Liu_1998_J.Toxicol.Environ.Health_53_531

Organophosphorus pesticides (OPs) exert acute toxicity through inhibition of acetylcholinesterase (AChE) in target tissues. Previous studies in our laboratory have demonstrated, however, that dosages of the OPs chlorpyrifos (CPF) or parathion (PS), which cause similar degrees of brain AChE inhibition in adult male rats, can produce marked differences in toxicity. While compensatory changes in postsynaptic receptors can modulate the clinical expression of AChE inhibition and lead to tolerance to these toxicants, we propose that OP-selective changes in presynaptic cholinergic processes can also regulate the ultimate consequences of AChE inhibition. The relative effects of either vehicle (peanut oil, 2 ml/kg, sc), CPF (280 mg/kg), or PS (6.6 mg/kg) on clinical signs of toxicity and AChE activity, high-affinity choline uptake (HACU), and potassium-evoked acetylcholine (ACh) release in striatum were examined for a 7-d period after exposure in adult female Sprague-Dawley rats. In vitro effects of CPF-oxon or paraoxon, the active oxidative metabolites of CPF and PS, on HACU were also examined in comparison with the prototype inhibitor hemicholinium-3 (HC-3). Similar to our previous findings in male rats, female rats treated with dosages of CPF or PS causing similar maximal degrees of AChE inhibition (82-96%) exhibited marked differences in response; that is, PS produced more extensive signs of acute toxicity (salivation, lacrimation, urination and/or defecation, i.e., SLUD signs and involuntary movements). CPF reduced striatal synaptosomal HACU at 1, 2, and 7 d after exposure, whereas PS only decreased HACU at 2 d posttreatment. While CPF-oxon was a weak inhibitor of HACU (IC50 > 200 microM), paraoxon had no effect on this process in vitro. Potassium-evoked ACh release in the presence of physostigmine (20 microM) was not affected by either OP at 1 d but was increased 2 d after either CPF or PS treatment and remained elevated at 7 d after exposure in CPF-treated rats only. ACh release in the presence of both physostigmine and the muscarinic antagonist atropine (1 microM) was decreased by both OPs as early as 1 d after exposure and remained lower at 2 d posttreatment. By 7 d, however, ACh release in response to atropine was decreased in CPF-treated animals only, suggesting that both CPF and PS affected muscarinic autoreceptor function but with somewhat different time courses. These results suggest that different OPs may selectively modify presynaptic cholinergic processes and that early, OP-selective changes in HACU/ACh synthesis may contribute to the differential toxicity noted following extensive AChE inhibition by either CPF or PS.