Mitochondria as a target of organophosphate and carbamate pesticides: Revisiting common mechanisms of action with new approach methodologies

Maxwell C.K. Leung, Joel N. Meyer

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Mitochondrial toxicity has been proposed as a potential cause of developmental defects in humans. We evaluated 51 organophosphate and carbamate pesticides using the U.S. EPA ToxCast and Tox21 databases. Only a small number of them bind directly to cholinesterases in the parent form. The hydrophobicity of organophosphate pesticides is correlated significantly to TSPO binding affinity, mitochondrial membrane potential reduction in HepG2 cells, and developmental toxicity in Caenorhabditis elegans and Danio rerio (p < 0.05). Structural analysis suggests that in some cases the Krebs cycle is a potential target of organophosphate and carbamate exposure at early life stages. The results support the hypothesis that mitochondrial effects of some organophosphate pesticides—particularly those that require enzymatic activation to the oxon form—may augment the documented effects of disruption of acetylcholine signaling. This study provides a proof of concept for applying new approach methodologies to interrogate mechanisms of action for cumulative risk assessment.

Original languageEnglish (US)
Pages (from-to)83-92
Number of pages10
JournalReproductive Toxicology
Volume89
DOIs
StatePublished - Oct 2019
Externally publishedYes

Keywords

  • Carbamate
  • Developmental toxicity
  • Mitochondria
  • Mixture toxicity
  • Organophosphate
  • Risk assessment
  • ToxCast

ASJC Scopus subject areas

  • Toxicology

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