treatments against the neurotoxic effects of acrylamideand of other neurotoxicants that may share its toxic mode of action.