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.

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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.