Regulation of high affinity choline uptake and its influence on age-related differences in sensitivity to organophosphorus insecticides

Scope and method of study. The purpose of this study was to examine the effects of two commonly used organophosphorus (OP) insecticides, parathion (PS) and chlorpyrifos (CPF), on high affinity choline uptake (NACU) and how these effects may contribute to differences in age-related sensitivity following exposure to these agents. PS and CPF elicit toxicity primarily through inhibition of acetylcholinesterase (AChE), resulting in accumulation of the neurotransmitter acetylcholine (ACh) in the synapse and consequent cholinergic toxicity (e.g. autonomic dysfunction and excess involuntary movements). AChE inhibition and changes in HACU in the cortex and striatum of neonatal, juvenile and adult rats (n = 8–15/treatment group) were evaluated at 4, 24 or 96 hr after oral exposure to acute high doses of parathion or chlorpyrifos.; Findings and conclusions. LD₁₀ dosages of PS and CPF elicited similar levels of peak AChE inhibition; however, time to peak inhibition and degree of recovery from inhibition varied greatly with age. HACU was increased in a time-dependent manner after treatment with PS, with maximal increases occurring 4 hours after exposure in neonatal striatum (52%) and minimal increases in juvenile cortex (19%) and striatum (23%), compared to moderate increases in adult cortex (41%) and striatum (36%) 96 hours after treatment. In contrast, HACU was reduced in a time-dependent manner by exposure to CPF, i.e., uptake was maximally reduced (43%) in neonates at 4 hr, moderately reduced (22%) in juveniles at 24 hr and least affected (18% reduction) in adults at 96 hr. The time-dependent increases in HACU after PS exposure may contribute to the greater sensitivity of younger rats to acute high-dose exposures. Alternatively, the early reduction in HACU following high-dose exposure to CPF could potentially modulate the toxic effects of AChE inhibition by limiting the amount of ACh released into the synapse. Changes in HACU may therefore differentially contribute to age-related neurotoxicity following AChE inhibition with these two OP insecticides.