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

Abstract

Repeated developmental exposure to the organophosphate insecticide chlorpyrifos (CPF) inhibits brain fatty acid 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 (2AG), respectively. Peripherally, AEA and 2AG 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 10–16 to either: 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 (a specific FAAH inhibitor). At 12 hrs post-exposure, 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 2AG hydrolysis and MAGL-specific activity in brain and spleen (high dosage only). In liver, total 2AG hydrolysis was inhibited by all treatments and could be attributed to inhibition of non-MAGL-mediated 2AG 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.

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

“…It is, in part, comprised of (a) the CB1 receptor; (b) two principal endogenous ligands (2‐arachidonoylglycerol and anandamide [AEA]); (c) the serine hydrolases monoacylglycerol lipase; (d) and endocannabinoid metabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase) (Di Marzo et al, ), as well as other signaling pathways involved in neurodevelopment (Berghuis, ; Dalton & Howlett, ). CPF has been shown to disrupt this system in adult (Liu & Pope, ; Nomura et al, ; Nomura & Casida, ; Quistad, Klintenberg, Caboni, Liang, & Casida, ; Quistad, Nomura, Sparks, Segall, & Casida, ; Quistad, Sparks, & Casida, ) and preweaning rats (Buntyn et al, ; Carr, Adams, Kepler, Ward, & Ross, ; Carr et al, ; Carr, Graves, Mangum, Nail, & Ross, ). Furthermore, the endocannabinoid system is partly involved in anxiety responses (Carr et al, ; Ruehle, Rey, Remmers, & Lutz, ).…”

“…A few studies examined behaviors associated with disruptions in the endocannabinoid system (Buntyn et al, 2017;Carr et al, 2017), which regulates diverse metabolic and neurodevelopmental processes in the brain (Di Marzo, 2011;Maccarrone, Guzman, Mackie, Doherty, & Harkany, 2014). It is, in part, comprised of (a) the CB1 receptor; (b) two principal endogenous ligands (2-arachidonoylglycerol and anandamide [AEA]); (c) the serine hydrolases monoacylglycerol lipase; (d) and endocannabinoid metabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase) (Di Marzo et al, 2001), as well as other signaling pathways involved in neurodevelopment (Berghuis, 2007;Dalton & Howlett, 2012).…”

“…Furthermore, the endocannabinoid system is partly involved in anxiety responses Ruehle, Rey, Remmers, & Lutz, 2012). Decreased anxiety in pups treated with CPF from PND 10-16 was observed at all CPF doses (LOEL = 0.5 mg kg −1 day −1 ) ) with a concomitant increased FAAH inhibition in the forebrain when tested on PND 25 (Buntyn et al, 2017;Carr et al, 2017). There is a weight-of-evidence indicating that endocannabinoid system disruption at low CPF doses results in long-term neurodevelopmental effects (Leung et al, 2019).…”

“…For example, decreased locomotor activity, neuromotor function (NMF), cognition, anxiety/depression, and social behaviors induced by CPF exposure to children during early development could be modeled in rodents. In rodents, CPF exposure during critical neurodevelopment stages has been associated with disruptions in the endocannabinoid (Buntyn et al, ; Carr et al, ; Carr, Alugubelly, & Mohammed, , chap. 5; Qiao, Seidler, & Slotkin, ; Qiao, Seidler, Tate, Cousins, & Slotkin, ; Zheng, Olivier, Won, & Pope, ), dopaminergic (Aldridge, Meyer, Seidler, & Slotkin, ), and serotonergic systems (Aldridge, Levin, Seidler, & Slotkin, ; Aldridge, Seidler, Meyer, Thillai, & Slotkin, ; Aldridge, Seidler, & Slotkin, ).…”

Pre‐clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion‐induced toxicity

“…To assess the effects of malathion and Cℓ-HIN, after 12 hours of fasting, male rats were divided into four groups and received the following co-treatment: 36,37 Twelve hours after treatment with malathion and/or Cℓ-HIN and/or vehicles, following overnight fasting, all rats were anaesthetized for blood collection by heart puncture. Exposure time was based on a pilot study of our research group and the results described by Buntyn et al 38 Blood and cerebral cortex samples were used for cholinesterase and/or paraoxonase-1 (PON-1) assays.…”