有机磷（OP）引起的迟发性神经毒性（OPIDN）是一种神经退行性疾病，其主要特征是周围神经轴突的变性降解。具有溶血磷脂酶（LysoPLA）和磷脂酶B（PLB）活性的神经病靶酯酶（NTE）被认为是OPIDN的主要靶标。OPIDN的发生具有动物种属敏感性差异：成年鸡在对神经毒性OP的易感性以及随后表现出来的毒性症状方面与人极为相似，故其一直被用作研究OPIDN的动物模型，而医学研究中最常用的实验动物小鼠，在接触神经毒性OP后通常不出现典型的OPIDN症状。然而，这种OPIDN敏感性的动物种属差异的原因迄今未能阐明。
中国科学院动物研究所伍一军研究组的科研人员近年来开展了OPIDN的敏感性动物种属差异的研究，他们分别以成年鸡和小鼠为实验动物，比较研究了这两种对OPIDN敏感性完全不同的动物在染毒OPIDN的经典药物¾三邻甲苯基磷酸酯（TOCP）后其神经系统（脑、脊髓和坐骨神经）不同时间点的NTE、LysoPLA和PLB活性及其底物卵磷脂（PC）和溶血卵磷脂（LPC）稳态变化。结果发现，TOCP对鸡和小鼠神经组织中PC和LPC的稳态并没有影响，说明以前关于“NTE被OP抑制后其生理底物PC/LPC浓度变化可能是这两种动物接触OP后神经毒性不同的原因”的假设并不成立。进一步分析发现，TOCP对这两种动物神经组织中NTE、LysoPLA和PLB活性的抑制表现出不同的特点，小鼠神经组织中这三种丝氨酸水解酶受TOCP抑制及其后恢复的速率均较在母鸡中的高，提示OP在小鼠体内代谢速率及其代谢物的消除都比鸡的要快，而起动OPIDN的发生则需要OP抑制这些酶达到一定程度并保持一定的时间。根据上述比较研究的结果，研究小组首次提出鸡和小鼠这两种动物对OPIDN易感性不同及其毒性症状的差异可能与OP对这两种动物神经组织中的NTE、LysoPLA和 PLB的抑制模式不同有关。
以上研究结果分别发表在毒理学国际权威学术期刊 Toxicological Sciences（Hou W-Y, Long D-X, Wu Y-J. Toxicological Sciences. 2009, 109:276-285）和 Toxicology （Hou W-Y, Long D-X, Wang H-P, Wang Q, Wu Y-J. Toxicology. 2008, 252:56-63.）上。论文第一作者侯威远为已毕业的博士研究生，联系作者伍一军为分子毒理学研究组组长。
该研究工作得到了国家自然科学基金项目（30470228；30870537）的资助。（生物谷Bioon.com）
生物谷推荐原始出处：
Toxicological Sciences 2009 109(2):276-285; doi:10.1093/toxsci/kfp068
The Homeostasis of Phosphatidylcholine and Lysophosphatidylcholine in Nervous Tissues of Mice was not Disrupted after Administration of Tri-o-cresyl Phosphate
Wei-Yuan Hou*,, Ding-Xin Long* and Yi-Jun Wu*,1
* Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, P.R. China Graduate School of the Chinese Academy of Sciences, Beijing 100039, P.R. China
Neuropathy target esterase (NTE) is proven to act as a lysophospholipase (LysoPLA) in mice and phospholipase B (PLB) in cultured mammalian cells. In sensitive species, organophosphate (OP)–induced delayed neurotoxicity is initiated when NTE is inhibited by > 70% and then aged. It is hypothesized that homeostasis of phosphatidylcholine (PC) and/or lysophosphatidylcholine (LPC) in mice might be disrupted by the OPs since NTE and other phospholipases could be inhibited. To test this hypothesis, we treated mice using tri-o-cresyl phosphate (TOCP), which can inhibit and age NTE. Phenylmethylsulfonyl fluoride (PMSF), which inhibits NTE but cannot age, was used as a negative control. Effects on activity of NTE, LysoPLA, and PLB, the levels of PC, LPC, and glycerophosphocholine (GPC), and the aging of NTE in the brain, spinal cord, and sciatic nerve were examined. The results showed that the activities of NTE, NTE-LysoPLA, LysoPLA, NTE-PLB, and PLB were significantly inhibited in both TOCP- and PMSF-treated mice, and the inhibition of NTE and NTE-LysoPLA or NTE-PLB showed a high correlation coefficient. The NTE inhibited by TOCP was of the aged type, while nearly all NTE inhibited by PMSF was of the unaged type. Although the GPC level was remarkedly decreased, no significant change of PC and LPC levels was observed. However, the inhibition of these enzymes in mice by TOCP exhibited different characteristics from the TOCP-treated hens that we previously reported, which indicates that these enzymes were inhibited and then recovered more rapidly in mice than in hens. All results suggest that PC and LPC homeostasis was not disrupted in mice after exposure to TOCP. Differences in inhibition of NTE, LysoPLA, and PLB activities by TOCP between mice and hens may elucidate why these two species display different signs after exposure to the same neuropathic OPs.
