Induction of Endocannabinoid Levels in Juvenile Rat Brain Following Developmental Chlorpyrifos Exposure

Abstract

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.

Acute and developmental behavioral effects of flame retardants and related chemicals in zebrafish

“…Structurally related compounds have previously been shown to affect brain development (Carr et al, 2013, 2014; Dishaw et al, 2011; Slotkin et al, 2006, 2009; Slotkin and Seidler, 2005, 2011). Hence, it is important to deploy a test system for rapid assessment of nervous system perturbations.…”

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

“…Given the importance of the endocannabinoids in brain development, it is possible that developmental OP exposure could alter the normal endocannabinoid levels and result in deleterious effects on brain maturation. Therefore, we previously initiated investigations on the effects of repeated exposure to CPF in the brain of developing rats (Carr et al, 2011; 2013). Following 7 days of daily CPF exposure, 2-AG and AEA hydrolysis activities in the brain were inhibited in a dose-related manner at 4 h post-exposure, and the extent of inhibition from highest to lowest level was AEA hydrolysis>acetylcholine hydrolysis>2-AG hydrolysis (Carr et al, 2011).…”

“…Following 7 days of daily CPF exposure, 2-AG and AEA hydrolysis activities in the brain were inhibited in a dose-related manner at 4 h post-exposure, and the extent of inhibition from highest to lowest level was AEA hydrolysis>acetylcholine hydrolysis>2-AG hydrolysis (Carr et al, 2011). Using the same exposure paradigm, we determined the peak time of inhibition for MAGL (4 h post-exposure) and brain ChE and FAAH (12 h post-exposure) and that levels of 2-AG and AEA were significantly elevated (Carr et al, 2013). However, significant brain ChE inhibition was still observed at all dosages administered and it was not clear whether CPF exposure can induce significant effects on endocannbinoid metabolism in the absence of brain ChE inhibition.…”

Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum

“…FAAH is also critical in the breakdown of the eCBLs PEA and OEA. While the primary and often most sensitive macromolecular target for many OPs is AChE, a number of OPs including parathion and chlorpyrifos ( in vivo ) and paraoxon and chlorpyrifos oxon ( in vitro ) are potent inhibitors of FAAH (Quistad et al ., 2001, 2006; Nomura et al ., 2008; Nallapaneni et al ., 2006, 2008; Liu et al ., 2013) and can elevate brain levels of AEA (Nomura et al ., 2008; Carr et al ., 2013). Monoacylglycerol lipase (MAGL) is the main enzyme involved in 2AG hydrolysis (Blankman et al ., 2007; Hashimotodani et al ., 2007; Savinainen et al ., 2012).…”

“…MAGL is also inhibited by a number of OPs but, in general, MAGL is less sensitive than FAAH to inhibition by OPs (Quistad et al ., 2001, 2006; Nomura et al ., 2008; Nomura and Casida, 2011; Liu et al ., 2013). OP-mediated inhibition of MAGL has been reported to increase brain levels of 2AG in mice and rats (Nomura et al ., 2008; Nomura and Casida, 2011; Carr et al ., 2013). We previously reported that in vivo exposure to either parathion or chlorpyrifos led to similar degrees of inhibition in both FAAH and MAGL activities in the hippocampus, with concomitant increases (more so with chlorpyrifos) in extracellular AEA levels.…”