Neuropathological examination of fetal rat brain in the 5-bromo-2'-deoxyuridine-induced neurodevelopmental disorder model.

The majority of prior developmental neurotoxicity studies focused on postnatal subjects rather than on the fetus. In the present paper, we demonstrate the use of histological examination of fetal rat (embryonic day 16.5) brain serial sections, employing Nissl staining and microtubule-associated protein 2 (MAP2) immunohistochemistry, in evaluating a chemical-induced neurodevelopmental disorder. Since prenatal treatment with 5-bromo-2'-deoxyuridine (BrdU) is known to induce behavioral abnormalities such as locomotor hyperactivity in offspring, pregnant rats were administered 50 mg/kg on gestation days 9.5 through 15.5. The fetal brains at embryonic day 16.5 were collected and processed for neuropathological study. Cell death, including DNA strand breaks, was observed in specific areas of the fetal brain such as the neuroepithelium, intermediate zone and/or differentiating zones (e.g. neocortex and striatum) in exposed fetuses. In addition, the neocortex had an abnormal appearance cortical plate, which was also detected by MAP2 immunohistochemistry. The abnormal cortical plate was observed consistently, while the grade of cell death was generally very mild and variable. No significant alteration was detected in the brainstem. The present study reveals that histological observation of the fetal brain includes sensitive endpoints in developmental neurotoxicity, and that BrdU, at a dose generally administered to label proliferating cells, affects the development of the fetal neocortex.