Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Reprod Toxicol. 2013 Jan;35:125-36. doi: 10.1016/j.reprotox.2012.10.008. Epub 2012 Oct 23.
To examine the effects of developmental exposure to chlorpyrifos (CPF) on neurogenesis in the hippocampal dentate gyrus, pregnant rats were treated with 2.8, 14 or 70 ppm CPF in the diet from gestational day 10 to day 21 after delivery. Dams had decreased cholinesterase (ChE) activities in red blood cells (RBC) at intakes of ≥2.8 ppm and in brain at 70 ppm. Offspring on postnatal day (PND) 21 had decreased ChE activities in the RBC and brain at 70 ppm. There were no behavioral abnormalities in the offspring. Immunohistochemical analysis showed decreases in the numbers of cells positive for proliferating cell nuclear antigen and T box brain 2 in the subgranular zone (SGZ) of the dentate gyrus on PND 21 at 70 ppm, while other progenitor cell populations and the apoptotic cell number were unaffected in this zone. However, on PND 77 all changes had disappeared. The distribution of the progenitor cell population expressing nicotinic acetylcholine receptor α7 and lacking expression of postmitotic neuron-specific nuclear protein was unchanged by CPF-exposure, suggesting no effect of cholinergic stimulation on neurogenesis. These results suggest that developmental exposure to CPF directly but transiently affect the proliferation of type-2 progenitor cell populations in the hippocampal neurogenesis. The lowest-observed-adverse-effect level (LOAEL) of CPF was determined to be 2.8 ppm (0.36 mg/kg body weight/day) for dams by the inhibition of ChE activity in the RBC at this dose. As for offspring, no-observed-adverse-effect level (NOAEL) was determined to be 14 ppm (1.86 mg/kg body weight/day) by the decrease of type-2 progenitor cell proliferation in the SGZ and the inhibition of ChE activity in the RBC and brain at 70 ppm. The NOAEL of dams based on the offspring's effects was approximately 2800 times higher than the estimated consumption of CPF through food in the general population and in pregnant women as examined in Japan.
为了研究孕期接触毒死蜱（CPF）对海马齿状回神经发生的影响，研究人员在妊娠第 10 天至产后第 21 天，通过饮食给怀孕的老鼠喂食 2.8、14 或 70ppm 的 CPF。母体的红细胞（RBC）和大脑中的胆碱酯酶（ChE）活性在摄入≥2.8ppm 的 CPF 时下降，而在摄入 70ppm 的 CPF 时则下降。出生后第 21 天（PND）的幼崽在 70ppm 的 CPF 下，其 RBC 和大脑中的 ChE 活性下降。幼崽没有出现行为异常。免疫组织化学分析显示，在 PND21 时，70ppm CPF 组齿状回颗粒下区（SGZ）中增殖细胞核抗原（PCNA）和 T 盒脑 2 阳性细胞的数量减少，而在该区，其他祖细胞群体和凋亡细胞数量未受影响。然而，在 PND77 时，所有的变化都消失了。CPF 暴露对表达烟碱型乙酰胆碱受体 α7 且缺乏有丝分裂后神经元特异性核蛋白表达的祖细胞群体的分布没有影响，这表明胆碱能刺激对神经发生没有影响。这些结果表明，CPF 的发育暴露直接但短暂地影响了海马神经发生中 2 型祖细胞群体的增殖。通过该剂量下 RBC 中 ChE 活性的抑制，CPF 对母体的最低观察到的不良效应水平（LOAEL）为 2.8ppm（0.36mg/kg 体重/天）。对于后代，通过 70ppm CPF 下 SGZ 中 2 型祖细胞增殖减少和 RBC 及大脑中 ChE 活性抑制，确定无观察到的不良效应水平（NOAEL）为 14ppm（1.86mg/kg 体重/天）。基于后代的影响，母体的 NOAEL 大约是日本人群和孕妇通过食物摄入 CPF 的估计量的 2800 倍。
