Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

Abstract

Background: Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function.Objectives: In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles.Methods: In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission.Discussion: ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress.Conclusions: These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins.

A Negative-Feedback Loop between the Detoxification/Antioxidant Response Factor SKN-1 and Its Repressor WDR-23 Matches Organism Needs with Environmental Conditions

“…To test if other xenobiotics are capable of activating wdr-23, we also tested the neurotoxin and suspected carcinogen acrylamide, an electrophile present in cooked food (41) that forms protein adducts (42), elevates reactive oxygen species and lipid peroxidation, depletes glutathione (43,44), and strongly activates SKN-1 target genes in C. elegans (45). As shown in Fig.…”

Acrylamide alters neurotransmitter induced calcium responses in murine ESC-derived and primary neurons

“…It has been suggested that it forms covalent bonds with soft nucleophiles (e.g. SH of cysteine) in synaptic compartments (LoPachin and Gavin, 2012). This interaction is well documented for NO (LoPachin and Barber, 2006).…”

“…Tunnel workers, exposed to ACR, showed disturbed neuronal function, but no effects on structural integrity of the nervous system (Goffeng et al, 2008). Recently, the affinity of ACR to cysteine thiolate groups located in active sites of synaptic compartments has been discussed as molecular mechanism of ACR neurotoxicity (LoPachin and Gavin, 2012). These findings and mechanistic considerations of Goffeng, Crofton and colleagues led us to the hypothesis that an acute exposure to low concentrations of ACR rather impairs neuronal function than neuronal structure.…”

Evaluation of the Neuroprotective Effect of Silymarin on Acrylamide-Induced Neurotoxicity

“…Recent evidence suggests that ACR forms adducts within presynaptic proteins, resulting in altered neurotransmission and inactivation of enzymes involved in neuronal energy production (36,37). ACR conjugates with reduced glutathione (GSH) as the main antioxidant for detoxification.…”