Induction of endocannabinoid levels in juvenile rat brain following developmental chlorpyrifos exposure

Toxicol Sci. 2013 Sep;135(1):193-201. doi: 10.1093/toxsci/kft126. Epub 2013 Jun 12.


The endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) play vital roles during nervous system development. The degradation of 2-AG and AEA is mediated by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. These enzymes are inhibited following developmental chlorpyrifos (CPF) exposure. To investigate whether this inhibition is persistent or whether accumulation of endocannabinoids in the brain occurs, 10-day-old rat pups were orally exposed daily for 7 days to either corn oil or increasing dosages of CPF (1, 2.5, or 5mg/kg), and forebrains were collected at 4, 12, 24, and 48h following the last administration. All dosages inhibited cholinesterase (ChE), FAAH, and MAGL, and elevated AEA and 2-AG levels with the greatest effect occurring at 12h with ChE, FAAH, AEA, and 2-AG and at 4h with MAGL. With the high dosage, return to control levels occurred with 2-AG (48h) only. With the medium dosage, return to control levels occurred with MAGL, 2-AG, and AEA (48h) but not with ChE or FAAH. With the low dosage, return to control levels occurred with MAGL (12h), ChE and 2-AG (24h), and AEA (48h) but not with FAAH. With the lowest dosage, peak inhibition of FAAH (52%) is greater than that of ChE (24%) and that level of FAAH inhibition is sufficient to induce a persistent pattern of elevated AEA. It is possible that this pattern of elevation could alter the appropriate development of neuronal brain circuits.

Keywords: chlorpyrifos; developmental; neurotoxicity; organophosphate.; pesticides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Amidohydrolases / antagonists & inhibitors
  • Amidohydrolases / metabolism
  • Animals
  • Arachidonic Acids / analysis*
  • Brain / drug effects*
  • Brain / metabolism
  • Chlorpyrifos / toxicity*
  • Cholinesterase Inhibitors / toxicity*
  • Endocannabinoids / analysis*
  • Female
  • Glycerides / analysis*
  • Insecticides / toxicity*
  • Male
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / metabolism
  • Polyunsaturated Alkamides / analysis*
  • Rats
  • Rats, Sprague-Dawley


  • Arachidonic Acids
  • Cholinesterase Inhibitors
  • Endocannabinoids
  • Glycerides
  • Insecticides
  • Polyunsaturated Alkamides
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Chlorpyrifos
  • anandamide