Anesthesia-induced developmental neurotoxicity in children: past, present, and future

Since 1999, a large body of evidence from various animal models indicates a link between anesthesia exposure in early stage of life and subsequent neurodevelopmental impairments1namely, almost all commonly used intravenous and inhalational anesthetics, including gamma- aminobutyric acid agonists and N-methyl-D-aspartate antagonists, can induce dose- and age-dependent neuronal apoptosis and death in vitro. Moreover, abundant data from nematodes to primate animals have shown a variety of anatomic and neurodevelopmental sequelae from anesthesia exposure in young animals.[2,3] In the rodents, the most prominent manifestations of anesthesia-induced developmental neurotoxicity (AIDN) are often observed at post-natal day 7 .

Anesthesia-induced neurotoxicity in an animal model of the developing brain:mechanism and therapies

Children are being exposed to an increasingly greater variety of anesthetics with advances in pediatric and obstetric surgery. Recent animal and retrospective human data suggest that the general anes- thetics commonly used in pediatric medicine could he damaging to the developing brain when used at clinical concentrations. In viw~ primate and rodent models have shown that neonatal exposure to clinical concentrations of anesthetics causes neural apoptosis and long-term cognitive impairment. Many general anesthetics.

Developmental effects of Malathion exposure on locomotor activity and anxiety-like behavior in Wistar rat

Developmental exposure to organophosphate insecticide is well known to induce neurobeha-vioral impairments, at late period. The present study aims to investigate the effects of chronic exposure to Malathion, from in utero to young adult stage, on locomotor skills and anxiety like- behavior among wistar rat. Four groups of female rats, bred with one non-pesticide exposed male, are used. On gestational day 6, three groups receive daily, by intragastric gavage, 3 different doses of Malathion dissolved in corn oil (100, 200 and 300 mg/kg body weight). The control group receives the corn oil only. On postnatal day 21, weaned offsprings are submitted to the similar treatment until adult age. Spontaneous locomotor activity is evaluated using the Open-Field test (OF) and anxiety-like behavior is measured using both Open-Field (OF) test and Elevate Plus-Maze (EPM). Malathion at 300 mg/kg is toxic to pregnant dams, and pups are stillborns. In males, Malathionlevelat 100 and 200 mg/kg induced significant impairment of spontaneous locomotor activities, which is reflected by high decrease of number of squares crossed in OF. In contrast, no discernible changes are observed within females Malathion-treated-group. However, females exposed to both malathion levels develop further anxiety-like response, expressed by significant reductions of exploratory activities in OF and time spent in open arm of EPM. Neurochemistry assay shows that cerebellum and neocortex acetylcholinesterase (AChE) activity inhibition are significantly increased with neurobehavioral deficits in males, relative to females. Overall, neurobehavioral outcomes of current study reveal that developmental exposure to Malathion induces sex-selective effects with greater changes in females.

Developmental Effects of Malathion Exposure on Recognition Memory and Spatial Learning in Males Wistar Rats

Most cognitive effects of Organophosphate Pesticides (OP) are induced after exposure to parathion, chlorpyrifos and diazinon, which the usage has been restricted because of overt signs of their toxicities. In this study, we investigate whether developmental exposure to Malathion could impair spatial learning and recognition memory in male rats. Animals exposed by intragastric route, from in utero to young adult stage, to incremental doses of Malathion dissolved in corn oil;100, 200 and 300 mg/kg of body weight, and one control group are given corn oil. Then, cognitive and behaveioral abilities are assessed using Barnes maze and object recognition memory task. Malathion administration at 300 mg/kg is toxic to pregnant dams, and pups are stillborns. Rats exposed to 200 mg/kg make a significant working memory error, and require more time to find an escape box during the initial training phase of Barnes maze. However, fewer errors are made in rats exposed to 100 mg/kg. For reversal learning task, the high dose group shows great deficits in spatial strategy to locate the new position of the box. With respect to recognition task, both dose 100 and 200 mg/kg impair significant short-term (2 h after habituation phase) object recognition memory, but long-term (24 h after habituation phase) recognition memory is intact in high dose group. The current study also reveals that all treatments induce high significant neocortex acetylcholinesterase (AChE) activity inhibition, but 100 mg/kg dose is not sufficient to disrupt great hippocampal activity alteration. These results suggest that developmental exposure to Malathion, despite low toxicity described, may induce late-emerging spatial learning and recognition memorialterations. Moreover, Cortical and hippocampal area that support strongly these behaviors remain sensitive to incremental doses of Malathion.

