Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats

Repeated developmental exposure to the organophosphate (OP) insecticide chlorpyrifos (CPF) inhibits brain fatty acid amide hydrolase (FAAH) activity at low levels, whereas at higher levels, it inhibits brain monoacylglycerol Lipase (MAGL) activity. FAAH and MAGL hydrolyze the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively. Peripherally, AEA and 2-AG have physiological roles in the regulation of lipid metabolism and immune function, and altering the normal levels of these lipid mediators can negatively affect these processes. Exposure to CPF alters brain endocannabinoid hydrolysis activity, but it is unclear whether low-level exposure alters this activity in peripheral tissues important in metabolic and immune function. Therefore, rat pups were exposed orally from day 10 to 16 to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 (a specific FAAH Inhibitor). At 12 hours postexposure, FAAH, MAGL, and cholinesterase (ChE) activities were determined. All treatments inhibited FAAH activity in brain, spleen, and liver. CPF inhibited ChE activity in spleen and liver (all dosages) and in brain (highest dosage only). CPF inhibited total 2-AG hydrolysis and MAGL-specific activity in brain and spleen (high dosage only). In liver, total 2-AG hydrolysis was inhibited by all treatments and could be attributed to inhibition of non-MAGL-mediated 2-AG hydrolysis, indicating involvement of other Enzymes. MAGL-specific activity in liver was inhibited only by the high CPF dosage, whereas PF-04457845 slightly increased this activity. Overall, exposure to low levels of CPF and to PF-04457845 can alter endocannabinoid metabolism in peripheral tissues, thus potentially affecting physiological processes.