Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans.
Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans.
复制标题
早期发育接触挥发性麻醉剂会导致秀丽隐杆线虫的行为缺陷。
DOI：
10.1213/ane.0b013e31826d37c5
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发表时间：
2013-01
影响因子：
5.7
通讯作者：
Morgan PG
中科院分区：
文献类型：
--
作者：
Gentry KR;Steele LM;Sedensky MM;Morgan PG
越来越多的动物研究证据表明，在生命早期暴露于麻醉剂会导致发育中的神经系统细胞凋亡。这种神经元的损失在成年后会产生功能性后果。临床回顾性研究表明，儿童早期多次麻醉暴露也与以后的学习障碍有关。尽管人们对这一现象非常关注，但对麻醉剂引发神经细胞死亡的机制知之甚少。秀丽隐杆线虫是一种功能强大的遗传动物模型，具有精确表征的神经发育和细胞死亡途径，为研究麻醉诱导的神经毒性提供了极好的机会。我们假设，在生命早期将线虫暴露于挥发性麻醉剂会诱导神经元细胞死亡，产生成年后表现出的行为缺陷。在同步化和孵化后，将蠕虫暴露于挥发性麻醉剂（95%有效浓度）4小时。在生命的第4天，测试暴露和对照蠕虫感知和移动到引诱剂（即，化学税）。我们使用标准化的趋化性指数确定成功的趋化率。在第一幼虫期暴露于异氟烷（ISO）或七氟烷（SEVO）后，野生型线虫表现出明显的趋化指数缺陷（趋化指数：未处理，85 ± 2; ISO，52 ± 2; SEVO，47 ± 2;两种暴露均P < 0.05）。线粒体突变型gas-1对麻醉剂暴露的影响增强（趋化指数：未处理，71 ± 2; ISO，29 ± 12; SEVO，24 ± 13;两种暴露均P < 0.05）。相比之下，由于介导程序性细胞死亡（ced-3）的途径中的突变而不能经历细胞凋亡的动物保留了它们感知并向引诱物移动的能力（趋化性指数：未处理，76 ± 10; ISO，73 ± 9; SEVO，76 ± 10）。此外，我们发现线虫对麻醉剂神经毒性最敏感的窗口发生在孵化后的第一个幼虫阶段（L1）。这与该模型中的神经发生期相吻合。所有值均为平均值± SD。这些数据表明，麻醉剂影响线虫的神经行为，扩大门的范围，其中早期暴露于挥发性麻醉剂已被证明会导致功能性神经功能缺损。这意味着麻醉剂诱导的神经毒性是通过一种古老的潜在机制发生的。线虫是一种易于处理的模式生物，可以用来研究整个基因组中介导挥发性麻醉剂对发育中的神经系统的毒性作用的分子。
Mounting evidence from animal studies shows that anesthetic exposure in early life leads to apoptosis in the developing nervous system. This loss of neurons has functional consequences in adulthood. Clinical retrospective reviews have suggested that multiple anesthetic exposures in early childhood are associated with learning disabilities later in life as well. Despite much concern about this phenomenon, little is known about the mechanism by which anesthetics initiate neuronal cell death. Caenorhabditis elegans, a powerful genetic animal model, with precisely characterized neural development and cell death pathways, affords an excellent opportunity to study anesthetic-induced neurotoxicity. We hypothesized that exposing the nematode to volatile anesthetics early in life would induce neuron cell death, producing a behavioral defect that would be manifested in adulthood. After synchronization and hatching, larval worms were exposed to volatile anesthetics at their 95% effective concentration for 4 hours. On day 4 of life, exposed and control worms were tested for their ability to sense and move to an attractant (i.e., to chemotax). We determined the rate of successful chemotaxis using a standardized chemotaxis index. Wild-type nematodes demonstrated striking deficits in chemotaxis indices after exposure to isoflurane (ISO) or sevoflurane (SEVO) in the first larval stage (chemotaxis index: untreated, 85 ± 2; ISO, 52 ± 2; SEVO, 47 ± 2; P < 0.05 for both exposures). The mitochondrial mutant gas-1 had a heightened effect from the anesthetic exposure (chemotaxis index: untreated, 71 ± 2; ISO, 29 ± 12; SEVO, 24 ± 13; P < 0.05 for both exposures). In contrast, animals unable to undergo apoptosis because of a mutation in the pathway that mediates programmed cell death (ced-3) retained their ability to sense and move toward an attractant (chemotaxis index: untreated, 76 ± 10; ISO, 73 ± 9; SEVO, 76 ± 10). Furthermore, we discovered that the window of greatest susceptibility to anesthetic neurotoxicity in nematodes occurs in the first larval stage after hatching (L1). This coincides with a period of neurogenesis in this model. All values are means ± SD. These data indicate that anesthetics affect neurobehavior in nematodes, extending the range of phyla in which early exposure to volatile anesthetics has been shown to cause functional neurological deficits. This implies that anesthetic-induced neurotoxicity occurs via an ancient underlying mechanism. C elegans is a tractable model organism with which to survey an entire genome for molecules that mediate the toxic effects of volatile anesthetics on the developing nervous system.