Neurobehavioral Assessment of Rats Exposed to Yttrium Nitrate during Development

Objective The aim of this study was to assess the effects of yttrium nitrate on neurobehaviora development in Sprague-Dawley rats. Methods Dams were orally exposed to 0, 5, 15, or 45 mg/kg daily of yttrium nitrate from gestation day （GD） 6 to postnatal day （PND） 21. Body weight and food consumption were monitored weekly. Neurobehavior was assessed by developmental landmarks and reflexes, motor activity, hot plate, Rota-rod and cognitive tests. Additionally, brain weights were measured on PND 21 and 70. Results No significant difference was noted among all groups for maternal body weight and food consumption. All yttrium-exposed offspring showed an increase in body weight on PND 21; however, no significant difference in body weight for exposed pups versus controls was observed 2 weeks or more after the yttrium solution was discontinued. The groups given 5 mg/kg daily decreased significantly in the duration of female forelime grip strength and ambulation on PND 13. There was no significant difference between yttrium-exposed offspring and controls with respect to other behavioral ontogeny parameters and postnatal behavioral test results. Conclusion Exposure of rats to yttrium nitrate in concentrations up to 45 mg/kg daily had no adverse effects on their neurobehavioral development.

Drosophila melanogaster as an indispensable model to decipher the mode of action of neurotoxic compounds

Exposure to some toxic compounds causes structural and behavioral anomalies associated with the neurons in the later stage of life.Those toxic compounds are termed as a neurotoxicant,which can be a physical factor,a toxin,an infection,radiation,or maybe a drug.The incongruities caused due to a neurotoxicant further depend on the toxicity of the compound.More importantly,the neurotoxicity of the compound is associated with the concentration and the time point of exposure.The neurodevelopmental defect appears depending on the toxicity of the compound.A neurodevelopmental defect may be associated with a delay in developmental time,defective growth,structural abnormality of many organs,including sensory organs,behavioral abnormalities,or death in the fetus stage.Numerous model organisms are employed to assess the effect of neurotoxicants.The current review summarizes several methods used to check the effect of neurotoxicant and their effect using the model organism Drosophila melanogaster.

全氟辛烷磺酸对人骨髓间充质干细胞成神经分化的损伤作用

流行病学结果显示全氟辛烷磺酸(perfluorooctane sulfonate,PFOS)暴露与儿童认知能力降低相关,动物毒理学研究表明围产期PFOS暴露造成子代认知能力下降等神经损伤。但是发育中神经系统对PFOS暴露响应更敏感的毒理学机制尚不清楚。本研究基于人骨髓间充质干细胞(human bone marrow derived mesenchymal stem cells,hBMSCs)体外神经分化模型,评估环境相关浓度PFOS暴露对不同分化阶段细胞的毒性效应。在无显著细胞毒性浓度下,分化过程中暴露于20~500 nmol·L^(-1)PFOS对神经元突触产生抑制效应并呈剂量依赖性,抑制率为24.2%~43.9%。细胞经诱导成神经分化后暴露于PFOS,仅在500 nmol·L^(-1)暴露组产生了显著抑制效应,抑制率为17.7%。通过免疫荧光染色检测神经元标志物微管相关蛋白2(microtubule-associated protein 2,MAP2),分化过程中100 nmol·L^(-1)和500 nmol·L^(-1)的PFOS暴露显著抑制了MAP2的表达,抑制率分别为15.9%和18.6%,但分化后PFOS暴露未对MAP2表达产生显著影响。通过对Ca 2+进行实时成像及图像捕捉,发现PFOS暴露刺激成神经分化的细胞钙瞬变,500 nmol·L^(-1)的PFOS暴露诱导钙瞬变峰值F/F 0升高至对照组的1.25倍,提示细胞成神经分化及神经元信号转导等受到干扰。研究结果发现成神经分化过程中细胞对PFOS暴露更为敏感,从细胞分化层面提示了PFOS发育神经毒性的潜在毒理机制,须进一步研究PFOS对细胞分化和细胞命运的敏感靶标,为该类新污染物的健康风险评价和管控提供依据。

麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性

依托咪酯(etomidate,ET)在临床上常被用作麻醉剂。ET长期高剂量地使用会导致人类意识下降和认知障碍等负面效应。但ET对鱼类的神经毒性机制尚不清楚。在本文中,2 hpf(hours post-fertilization)的斑马鱼胚胎暴露于不同浓度ET(0.010、0.091、0.501、9.400、84.31和664.4μg·L^(-1))至168 hpf。通过分析ET对斑马鱼胚胎生理发育、早期行为、细胞凋亡以及多巴胺(dopamine,DA)和γ氨基丁酸(gamma aminobutyric acid,GABA)通路相关基因转录表达水平的影响,评估其对斑马鱼幼鱼神经发育毒性。结果表明,664.4μg·L^(-1)ET显著增大48 hpf和60 hpf斑马鱼胚胎孵化率。0.091μg·L^(-1)和0.501μg·L^(-1)ET诱导168 hpf幼鱼体长减少。0.010、0.091、0.501、9.400、84.31和664.4μg·L^(-1)ET增大48 hpf胚胎畸形评分。0.501、9.400、84.31和664.4μg·L^(-1)ET暴露显著增大96 hpf胚胎畸形评分。0.501、9.400和664.4μg·L^(-1)ET显著增大168 hpf胚胎畸形评分。0.010μg·L^(-1)ET促进了大脑细胞凋亡,而664.4μg·L^(-1)ET抑制了大脑细胞凋亡。行为分析显示,ET所有浓度均抑制触碰行为。0.091μg·L^(-1)ET增强幼鱼游泳行为,而664.4μg·L^(-1)ET减弱游泳行为。并且ET以浓度依赖的方式导致焦虑行为增加。qPCR分析结果表明,低浓度ET显著上调了DA和GABA通路相关基因的转录表达水平,而高浓度ET显著抑制了这些基因的转录表达水平。这些结果表明,ET对发育早期斑马鱼具有明显的神经发育毒性。

Studying developmental neurotoxic effects of bisphenol A(BPA) using embryonic stem cells

There is little to no toxicity information regarding thousands of chemicals to which people are exposed daily.In fact,of the84,000 chemicals listed in the United States Toxic Substances Control Act Inventory,there is limited information available on their effects on neural development（Betts,2010;US EPA,2015）.

十二烷基苯磺酸钠暴露对黄颡鱼(Pelteobagrus fulvidraco)胚胎发育毒性和仔鱼神经毒性的影响

该研究旨在探明十二烷基苯磺酸钠(SDBS)对黄颡鱼(Pelteobagrus fulvidraco)胚胎发育毒性和仔鱼神经毒性的影响,科学评估水体中SDBS污染的环境生态风险。将受精后4 h的黄颡鱼胚胎暴露于质量浓度为0、0.2、0.4、0.6、0.8 mg·L^(-1)的SDBS中,观察胚胎孵化累计死亡率、畸形率;并通过检测5日龄仔鱼脑组织中乙酰胆碱酯酶活性及相关基因的转录水平、5-羟色胺及相关基因的转录水平,探讨其神经毒性的潜在机制。结果显示,与对照相比,暴露处理的黄颡鱼胚胎孵化畸形率提高4.5~14.5百分点(P<0.05),死亡率提高7.8~23.4百分点(P<0.05)。与对照相比,暴露处理正常仔鱼和畸形仔鱼的乙酰胆碱酯酶活性分别显著降低12.0%~50.5%和15.0%~53.9%(P<0.05),暴露处理仔鱼乙酰胆碱酯酶基因mRNA转录水平下降;暴露处理正常仔鱼和畸形仔鱼5-羟色胺含量分别显著降低2.6%~9.9%和3.0%~11.1%(P<0.05),暴露处理仔鱼5-羟色胺基因的转录水平降低。上述结果表明,十二烷基苯磺酸钠暴露显著提高了黄颡鱼胚胎孵化的死亡率和畸形率;SDBS通过抑制乙酰胆碱酯酶活性和5-羟色胺含量水平影响神经传导,抑制神经递质相关基因表达,从而对黄颡鱼产生胚胎发育毒性及神经毒性作用。

