Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

Abstract

Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF), were investigated. Rats were injected with CPF s.c. (dose range, 2.5-18.0 mg/kg) every other day over the course of 30 days and then were given a 2-week CPF-free washout period. In behavioral experiments conducted during the washout period, dosedependent decrements in a water-maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open-field activity, Rotorod performance, grip strength, or a spontaneous novel object recognition task.After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol were minimal in plasma and brain; however, cholinesterase inhibition was still detectable. Furthermore, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high-affinity choline transporter, and the ␣ 7 -nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

“…In turn, the fact that the two agents diverge in important ways reinforces the fact that the developmental neurotoxicity does not depend solely on the shared property of cholinesterase inhibition but rather reflects critical contributions of other mechanisms such as effects on neurotrophic factors [77,79]. Indeed, recent studies reinforce the separation of the effects observed here from those that depend on anticholinesterase effects: chronic, intermittent chlorpyrifos exposures in adults that are nonsymptomatic but well above the threshold for cholinesterase inhibition produce cognitive impairment in association with deficits in ntrk1, a subtype that was unaffected in our studies with lower exposures in the developing rat brain [90].…”

Effects of Chlorpyrifos and Chlorpyrifos-Oxon on the Dynamics and Movement of Mitochondria in Rat Cortical Neurons

“…The results indicated that ⌬⌿m and ATP production in CPF-and CPO-treated neurons were not altered significantly at physiologically relevant concentrations, (i.e., for subthreshold dosing, see Terry et al, 2007), suggesting that direct mitochondrial toxicity or impairments in the ability of mitochondria to generate ATP were not likely to be responsible for the OP-related effects on mitochondrial Red images on the right (emission peak 590 nm) indicate the accumulation and aggregation of the reagent in healthy mitochondria (i.e., with an intact ⌬⌿m). Thus, 20 M CPF and CPO were not associated with a compromise in ⌬⌿m, whereas the lack of red labeling in the cells exposed to 500 M CPF or CPO indicates a compromise of the mitochondrial ⌬⌿m.…”

Mass spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin: A potential mechanism of long term toxicity by organophosphorus agents

“…However, low dose exposure that causes minimal inhibition of AChE and no obvious cholinergic symptoms has been linked to memory loss, sleep disorder, depression, learning and language impairment, and decreased motor skills in humans [2][3][4]. Rats treated with low doses of chlorpyrifos have behavioral deficits in a water-maze hidden platform task and in prepulse inhibition [5]. The mechanism to explain cognitive deficits from low dose exposure is thought to be inhibition of fast axonal transport [5].…”

“…Rats treated with low doses of chlorpyrifos have behavioral deficits in a water-maze hidden platform task and in prepulse inhibition [5]. The mechanism to explain cognitive deficits from low dose exposure is thought to be inhibition of fast axonal transport [5]. Axonal transport was impaired in sciatic nerves isolated from chlorpyrifos treated rats [5,6].…”

“…The mechanism to explain cognitive deficits from low dose exposure is thought to be inhibition of fast axonal transport [5]. Axonal transport was impaired in sciatic nerves isolated from chlorpyrifos treated rats [5,6]. Transport of nutrients to nerve endings is accomplished via microtubules that serve as the highway on which kinesin molecules carry their cargo [7].…”