Developmental neurotoxicity of chlorpyrifos modeled in vitro: Comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesisin PC12 and C6 cells

The widely used organophosphate pesticide chlorpyrifos is a suspected neuro teratogen. In the current study, we compared the effects of chlorpyrifos an d its major metabolites in two in vitro models, neuronotypic PC12 cells and gliotypic C6 cells. Chlorpyrifos inhibited DNA synthesis in both cell line s but had a greater effect on gliotypic cells. Chlorpyrifos oxon, the activ e metabolite that inhibits cholinesterase, also decreased DNA synthesis in PC12 and C6 cells with a preferential effect on the latter. Trichloropyridi nol, the major catabolic product of chlorpyrifos, had a much smaller, but n evertheless statistically significant, effect that was equivalent in both c ell lines. Diazinon, another organophosphate pesticide, also inhibited DNA synthesis with preference toward C6 cells, but was less effective than was chlorpyrifos. Physostigmine, a non-organophosphate cholinesterase inhibitor , was less effective than either chlorpyrifos or diazinon, but still caused significant inhibition of DNA synthesis in C6 cells. We also found that th e addition of sera protected the cells from the adverse effects of chlorpyr ifos and that the effect could be reproduced by addition of albumin. These results indicate that chlorpyrifos and other organophosphates such as diazi non have immediate, direct effects on neural cell replication, preferential ly for gliotypic cells. In light of the protective effect of serum proteins , the fact that the fetus and newborn possess lower concentrations of these proteins suggests that greater neurotoxic effects may occur at blood level s of chlorpyrifos that are nontomc to adults.