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

Exposure to acrylamide may lead to different neurotoxic effects in humans and in experimental animals. To gain insights into this poorly understood type of neurotoxicological damage, we used a multi-omic approach to characterize the molecular changes occurring in the zebrafish brain exposed to acrylamide at metabolite, transcript and protein levels. We detected the formation of acrylamide adducts with thiol groups from both metabolites and protein residues, leading to a quasi-complete depletion of glutathione and to the inactivation of different components of the thioredoxin system. 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 consider that our mechanistical approach may help developing new treatments against the neurotoxic effects of acrylamide and of other neurotoxicants that may share its toxic mode of action.This work was supported by the NATO SfP project MD.SFPP 984777 (D.R., A.A.), the Advanced Grant ERC-2012-AdG-320737 (D.R., B.P., F. P.-C.), the Spanish Government (CTM2017-83242-R, RTI2018-096175-B-I00); D.R., B.P.) and the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (grant No. 1775/12 to A.A.). M.F. acknowledges financial support from the Beatriu de Pinós programme (grant No. 2016 BP 00233) provided by the Secretariat of Universities and Research department of the Department for Business and Knowledge, Catalan Government. The 500 MHz spectrometer was purchased in part through a Research Infrastructure MINECO-FEDER fund (Grant CSIC13-4E-2076).Peer reviewe