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目的 探究丙戊酸钠(valproate,VPA)对斑马鱼幼鱼的神经发育毒性。方法 采用急性暴露模式，将8～108 hpf(受精后小时数)斑马鱼胚胎暴露于系列浓度VPA。于5 dpf(受精后天数)测定幼鱼光暗行为游速，确定其效应浓度与敏感窗口;在25～26 dpf进行社会偏好与镜面攻击测试;行为学分析后，取5 dpf幼鱼进行阿尔辛蓝染色，以定量软骨发育指标验证VPA发育毒性。结果 在8～108 hpf暴露期间，VPA对斑马鱼的最大无致畸效应浓度为400μmol/L，效应范围为200～400μmol/L(F=402.90,F=131.60,P<0.05)，敏感窗口为8～24 hpf(F=7.09,F=42.43,P<0.05)和72～96 hpf(F=27.48,F=26.72,P<0.05);敏感窗口暴露VPA导致幼鱼社交与运动能力减弱，并在72～96 hpf窗口特异性引起软骨发育异常，但不影响体长。结论 VPA对斑马鱼的发育毒性呈现窗口特异性，在早期神经发生期暴露特异性导致社交行为缺陷，而在颅面软骨形成关键期暴露则同时引发社交缺陷与软骨发育抑制。提示其毒性机制可能分别干扰了早期神经环路建立和神经嵴细胞介导的颅面发育过程。
Abstract：Objective To investigate of the neurodevelopmental toxicity of sodium valproate( VPA) in zebrafish larvae.Methods The neurodevelopmental toxicity of VPA was evaluated using an acute exposure paradigm in zebrafish embryos from 8 to 108 hpf.First,Larval locomotion in response to light-dark transitions was assessed at 5 dpf to identify the effective concentration and sensitive window.Next,social behavior( social preference and mirror attack tests) was evaluated at 25～26 dpf. Finally,The developmental toxicity was determined by alcian blue staining and quantitative analysis of craniofacial cartilage in 5 dpf larvae. Results During exposure from 8 to 108 hpf,the maximum non-teratogenic concentration of VPA in zebrafish was 400 μmol/L,with effects observed between 200 ～ 400 μmol/L( F = 402.90,F =131. 60,P<0. 05). Sensitive windows were identified at 8 ～ 24 hpf( F = 7.09,F = 42.43,P<0. 05) and 72 ～ 96 hpf( F = 27.48,F = 26.72,P<0. 05). Exposure during these windows VPA could impair social and motor abilities in larvae and specifically induce cartilage abnormalities at72 ～ 96 hpf,without affecting body length. Conclusion VPA exerts window-specific developmental toxicity in zebrafish: during early neurogenesis period it selectively impairs social behavior,whereas during craniofacial chondrogenesis period it causes concurrent social deficits and cartilage maldevelopment. These result imply distinct disruption of early neural circuit formation and neural crest-dependent craniofacial development,respectively.
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基本信息:
DOI：10.16421/j.cnki.1002-3127.2026.01.003
中图分类号:R965
引用信息:
[1]余金侠,王源醒,晏思旖,等.探究丙戊酸钠对斑马鱼幼鱼的发育毒性[J].毒理学杂志,2026,40(01):27-34.DOI:10.16421/j.cnki.1002-3127.2026.01.003.
基金信息:
国家自然科学基金(21477089); 浙江省自然科学基金(LQ18B070004)
2025-06-14
2025
2025-12-03
2025
1
2026-02-25
2026-02-25