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A new approach for the detection of developmental neurotoxicity induced by prenatal chemical exposure and an analysis of the critical period for the induction of neurodevelopmental disorders.

检测产前化学品暴露引起的发育神经毒性的新方法以及诱导神经发育障碍的关键期分析。

基本信息

批准号：
17590525
负责人：
KUWAGATA Makiko
金额：
$ 1.28万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590525/
关键词：
Developmental Neurotoxicity Fetal Brain Hyperactivity Autism BrdU Valproic Aid Developmental Disorder Locomotion バルブロ酸

项目摘要

In this research, using two animal models for neurodevelopmental disorders (ND) such as hyperactivity (an easy model to detect some behavioral changes in a behavioral test) and autism (difficult model), the usefulness of histopathological observation of the fetal rodent brain after chemical exposure, and the analysis of the critical period for induction of ND were evaluated. The relationship between findings obtained from fetal brain and postnatal behavioral abnormality was also investigated.We already reported that 5-bromo-2'-deoxyuridine (BrdU) induced hyperactivity in offspring when BrdU was administered to rats on gestational days (GD) 9 to 15. In this study, a treatment period was divided before (GD9-10) and after the closure of neural tube (GD11-13, GD14-15). The critical period of hyperactivity induced by prenatal BrdU exposure was estimated to begin after closure of the neural tube and continued for a relatively long period. On observation of GD16 fetal brain, dysgenesis of the cortical plate (CP) was observed in the GD11-13, GD14-15 and GD9-15 (positive control)-treated groups. The findings in GD16 fetal brain (abnormal CP) reflected the grade of hyperactivity in the offspring.As a proposed rat model of autism, valproic acid (VPA, 800mg/kg) was administered to rats on GD9 or GD11 (before and after closure of the neural tube). GD9 treatment increased fetal mortality. Dysgenesis of CP was observed in both GD9 and GD11 treatments. Retardation of development of pons was detected in GD11-treated group.In conclusions, examination of fetal brains shortly after chemical exposure is a good new endpoint to support postnatal observation in developmental neurotoxicity (DNT) tests. The concept of critical period of ND should be important to improve the sensitivity and reproducibility of a DNT test.

本研究采用多动（行为测试中容易发现某些行为变化的模型）和自闭症（困难模型）两种神经发育障碍（ND）动物模型，评价化学暴露后鼠胎脑组织病理学观察的有用性，并分析诱发ND的关键时期。胎儿脑检查结果与产后行为异常之间的关系也进行了研究。我们已经报道了5-溴-2'-脱氧尿嘧啶（BrdU）在妊娠第9至15天（GD）给予大鼠BrdU时诱导后代多动症。本研究将治疗期分为关闭神经管前（GD9-10）和关闭神经管后（GD11-13、GD14-15）。产前BrdU暴露引起的多动的关键期估计在神经管闭合后开始，并持续较长时间。在GD16胎脑观察中，GD11-13、GD14-15和GD9-15（阳性对照）处理组出现皮质板（CP）发育不良。GD16胎儿脑的发现（异常CP）反映了后代多动症的程度。将丙戊酸（VPA, 800mg/kg）作为自闭症大鼠模型，在GD9或GD11（神经管闭合前后）给药。GD9治疗增加了胎儿死亡率。GD9和GD11处理均观察到CP发育不良。gd11处理组脑桥发育迟缓。总之，在化学物质暴露后不久对胎儿大脑进行检查是支持发育性神经毒性（DNT）试验中产后观察的一个很好的新终点。ND关键时期的概念对于提高DNT检测的灵敏度和可重复性具有重要意义。