Nicotine evokes cell death in embryonic rat brain during neurulation

Maternal cigarette smoking during pregnancy represents the most prevalent e xposure to a suspected neuroteratogen, nicotine. Although animal models hav e demonstrated brain cell loss and synaptic abnormalities after prenatal ni cotine exposure, the multiple effects of nicotine on the maternal-fetal uni t make it difficult to prove that nicotine itself is a neuroteratogen. In t he current study, whole rat embryo culture was used to study the effects of nicotine at the neural tube stage of development. Beginning on embryonic d ay 9.5, embryos were exposed to 1, 10 or 100 mu M nicotine. After 48 hr, em bryos were examined for dysmorphogenesis and were then processed for light microscopic examination of the neuroepithelium. Examination of the forebrai n, midbrain and hindbrain regions revealed extensive cytotoxicity, evidence d by cytoplasmic vacuolation, enlargement of intercellular spaces and a sha rply increased incidence of pyknotic/apoptotic cells. These alterations wer e evident in the absence of generalized dysmorphogenesis and were detectabl e even at the lowest concentration of nicotine. At the highest concentratio n, abnormalities were present in the majority of cells. Superimposed on cel l damage, we found an increase in mitotic figures. Although enhanced mitosi s could represent partial compensation for cell loss, the regional selectiv ity and concentration dependence of the mitogenic effect differed significa ntly from that of cell death, suggesting separable mechanisms. The present results support the view that nicotine is a neuroteratogen, specifically ta rgeting brain development at concentrations below the threshold for dysmorp hogenesis.