New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways

Arch Toxicol. 2018 May;92(5):1717-1728. doi: 10.1007/s00204-018-2174-3. Epub 2018 Feb 5.


Recently, we have provided evidence, suggesting that mice expressing the human apolipoprotein E3 (apoE3) are more prone to develop an obesity-like phenotype and a diabetic profile when subchronically fed a chlorpyrifos (CPF)-supplemented diet. The aim of the current study was to examine the underlying mechanisms through which CPF alters both insulin- and leptin-signalling pathways in an APOE-dependent manner. Both adult apoE3- and E4-targeted replacement and C57BL/6 mice were exposed to CPF at 0 or 2 mg/kg body weight/day through the diet for 8 consecutive weeks. We determined the expression of JAK2, p-JAK2, STAT3, p-STAT3, SOCS3, IRS-1, p-IRS-1, AKT, p-AKT, GSK3β, p-GSK3β, and apoE in the liver, as well as hepatic mRNA levels of pon1, pon2, and pon3. CPF markedly disrupted both leptin and insulin homeostasis, particularly in apoE3 mice. Indeed, only CPF-fed apoE3 mice exhibited an increased phosphorylation ratio of STAT3, as well as increased total SOCS3 protein levels. Similarly, the exposure to CPF drastically reduced the phosphorylation ratio of both AKT and GSK3β, especially in apoE3 mice. Overall, CPF reduced the expression of the three pon genes, principally in C57BL/6 and apoE3 mice. These results provide notable mechanistic insights on the metabolic effects of the pesticide CPF, and attest the increased vulnerability of apoE3 carriers to its metabolic-disruptor role.

Keywords: Apolipoprotein E; Chlorpyrifos; Diabetes; Insulin; Leptin; Paraoxonase; Pesticide.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics*
  • Apolipoproteins E / metabolism
  • Aryldialkylphosphatase / genetics
  • Chlorpyrifos / toxicity*
  • Cholinesterases / metabolism
  • Dietary Exposure
  • Insecticides / toxicity
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins / metabolism
  • Janus Kinase 2 / metabolism
  • Leptin / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Signal Transduction / drug effects


  • ApoE protein, human
  • Apolipoproteins E
  • Insecticides
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Leptin
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Cholinesterases
  • Aryldialkylphosphatase
  • PON1 protein, mouse
  • Chlorpyrifos