Genomic comparisons between hepatocarcinogenic and non-hepatocarcinogenic organophosphate insecticides in the mouse liver

Toxicology. 2022 Jan 15:465:153046. doi: 10.1016/j.tox.2021.153046. Epub 2021 Nov 20.


Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.

Keywords: Adverse outcome pathway (AOP); Fenthion; Liver carcinogenesis; Methidathion; Nuclear receptor; Parathion; Transcriptomics.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / agonists
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Constitutive Androstane Receptor / agonists
  • Constitutive Androstane Receptor / genetics
  • Constitutive Androstane Receptor / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Fenthion / toxicity
  • Gene Expression Profiling
  • Genomics*
  • Insecticides / toxicity*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Organophosphorus Compounds / toxicity*
  • Organothiophosphorus Compounds / toxicity
  • PPAR alpha / agonists
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Parathion / toxicity
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Transcriptome / drug effects*


  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Constitutive Androstane Receptor
  • Insecticides
  • Nr1i3 protein, mouse
  • Organophosphorus Compounds
  • Organothiophosphorus Compounds
  • PPAR alpha
  • Ppara protein, mouse
  • Receptors, Aryl Hydrocarbon
  • STAT5 Transcription Factor
  • Stat5b protein, mouse
  • Parathion
  • Cytochrome P-450 Enzyme System
  • Fenthion
  • methidathion