The inhibition of neural crest cell (NCC) migration has been considered as a possible pathogenic mechanism underlying chemical developmental toxicity. In this study, we examined the effects of 13 developmentally toxic chemicals on the migration of rat cephalic NCCs (cNCCs) by using a simple in vitro assay. cNCCs were cultured for 48 h as emigrants from rhombencephalic neural tubes explanted from rat embryos at day 10.5 of gestation. The chemicals were added to the culture medium at 24 h of culture. Migration of cNCCs was measured as the change in the radius (radius ratio) calculated from the circular spread of cNCCs between 24 and 48 h of culture. Of the chemicals examined, 13-cis-retinoic acid, ethanol, ibuprofen, lead acetate, salicylic acid, and selenate inhibited the migration of cNCCs at their embryotoxic concentrations; no effects were observed for acetaminophen, caffeine, indium, phenytoin, selenite, tributyltin, and valproic acid. In a cNCC proliferation assay, ethanol, ibuprofen, salicylic acid, selenate, and tributyltin inhibited cell proliferation, suggesting the contribution of the reduced cell number to the inhibited migration of cNCCs. It was determined that several developmentally toxic chemicals inhibited the migration of cNCCs, the effects of which were manifested as various craniofacial abnormalities.

The involvement of nitric oxide (NO) signaling in apoptosis was examined in the placental bed of mid-to-late pregnant rats. Pregnant rats were treated with L-NAME, a nitric oxide synthase inhibitor, by subcutaneous infusion for 48 hours before the examination at day 13.5, 17.5, or 21.5. L-NAME induced apoptosis in the placental bed to a limited extent at days 13.5 and 17.5, but not at day 21.5. When the placental bed was examined at day 17.5, the protein expression of both executioner (C-Cas3) and inhibitor (XIAP) of apoptosis was increased by L-NAME, but they did not co-localized with apoptosis. It was presumed that placental bed apoptosis induced by L-NAME is regulated through the expression of both executioner and inhibitor, possibly involving protein S-nitrosylation.

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-Protein expression changes were examined in day 10.5 rat embryos cultured for 24 hr in the presence of valproic acid (VPA), using two-dimensional electrophoresis and mass spectrometry. Exposure to VPA at an embryotoxic concentration of 1.2 mM resulted in quantitative changes in many embryonic protein spots (22 decreased and 29 increased). For the increased protein spots, 10 proteins were identified, including alpha-fetoprotein, phosphorylated cofilin-1, and serum albumin. These proteins are candidate protein biomarkers that may be involved in embryotoxic mechanisms.