Molecular mechanism of acrylamide neurotoxicity: Lessons learned from organic chemistry

Richard M. LoPachin, Terrence Gavin

Research output: Contribution to journalReview article

95 Scopus citations

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: Invivo proteomic and inchemico 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.

Original languageEnglish (US)
Pages (from-to)1650-1657
Number of pages8
JournalEnvironmental health perspectives
Volume120
Issue number12
DOIs
StatePublished - 2012

Keywords

  • HSAB theory
  • Oxidative stress
  • Protein adducts
  • Soft electrophile
  • Toxic axonopathy
  • Type-2 alkenes
  • α,β-unsaturated carbonyl derivatives

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Fingerprint Dive into the research topics of 'Molecular mechanism of acrylamide neurotoxicity: Lessons learned from organic chemistry'. Together they form a unique fingerprint.

  • Cite this