CHLORPYRIFOS ELICITS MITOTIC ABNORMALITIES AND APOPTOSIS IN NEUROEPITHELIUM OF CULTURED RAT EMBRYOS

Chlorpyrifos is used increasingly as a pesticide in place of more toxi c alternatives such as parathion, Although chlorpyrifos is not a poten t dysmorphogen, recent reports that fetal or infant exposures may exce ed acceptable limits have raised concern about the potentially move su btle effects on brain development. In the current study, whole rat emb ryo culture was used to study the effects of chlorpyrifos at the neura l tube stage of development. On embryonic day 9.5, embryos were expose d to 0.5, 5, or 50 mu g/ml of chlorpyrifos. After 48 hr (embryonic day 11.5), embryos were examined for dysmorphogenesis and were then proce ssed for light microscopic examination of the neuroepithelium. Examina tion of 1-mu m-thick toluidine blue-stained sections of the forebrain and hindbrain region revealed reduced and altered mitotic figures, wit h dispersion and disorientation of the mitotic layer. In addition, cyt otoxicity was evidenced by cytoplasmic vacuolation, enlargement of int ercellular spaces, and the presence of a significant number of apoptot ic cells. These alterations were evident even at the lowest concentrat ion of chlorpyrifos, which produced no dysmorphogenesis. The effects w ere intensified at higher concentrations, which were just at the thres hold for dysmorphogenesis; the neuroepithelial abnormalities, however, were still present in embryos that weve not dysmorphogenic. Our resul ts in vat embryo culture support the idea that chlorpyrifos specifical ly targets brain development at low concentrations, indicating the nee d to reevaluate the safety of this compound for exposure in vivo. Tera tology 58:62-68, 1998. (C) 1998 Wiley-Liss, Inc.