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.

在这项研究中，使用两种神经发育障碍（ND）的动物模型，如多动（一个容易的模型，以检测一些行为的变化，在行为测试）和自闭症（困难的模型），组织病理学观察的有用性啮齿动物胚胎脑化学暴露后，和分析的关键时期诱导ND进行了评估。我们已经报道了5-溴-2 '-脱氧尿苷（BrdU）在妊娠第9至15天（GD）给大鼠注射时可诱导后代的多动性。在本研究中，将治疗期分为神经管闭合前（GD 9 -10）和神经管闭合后（GD 11 -13，GD 14 -15）。估计产前BrdU暴露引起的多动症的关键期在神经管关闭后开始，并持续相对较长的时间。在观察GD 16胎仔脑时，在GD 11 -13、GD 14 -15和GD 9 -15（阳性对照）给药组中观察到皮质板（CP）发育不全。在GD 9或GD 11（神经管闭合前后）给予大鼠丙戊酸（VPA，800 mg/kg）作为拟建立的孤独症大鼠模型。GD 9处理增加了胎儿死亡率。在GD 9和GD 11处理中均观察到CP的发育不良。GD 11处理组中检测到脑桥发育迟缓。总之，化学暴露后不久检查胎脑是一个很好的新终点，以支持发育神经毒性（DNT）试验中的出生后观察。ND临界期的概念对提高DNT试验的敏感性和重复性具有重要意义。

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.