DEVELOPMENTAL NEUROTOXICITY OF CHLORPYRIFOS - CELLULAR MECHANISMS

Chlorpyrifos, one of the most widely used pesticides, exhibits greater toxicity during development than in adulthood. We administered chlorp yrifos to neonatal rats in apparently subtoxic doses that caused no mo rtality and little or no weight deficits and examined developing brain regions (cerebellum, forebrain, brainstem) for signs of interference with cell development. One-day-old rats given 2 mg/kg sc of chlorpyrif os showed significant inhibition of DNA synthesis in all brain regions within 4 hr of treatment; equivalent results were obtained when a sma ll dose (0.6 mu g) was introduced directly into the brain via intracis ternal injection, indicating that the actions were not secondary to sy stemic toxicity, Inhibition of DNA synthesis was also seen at 8 days o f age; however, at this point, there was regional selectivity, with sp aring of the cerebellum. Between 1 and 8 days of age, brain regions de velop wide disparities in cholinergic innervation; accordingly, we tes ted whether the effect of chlorpyrifos was mediated through cholinergi c actions on nicotinic receptors known to mediate inhibition of DNA sy nthesis. Pretreatment with mecamylamine caused a decline in DNA synthe sis by itself, but nevertheless prevented the effect of chlorpyrifos. Additionally, chlorpyrifos administration at 1 day of age caused an ev en larger inhibition of protein synthesis throughout the brain; the ef fect was distinct from that on DNA synthesis, as it diminished substan tially by 8 days of age and did not develop any regional selectivity. The effects of chlorpyrifos on DNA and protein synthesis were not seco ndary to generalized cell damage or suppression of cell metabolism, as evidenced by maintenance of normal ornithine decarboxylase activities . These results indicate that low doses of chlorpyrifos target the dev eloping brain during the critical period in which cell division is occ urring, effects which may produce eventual cellular, synaptic, and beh avioral aberrations after repeated or prolonged subtoxic exposures. (C ) 1995 Academic Press, Inc.