全氟辛烷磺酸神经发育毒性机制研究进展

全氟辛烷磺酸(PFOS)是全氟化合物的终端降解产物,在生态环境中能够通过食物链进入生物组织并蓄积,对环境和生物存在潜在危害。动物实验研究发现,PFOS能够通过胎盘和血脑屏障,影响发育期神经系统,其持续性和严重性已引起国内外学者的广泛关注。本文通过对PFOS神经发育毒性效应及其主要机制研究进展进行综述,分析目前研究现状,并对未来PFOS神经发育毒性机制研究提出设想和展望。

四溴双酚A对斑马鱼胚胎发育毒性和神经毒性研究

目的研究四溴双酚A(Tetrabromobisphenol A,TBBPA)对斑马鱼胚胎的发育毒性和神经毒性。方法采用斑马鱼胚胎模型,利用胚胎暴露实验分析剂量效应和畸形表观等发育毒性指标;利用胚胎自主运动、接触反应和仔鱼游泳运动,分析神经毒性指标。结果TBBPA对斑马鱼胚胎的发育具有中度毒性,在受精后48h(Hours Post Fertilization,hpf)的半数致死量(Concentration that led to 50%mortality,LC50)和半数致畸量(Concentration that led to 50%malformations,EC50)分别是7.9和4.7μmol.L-1,以及在120hpf的LC50和EC50分别是5.3和1.9μmol.L-1。发育毒性效应具体表现为(1)在48,60,72,96hpf均表现为低浓度促进孵化,高浓度抑制孵化;(2)引起胚胎发生尾部弯曲、未吸收卵黄囊、心包囊肿、卵黄囊水肿、游囊关闭等畸形现象;(3)胚胎畸形率和死亡率均具有剂量依赖效应,即与暴露浓度成正比。TBBPA对斑马鱼的神经毒性表现为(1)增加胚胎在19～26hpf的自主运动频率;(2)降低胚胎在27,36,48hpf时的接触反应能力;(3)降低胚胎在120hpf的行为运动速度。结论TBBPA对斑马鱼胚胎具有发育毒性和神经行为毒性。

全氟化合物发育神经毒性研究进展

全氟化合物(PFCs)在工业生产和生活中广泛应用,已成为环境中一类普遍的污染物。由于PFCs污染表现出全球性、持久性和富集性等特征,其毒性备受关注。近期研究结果显示,PFCs除对肝脏、免疫系统和生殖内分泌系统等有明显影响外,还具有发育神经毒性。在总结了近年来PFCs发育神经毒性的研究进展基础上,讨论了PFCs发育神经毒性可能的几个机制,并且分析该领域研究存在的问题,提出应该加强环境相关剂量下PFCs发育神经毒性研究,关注PFCs与其他神经毒物复合暴露的发育神经毒性,以推进对实际环境中PFCs所产生的神经损伤的认识。

