Carr Russell L, Graves Casey A, Mangum Lee C, Nail Carole A, Ross Matthew K
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA.
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA.
Neurotoxicology. 2014 Jul;43:82-89. doi: 10.1016/j.neuro.2013.12.009. Epub 2013 Dec 25.
The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5mg/kg CPF by oral gavage. At 4 and 12h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4h, FAAH activity was significantly inhibited at 12h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of endocannabinoid signaling.
普遍的观点认为，毒死蜱（CPF）通过抑制胆碱酯酶（ChE）来介导其毒性。然而，近年来，发育期接触CPF的毒理学效应被归因于一种未知的非胆碱能作用机制。我们推测内源性大麻素系统可能是一个重要靶点，因为它在神经系统发育中起着至关重要的作用。我们之前报道过，重复接触CPF对脂肪酸酰胺水解酶（FAAH）的抑制作用比对前脑ChE或单酰甘油脂肪酶（MAGL）的抑制作用更强，FAAH是代谢内源性大麻素花生四烯乙醇胺（AEA）的酶，MAGL是代谢内源性大麻素2-花生四烯酸甘油（2-AG）的酶。这种接触导致幼年大鼠前脑2-AG和AEA的积累；然而，即使在使用的最低剂量水平（1.0mg/kg）下，前脑ChE抑制仍然存在。因此，尚不清楚在不抑制ChE的剂量水平下FAAH活性是否会受到抑制。为了确定这一点，10日龄的幼鼠通过口服灌胃每天暴露于玉米油或0.5mg/kg CPF中，持续7天。在给药最后一天的暴露后4小时和12小时，测定血清ChE和羧酸酯酶（CES）以及前脑ChE、MAGL和FAAH的活性，以及前脑AEA和2-AG水平。在4小时和12小时时，血清ChE和CES均受到显著抑制。在前脑ChE或MAGL的活性方面没有显著抑制，并且在两个时间点2-AG的量均没有显著变化。另一方面，虽然在4小时时未观察到统计学上的显著影响，但在12小时时FAAH活性受到显著抑制，导致AEA显著积累。虽然尚不清楚这种积累水平是否会影响大脑成熟，但这项研究表明，在不抑制脑ChE的水平下发育期接触CPF会改变内源性大麻素信号传导的成分。
