Maternal cigarette smoking during pregnancy represents the most prevalent exposure to a suspected neuroteratogen, nicotine. Although animal models have demonstrated brain cell loss and synaptic abnormalities after prenatal nicotine exposure, the multiple effects of nicotine on the maternal-fetal unit make it difficult to prove that nicotine itself is a neuroteratogen. In the current study, whole rat embryo culture was used to study the effects of nicotine at the neural tube stage of development. Beginning on embryonic day 9.5, embryos were exposed to 1, 10 or 100 microM nicotine. After 48 hr, embryos were examined for dysmorphogenesis and were then processed for light microscopic examination of the neuroepithelium. Examination of the forebrain, midbrain and hindbrain regions revealed extensive cytotoxicity, evidenced by cytoplasmic vacuolation, enlargement of intercellular spaces and a sharply increased incidence of pyknotic/apoptotic cells. These alterations were evident in the absence of generalized dysmorphogenesis and were detectable even at the lowest concentration of nicotine. At the highest concentration, abnormalities were present in the majority of cells. Superimposed on cell damage, we found an increase in mitotic figures. Although enhanced mitosis could represent partial compensation for cell loss, the regional selectivity and concentration dependence of the mitogenic effect differed significantly from that of cell death, suggesting separable mechanisms. The present results support the view that nicotine is a neuroteratogen, specifically targeting brain development at concentrations below the threshold for dysmorphogenesis.