氰戊菊酯通过干扰雌激素作用致神经发育毒性

Research of fenvalerate induced neurodevelopmental toxicity by interfering with the action of estrogen

目的 探讨雌激素干扰特性在氰戊菊酯神经发育毒性中的作用.方法 4周龄健康雌性ICR小鼠30只,随机分为6组：假手术组、假手术给予氰戊菊酯（5μg/g）处理组、卵巢切除后对照组、卵巢切除后给予雌激素（E2,10μg/g）处理组、卵巢切除后给予氰戊菊酯处理组、卵巢切除后给予雌激素和氰戊菊酯处理组,每组5只,腹腔注射给药,每天1次,连续7d,末次染毒24 h后分离海马.用免疫荧光组织化学技术检测海马CA1、CA3和DG区神经元标志物（NeuN）和星形胶质细胞标志物（GFAP）.结果 与假手术组[CA1（54.00±1.73）、CA3（59.00±1.73）、DG（100.00±4.58）]比较,假手术给予氰戊菊酯处理组[CA1（37.67±2.08）、CA3（41.33±1.15）、DG（80.67±0.58）]和卵巢切除后对照组[CA1（44.00±3.00）、CA3（51.00±3.00）、DG（83.00±1.72）]海马各区神经元（NeuN阳性）细胞数均明显减少,差异有统计学意义（P＜0.05）.与卵巢切除后对照组比较,卵巢切除后给予氰戊菊酯处理组海马各分区NeuN阳性细胞数无明显改变.与卵巢切除后给予氰戊菊酯处理组[CA1 （47.67±3.21）、DG（87.33±4.04）]比较,假手术后给予氰戊菊酯处理和卵巢切除后给予雌激素和氰戊菊酯处理[CA1 （40.00±1.00）、DG（78.67±2.31）]NeuN阳性细胞数均明显减少,差异有统计学意义（P＜0.05）.与假手术组[CA3（11.00±1.12）、DG（10.67±1.15）]比较,假手术后给予氰戊菊酯处理组[CA3（18.67±2.07）、DG（16.33±1.53）]星形胶质细胞（GFAP阳性）细胞明显增加,差异有统计学意义（P＜0.05）.与假手术后给予氰戊菊酯处理组比较,卵巢切除后给予氰戊菊酯处理组[CA3（12.00±1.00）、DG（11.68±1.16）]GFAP阳性细胞明显减少,差异有统计学意义（P＜0.05）.与卵巢切除后给予氰戊菊酯处理组比较,假手术后给予氰戊菊酯处理组和卵巢切除后给予雌激素和氰戊菊酯处理组[CA3（16.67±2.13）、DG（15.38±1.42）] GFAP阳性细胞数明显增加,差异有统计学意义（P＜0.05）.结论 氰戊菊酯干扰循环雌激素作用是其发挥神经发育毒性的重要作用机制.

Objective To investigate the estrogen interference property of fenvalerate in ncurodevelopmental toxicity.Methods Thirty 4-week-old healthy female ICR mice were randomly divided into 6 groups：sham operation group,ovariectomized control group,ovariectomized with estrogen （10 μg/g） group,ovariectomized with fenvalerate （5 μg/g） group,sham operation with fenvalerate group,and ovariectomized with estrogen and fenvalerate group,with 5 mice in each group.Fenvalerate was injected intraperitoneally once a day for 7 consecutive days.Mice were sacrificed at 24 h after the last exposure to separate the hippocampus.Immunofluorescence was used to detect neuron marker （NeuN） and astrocyte marker （GFAP） in hippocampal CA1,CA3,and DG regions.Results Compared with the sham operation group （numbers of NeuN-positive cells：CA 1 （54.00± 1.73）,CA3 （59.00± 1.73）,DG （100.00±4.58））,the sham operation with fenvalerate group （CA1 （37.67±2.08）,CA3 （41.33±1.15）,DG （80.67±0.58）） and ovariectomized control group （CA1 （44.00± 3.00）,CA3 （51.00±3.00）,DG （83.00±1.72）） showed significant decreases in number of neurons （NeuNpositive cells） in the hippocampus （P〈0.05）.Compared with the ovariectomized control group,the ovariectomized with fenvalerate group （CA1 （47.67±3.21）,CA3 （49.00±1.73）,DG （87.33±4.04）） showed no significant change in number of hippocampal NeuN-positive cells.Compared with the ovariectomized with fenvalerate group （CA1 （47.67±3.21）,DG （87.33±4.04））,the sham operation with fenvalerate group and ovariectomized with estrogen and fenvalerate group （CA1 （40.00±1.00）,DG （78.67±2.31）） experienced significant decreases in NeuN-positive cells （P〈0.05）.Compared with the sham operation group （CA3 （11.00± 1.12）,DG （10.67±1.15））,the sham operation with fenvalerate group （CA3 （18.67±2.07）,DG （16.33±1.53）） showed significant increase in number of astrocytes （GFAP-positive） cells （P〈0.05）.Compared with the sham operation with fenvalerate group,the ovariectomized with fenvalerate group （CA3 （12.00± 1.00）,DG （11.68± 1.16）） showed significant decrease in GFAP-positive cells （P〈0.05）.Compared with the ovariectomized with fenvalerate group,the sham operation with fenvalerate group and ovariectomized with estrogen and fenvalerate group （CA3 （16.67±2.13）,DG （15.38±1.42）） showed significant increases in GFAP-positive cells （P〈0.05）.Conclusion The interference with circulating estrogen is an important mechanism underlying the neurodevelopmental toxicity of fenvalerate.