甲状腺激素脱碘酶在孕哺期十溴联苯醚(BDE 209)暴露致子代小鼠神经发育毒性中的潜在作用

研究孕哺期BDE209暴露对母鼠胎盘和子代脑组织甲状腺激素脱碘酶（deiodinase,DI）基因表达的影响,及其在子鼠神经发育毒性效应中的作用。将75只雌性昆明小鼠随机分为对照组、低剂量组和高剂量组,暴露BDE20910 d后,与雄鼠合笼,每组选取怀孕时间相近（相差不过2 d）的8只母鼠孕期持续染毒至子鼠断乳。采用实时荧光定量PCR检测孕17～18 d胎盘、出生后60 d子鼠脑组织3种类型脱碘酶基因相对表达,利用Morris水迷宫评价出生后60 d子鼠学习记忆能力,测量第2、16、30和60天子鼠体重,观察孕哺期BDE 209暴露对子代生长发育的作用。结果显示,BDE 209对子鼠出生时体重未见明显影响,出生后30 d,高剂量BDE 209暴露组雌性子鼠体重显著低于对照组子鼠体重（p〈0.05）,而低、高剂量暴露组雄性子鼠体重均显著低于对照组子鼠体重（p〈0.05,p〈0.01）,出生后60 d,BDE 209对子鼠体重影响不明显。BDE 209暴露能够显著延长出生后60 d雌、雄性子鼠逃避潜伏期（p〈0.05或p〈0.01）。BDE209暴露显著降低母鼠胎盘中3种类型脱碘酶（主要是DI-3）基因表达（p〈0.05或p〈0.01）,同时,BDE 209暴露可诱导出生60 d后雄性子鼠脑组织中DI-1基因表达（p〈0.05或p〈0.01）,抑制雄性子鼠脑组织中DI-3基因表达（p〈0.05）,BDE 209暴露对出生后60 d雌鼠脑组织脱碘酶未见明显影响（p〉0.05）。研究结果表明,孕哺期BDE209暴露可能通过影响母鼠胎盘组织脱碘酶（特别是DI-3）基因表达,导致子鼠神经发育毒性效应-学习记忆能力障碍。

多溴联苯醚的环境毒理学研究进展

多溴联苯醚(PBDEs)是一类广泛使用的溴代阻燃剂,其大量生产和使用导致了越来越严重的环境污染.由于PBDEs具有较高的亲脂性,化学性质比较稳定,它们可远距离传输到地球各种环境介质中,并通过食物链累积放大,在生物体内蓄积产生毒性效应.本文针对近年来PBDEs毒性效应和致毒机制的研究进展,从PBDEs的内分泌干扰毒性、发育神经毒性和免疫毒性三个方面进行总结,并分析了当前研究需要解决的问题,展望了PBDEs毒理学的研究方向.

增塑剂DEHP的发育和神经毒性研究进展

就DEHP(邻苯二甲酸二乙基己酯)的发育和神经毒性研究进展进行了概述.婴幼儿的DEHP摄入量远高于成年人,母体内的DEHP可能通过胎盘脂质及锌代谢影响胚胎发育,抑制多器官的生长发育并有致畸作用;胚胎期和新生期DEHP可能主要作用于睾丸间质细胞而影响生殖系统发育.DEHP不仅导致大鼠胚胎神经管发育畸形,还可通过血脑屏障影响脑内芳香化酶活性,抑制出生后海马脑区神经元密度,改变果蝇触角叶投射神经元突触前传递,这些作用有可能会改变动物成年后的神经行为.

铅致新生大鼠脑氧化损伤及细胞凋亡的某些改变

目的 探讨发育期铅暴露所致神经毒性机制。方法 母鼠从怀孕始至仔鼠出生后 7d染铅致新生大鼠染铅模型 ,测定新生大鼠血、脑铅含量 ;同时测定脑组织脂质过氧化物 (LPO)水平、谷胱甘肽 (GSH)含量及超氧化物歧化酶(SOD)活性 ;另外应用原位末端标记TUNEL法测定脑组织海马区及其附近皮质细胞凋亡数量。结果 染铅使出生后 7d幼鼠脑LPO水平升高 ,GSH含量下降 ,SOD活性降低 ,且海马区附近皮质细胞凋亡数量增加 (高剂量染铅组每计数 10 0个细胞中凋亡细胞数为 2 2 6 7± 4 0 3,而对照组为 17 44± 3 32 ,P <0 0 5。)结论 铅所致发育神经毒性可能与活性氧自由基 (ROS)

