Organophosphorus (OP) insecticides are heavily employed in agricultural and residential uses, and have ample opportunity to expose infants and children from food and houses during critical times of their nervous system development. The mechanism of toxicity, inhibition of acetylcholinesterase (AChE), causes hyperactivity in cholinergic pathways, which can elicit compensatory neurochemical mechanisms to modulate the enhanced activity. AChE inhibition is considerably more persistent for the diethyl OP compounds than for the dimethyl OP compounds, leading to greater fluctuations in AChE activity following exposure to a dimethyl insecticide, such as methyl parathion, than to a diethyl insecticide, such as chlorpyrifos. Our preliminary results in rats have indicated more persistent whole brain muscarinic acetylcholine receptor (mAChR) decreases following early postnatal exposures to chlorpyrifos than to methyl parathion. Developmental exposures to OP insecticides cause behavioral deficits. Our preliminary results have indicated decreases in open field activity occurring only after, not during, chlorpyrifos exposures, suggesting possible permanent behavioral deficits from developmental exposures. The biochemical lesion occurs in both the central and peripheral nervous systems because of the distribution of AChE in both, so both central and peripheral effects could contribute to behavioral deficits. The possibility of permanent behavioral defects from the extended neurochemical alterations following AChE inhibition of diethyl OP insecticides has generated the following hypothesis for this project: Neurochemical aberrations and behavioral deficits will be more severe and long lasting from the more persistent phosphorylation of a diethyl OP insecticide (chlorpyrifos) during development than from a dimethyl OP insecticide (methyl parathion). The cholinergic parameters to be studied include: AChE, mAChR (total and surface), choline acetyltransferase, high affinity choline uptake, and adenylyl cyclase in brain regions, and AChE in peripheral tissues. The behavioral parameters to be studied include: developmental markers, surface righting, negative geotaxis, free-fall righting, locomotor activity, rotarod performance, grip strength, and memory and learning in two types of water mazes. The results will indicate whether certain OP insecticide chemistries elicit greater harm to the developing nervous system and whether children are likely to suffer from permanent harm to behavior, including cognition, from developmental exposures to OP insecticides.
