低浓度毒死蜱对胚胎神经前体细胞分裂平面取向的影响及其远期细胞形态效应
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摘要
有机磷农药毒死蜱(Chlorpyrifos, CPF)的广泛使用引起了神经发育毒性,且从胚胎神经管到出生后神经发育阶段均为易受损期。许多研究报道了CPF对细胞增殖和分化的影响,但很少阐述CPF对神经细胞分裂过程的影响。本文研究低浓度CPF对胚胎神经前体细胞分裂平面取向的影响及其远期细胞形态效应。
我们将5mg/kg/d CPF通过皮下注射(subcutaneous, sc)暴露于E7.5-11.5天孕鼠,在E12、E14和E16天时,制备胎脑组织石蜡切片在显微镜下测量脑室区(ventricular Zone,VZ)顶端前体细胞(apical progenitor cells, APs)和室下区(subvertricular zone, SVZ)中间前体细胞(intermediate progenitor cells, IPs)分裂平面的角度(即分裂平面与室表面的交角),分别统计水平分裂、倾斜分裂、垂直分裂的细胞数,同时计数脑室表层有丝分裂细胞数和总细胞数量及比例。另外,我们为了评估CPF对脑发育的远期细胞形态效应,观察分析CPF对出生后35天(postnatal days35, PND35)的子代鼠大脑皮层S1区、海马区和纹状体细胞形态的影响。
实验结果发现,VZ区中APs在皮层发育期主要以垂直分裂为主；相反,在SVZ区中,大多数的IPs以水平分裂为主。在CPF暴露后,E12、E14、E16的APs形态正常,但细胞分裂平面发生了变化,倾斜分裂和水平分裂细胞数增加而垂直分裂细胞数减少。同时有丝分裂细胞数／室表层细胞总数的比率相对稳定。而在SVZ区中,CPF暴露对IPs分裂平面取向的影响较小,其主要的水平分裂无发生明显变化,而其他分裂模式与对照组比较也没有明显改变。我们的结果表明神经发育期暴露CPF后对VZ区APs有丝分裂平面取向具有影响,显示出垂直分裂向水平分裂转换的趋势,也表明了CPF暴露后使细胞有丝分裂由对称分裂向不对称分裂转变；另外,由于有丝分裂细胞与总细胞之间的比率相对稳定,明确了有丝分裂平面取向的改变不是由于有丝分裂细胞数的减少而引起的。
研究子代鼠脑组织的实验结果发现,在海马区,CA1区平均厚度下降22.37%,CA3区平均厚度下降25.66%,而DG区平均厚度增加24.14%,与对照组比较,差异均有统计学意义(P<0.05)；S1区胶质细胞／神经元比值由22.41%上升至34.23%；纹状体区神经元总数下降32.78%在总细胞中比率下降10.13%。这些研究结果证明,在未表现出全身性中毒的亚中毒阈剂量下,CPF在妊娠期的暴露,能引起子代鼠脑结构的细微损伤。
The widely used organophosphate insecticide, chlorpyrifos (CPF) has elicited developmental neurotoxicity, and vulnerable period arrangs from the neural tube stage to nuring stage. Many studies reported the toxicity effects of CPF exposure on cell proliferation and differentiation. However, there still lacks research works on the cell division procession. The present study designed to explore the effects of CPF exposure on cleavage plane orientation and its related long-term effects on brain morphology.
We administered 5mg/kg of CPF sc daily on embryonic days (E)7.5-11.5. On E12, E14 and E16, we have measured the angles at which apical progenitor cells (APs) undergo cleavage in the ventricular zone (VZ) and intermediate progenitor cells (IPs) undergo cleavage in subventricular zone (S VZ) of the developing cerebrum, we counted respectively the cells number of vertical cleavage, oblique cleavage and horizontal cleavage; In addition, the mitotic/total cells ratio was also been assessed to obtain the whole view of VZ surface. To understand the long-term effects of cells morphology, on postnatal days (PND)35, quantitative morphologic examinations were measured in CA1, CA3, and dentate gyrus regions of the hippocampus, somatosensory cortex and stritum.
In the experiment, we found that most of cleavage plane orientations are vertical cleavage in the VZ, while most IPs divide with a horizontal orientation in the SVZ. After CPF treatment on E12, E14 and E16, vertical cleavage plane is deduced and obique and horizontal cleavage plane are increased; At the same time, CPF prenatal treatment donot decre ase the VZ mitotic cells number; Furthermore, CPF donot affect the cleavage plane orientation of the IPs in the SVZ at E14 and E16. At all three neurogenesis stages, we observed cleavage orientation shift from vertical to horizontal, implied the effects of CPF to switch the mode of division from symmetric division to asymmetric division, for horizontal orientation is the clear evidence of asymmetric division. The ratio of mitotic cells/total cells was found unchange in VZ surface during whole neurogenesis, which proved the orientation shift not caused by mitotic decreasing.