氯丙嗪在斑马鱼胚胎和早期幼鱼发育过程中的神经毒性作用

目的采用模式动物斑马鱼作为研究对象,观察氯丙嗪(chlorpromazine,CPZ)暴露对胚胎和幼鱼早期神经发育的影响。方法在一般毒性评价的基础上,通过整体胚胎细胞凋亡检测和脑组织病理学检查,了解CPZ对神经发育的器质性改变;采用神经行为学方法,包括幼鱼触动逃避反应、自发运动以及惊恐逃避反射等,研究氯丙嗪暴露所致的神经发育功能性障碍。结果斑马鱼胚胎受精后6 h(6 hpf)～72 hpf暴露于CPZ(≥5 mg/L)可引起胚胎和幼鱼死亡、致畸和幼鱼孵化延迟,并呈浓度和时间依赖性;采用吖啶橙染色检测36 hpf整体胚胎凋亡细胞,发现凋亡细胞主要集中在胚胎中脑、后脑、丘脑以及中后脑连接区、脊索和尾部等处;脑组织病理学检测发现,7dpf幼鱼颅腔增大、脑体积减小、脑细胞缩小且细胞间隙增宽。6～72 hpf CPZ(≥0.0625 mg/L)暴露后,幼鱼神经行为学研究发现,CPZ(≥0.125 mg/L)可引起3dpf幼鱼触觉运动能力下降;CPZ(≥0.5 mg/L)可浓度依赖性地抑制幼鱼自发运动,并出现僵直不动、震颤或快速刻板式转圈运动等行为改变;光惊恐实验中,暗环境下各暴露组幼鱼对突发强光刺激均表现为惊跳逃避,并且暗-光交替期运动加速度变化与对照组无显著差异;在撤除光源后,1mg/L和2 mg/L暴露组幼鱼暗适应时程缩短,而0.125 mg/L和0.25 mg/L暴露组暗适应时程延长,提示CPZ对外界刺激引发的幼鱼活跃游动有抑制和促进双重毒性作用。结论 CPZ暴露对斑马鱼胚胎和幼鱼具有明显的神经发育毒性作用。模式动物斑马鱼作为一种高通量筛选模型在外源性化合物神经发育毒性评价中具有较好的应用前景。

七氟醚对新生大鼠发育期学习记忆功能的影响及其可能的机制

目的观察七氟醚对新生大鼠发育期学习记忆功能的影响,并初步探讨其可能的机制。方法将72只出生7 d的SD大鼠随机分为3组,每组24只,雌雄各半。其中：A组,吸入3%七氟醚6 h;B组吸入2 h;C组为空白对照。8 d时,每组处死12只大鼠,分离血清待用。待大鼠发育至28-36 d时依次采用Morris水迷宫实验与Y型迷宫实验观察其学习记忆功能。并于37 d时,处死剩余大鼠,分离血清,同8 d时分离的血清一起检测S100β蛋白的表达量。结果 Morris水迷宫实验表明：发育至29-32 d时,A、B组平均逃避时间明显高于C组（P〈0.001）,其中31 d、32 d时,A组显著高于B组（P〈0.001）;而发育至33 d时,A、B、C各组间120 s内原平台象限活动时间和穿越原平台次数均无显著差异（P〉0.05）。Y型迷宫实验结果表明：34 d时A、B组大鼠全天总反应时间（TRT）和错误次数（EN）均显著高于C组,差异具有统计学意义（P〈0.05）,而35 d、36 d时各组间TRT和EN无显著差异（P〉0.05）。8 d时,A、B组大鼠血清中S100β蛋白含量均显著高于C组,差异具有统计学意义（P〈0.001）,且A组血清中S100β蛋白含量显著高于B组（P〈0.001）。但37 d时,各组间无显著差异（P〉0.05）。结论暴露于3%七氟醚,可一过性降低发育期SD大鼠的学习记忆能力,且这种影响与暴露时间长短呈正相关,其机制可能与七氟醚一过性增加大脑中S100β蛋白的表达有关。

铅致幼鼠海马回及附近皮质细胞凋亡的实验研究

目的 从细胞凋亡的角度探讨铅的发育神经毒性。方法 大鼠孕期及哺乳期不同剂量染铅 ,用原子吸收分光光度法测定仔鼠血、脑铅含量 ,取海马回及附近皮质用TUNEL法测定凋亡细胞数量。结果 染铅使出生后 7天幼鼠海马回及附近皮质的细胞凋亡数量增加 ,但对出生后 2 1天幼鼠的影响不明显。结论 铅可通过增加海马回及附近皮质细胞凋亡数量而表现出发育神经毒性。