Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition.
Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition.
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DOI：
10.1016/j.neuro.2013.12.009
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发表时间：
2014-07
期刊：
影响因子：
3.4
通讯作者：
Ross, Matthew K.
中科院分区：
文献类型：
--
作者：
Carr, Russell L.;Graves, Casey A.;Mangum, Lee C.;Nail, Carole A.;Ross, Matthew K.
普遍的理论认为，毒死蜱通过抑制胆碱酯酶介导其毒性。然而，近年来，发育CPF暴露的毒理学效应被归因于未知的非胆碱能作用机制。我们假设内源性大麻素系统可能是一个重要的目标，因为它在神经系统发育中的重要作用。我们以前曾报道，重复暴露于CPF的结果在更大的抑制脂肪酸酰胺水解酶（FAAH），代谢内源性大麻素anandamide（AEA）的酶，比抑制前脑胆碱酯酶或单酰基甘油脂肪酶（MAGL），代谢内源性大麻素2-花生四烯酸甘油（2-AG）的酶。这种暴露导致幼年大鼠前脑中2-AG和AEA的蓄积;然而，即使在使用的最低剂量水平（1.0 mg/kg），前脑胆碱酯酶抑制仍然存在。因此，尚不清楚FAAH活性在不抑制ChE的剂量水平下是否会被抑制。为了确定这一点，10日龄大鼠幼仔每天经口灌胃暴露于玉米油或0.5 mg/kg CPF，持续7天。于染毒后4 h和12 h测定血清胆碱酯酶（ChE）、羧酸酯酶（CES）活性、前脑胆碱酯酶（ChE）、MAGL和FAAH活性以及前脑乙酰胆碱酯酶（AEA）和2-氨基葡萄糖（2-AG）含量。血清ChE和CES在4和12 h均受到显著抑制。前脑ChE和MAGL活性无明显抑制，2-AG含量无明显变化。另一方面，虽然在4 h时未观察到统计学显著影响，但在12 h时FAAH活性受到显著抑制，导致AEA显著蓄积。虽然目前还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，在不抑制大脑胆碱酯酶的水平下，发育性CPF暴露可以改变内源性大麻素信号的成分。
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 (1.0 mg/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 0.5 mg/kg CPF by oral gavage. At 4 and 12 h 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 12 h. 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 4 h, FAAH activity was significantly inhibited at 12 h 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.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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