The results of CPF prenatal exposure on PND35, selective morphology impairments were observed. In the hippocampus, showing 22.3%,2566% thinning of the CA1 and CA3 layers. The dentate guys is enlarged 24.14%. In the somatosensory cortex, the ratio of glial/neuron is increased from 22.41% to 34.23%. In the striatum, CPF elicited the neuron/total cellular number ratio with fell off 10.13%. Even without obviously system toxicity, subtoxic dosage of CPF prenatal exposure could cause slight impairments of structure on the brain of the offsprings.
我们将5mg/kg/d CPF通过皮下注射(subcutaneous, sc)暴露于E7.5-11.5天孕鼠,在E12、E14和E16天时,制备胎脑组织石蜡切片在显微镜下测量脑室区(ventricular Zone,VZ)顶端前体细胞(apical progenitor cells, APs)和室下区(subvertricular zone, SVZ)中间前体细胞(intermediate progenitor cells, IPs)分裂平面的角度(即分裂平面与室表面的交角),分别统计水平分裂、倾斜分裂、垂直分裂的细胞数,同时计数脑室表层有丝分裂细胞数和总细胞数量及比例。另外,我们为了评估CPF对脑发育的远期细胞形态效应,观察分析CPF对出生后35天(postnatal days35, PND35)的子代鼠大脑皮层S1区、海马区和纹状体细胞形态的影响。
实验结果发现,VZ区中APs在皮层发育期主要以垂直分裂为主；相反,在SVZ区中,大多数的IPs以水平分裂为主。在CPF暴露后,E12、E14、E16的APs形态正常,但细胞分裂平面发生了变化,倾斜分裂和水平分裂细胞数增加而垂直分裂细胞数减少。同时有丝分裂细胞数／室表层细胞总数的比率相对稳定。而在SVZ区中,CPF暴露对IPs分裂平面取向的影响较小,其主要的水平分裂无发生明显变化,而其他分裂模式与对照组比较也没有明显改变。我们的结果表明神经发育期暴露CPF后对VZ区APs有丝分裂平面取向具有影响,显示出垂直分裂向水平分裂转换的趋势,也表明了CPF暴露后使细胞有丝分裂由对称分裂向不对称分裂转变；另外,由于有丝分裂细胞与总细胞之间的比率相对稳定,明确了有丝分裂平面取向的改变不是由于有丝分裂细胞数的减少而引起的。
研究子代鼠脑组织的实验结果发现,在海马区,CA1区平均厚度下降22.37%,CA3区平均厚度下降25.66%,而DG区平均厚度增加24.14%,与对照组比较,差异均有统计学意义(P<0.05)；S1区胶质细胞／神经元比值由22.41%上升至34.23%；纹状体区神经元总数下降32.78%在总细胞中比率下降10.13%。这些研究结果证明,在未表现出全身性中毒的亚中毒阈剂量下,CPF在妊娠期的暴露,能引起子代鼠脑结构的细微损伤。
The widely used organophosphate insecticide, chlorpyrifos (CPF) has elicited developmental neurotoxicity, and vulnerable period arrangs from the neural tube stage to nuring stage. Many studies reported the toxicity effects of CPF exposure on cell proliferation and differentiation. However, there still lacks research works on the cell division procession. The present study designed to explore the effects of CPF exposure on cleavage plane orientation and its related long-term effects on brain morphology.
We administered 5mg/kg of CPF sc daily on embryonic days (E)7.5-11.5. On E12, E14 and E16, we have measured the angles at which apical progenitor cells (APs) undergo cleavage in the ventricular zone (VZ) and intermediate progenitor cells (IPs) undergo cleavage in subventricular zone (S VZ) of the developing cerebrum, we counted respectively the cells number of vertical cleavage, oblique cleavage and horizontal cleavage; In addition, the mitotic/total cells ratio was also been assessed to obtain the whole view of VZ surface. To understand the long-term effects of cells morphology, on postnatal days (PND)35, quantitative morphologic examinations were measured in CA1, CA3, and dentate gyrus regions of the hippocampus, somatosensory cortex and stritum.
In the experiment, we found that most of cleavage plane orientations are vertical cleavage in the VZ, while most IPs divide with a horizontal orientation in the SVZ. After CPF treatment on E12, E14 and E16, vertical cleavage plane is deduced and obique and horizontal cleavage plane are increased; At the same time, CPF prenatal treatment donot decre ase the VZ mitotic cells number; Furthermore, CPF donot affect the cleavage plane orientation of the IPs in the SVZ at E14 and E16. At all three neurogenesis stages, we observed cleavage orientation shift from vertical to horizontal, implied the effects of CPF to switch the mode of division from symmetric division to asymmetric division, for horizontal orientation is the clear evidence of asymmetric division. The ratio of mitotic cells/total cells was found unchange in VZ surface during whole neurogenesis, which proved the orientation shift not caused by mitotic decreasing.
The results of CPF prenatal exposure on PND35, selective morphology impairments were observed. In the hippocampus, showing 22.3%,2566% thinning of the CA1 and CA3 layers. The dentate guys is enlarged 24.14%. In the somatosensory cortex, the ratio of glial/neuron is increased from 22.41% to 34.23%. In the striatum, CPF elicited the neuron/total cellular number ratio with fell off 10.13%. Even without obviously system toxicity, subtoxic dosage of CPF prenatal exposure could cause slight impairments of structure on the brain of the offsprings.
引文
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