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

Abstract

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.

A Zebrafish Model of Neurotoxicity by Binge-Like Methamphetamine Exposure

“…On the other hand, a number of studies support that the adult zebrafish brain exhibits an antioxidant defense system with high capacity. For instance, no lipid peroxidation was recently found in a zebrafish model for acute acrylamide neurotoxicity, despite the brain exhibited a total depletion of glutathione levels and a severely impaired thioredoxin system ( Raldúa et al, 2020 ). No lipid peroxidation was either found in the brain of zebrafish treated with paraquat at concentrations inducing 30–40% lethality, although the exposure to this herbicide resulted in a decrease in the superoxide dismutase (SOD) activity, catalase activity and GSH content ( Anand et al, 2021 ).…”

Approaches to Test the Neurotoxicity of Environmental Contaminants in the Zebrafish Model: From Behavior to Molecular Mechanisms

“…In a more recent study, a multi‐omics approach involving metabolome, transcriptome, and protein‐acrylamide adduct analyses made it possible to propose the complete AOP of acrylamide toxicity. The observed cellular events described previously are caused by an initial disruption of the main system responsible for controlling redox homeostasis and the glutathione and thioredoxin system through the formation of adducts of acrylamide with thiol groups of metabolites and proteins (Raldúa et al 2020). Another study has shown that exposure to carbon nanotubes resulted in increased levels of dopamine and serotonin neurotransmitters in the zebrafish brain (Da Rocha et al 2019), despite no specific link to phenotypic and physiological consequences.…”

Toxicity of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NKK) in early development: a wide-scope metabolomics assay in zebrafish embryos

“…The extraction method was adapted from Raldúa D. et al (Raldúa et al, 2020). In brief, zebrafish larvae were homogenized in 500 µL of pre-chilled CHCl3:MeOH (2:1, v/v) and 20 µL of IS solution, with two 5 mm stainless beads using a TissueLyser (Qiagen, CA, USA) at 50 Hz for 4 min.…”