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

Abstract

Organophosphate (OP)-based pesticides have been used extensively for decades, and as a result, they have become almost ubiquitous in our environment. There is clinical and animal evidence to suggest that chronic exposures to OPs can lead to cognitive dysfunction and other neurological abnormalities, although the mechanism for these effects is unknown. We previously reported that repeated, subthreshold exposures (defined as doses not associated with signs of acute toxicity) to the commonly used OP chlorpyrifos (CPF) resulted in protracted impairments in the performance of attention and memory-related tasks in rodents as well as deficits in axonal transport ex vivo (in the sciatic nerve). Here, we investigated the effects of CPF and its active metabolite CPF oxon (CPO) on the dynamics and movement of mitochondria in rat primary cortical neurons using time-lapse imaging techniques. Exposure to CPF (1.0 -20.0 M) or CPO (5.0 nM-20.0 M) for 1 or 24 h resulted in a concentration-dependent increase in mitochondrial length, a decrease in mitochondrial number (indicative of increased fusion events), and a decrease in their movement in axons. The changes occurred at concentrations of CPF and CPO that did not inhibit acetylcholinesterase activity (the commonly cited mechanism of acute OP toxicity), and they were not blocked by cholinergic receptor antagonists. Furthermore, the changes did not seem to be associated with direct (OP-related) effects on mitochondrial viability or function (i.e., mitochondrial membrane potential or ATP production). The results suggest that an underlying mechanism of organophosphate-based deficits in cognitive function might involve alterations in mitochondrial dynamics and/or their transport in axons.

The association between ambient exposure to organophosphates and Parkinson's disease risk

“…Monocrotophos have also been shown to induce apoptosis in neurons and inhibit metabolism 34. Chlorpyrifos and chlorpyrifos-oxon exposure resulted in increased mitochondrial length, decreased number of mitochondria and decreased mitochondria movement in axon at concentrations that did not inhibit AChE 36. Taken together, the evidence that OPs cause cell death specifically mediated through the disruption of mitochondrial functioning is not adequate and our results suggest that while a large number of OPs increased PD risk the mechanisms of action remain to be explored.…”

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

“…Since, there are limited data about the hepatotoxicity of OPs in humans, it is not certain whether changes in biochemical parameters indicate actual liver damage. (90)(91)(92)(93)(94), energy production (93,(95)(96)(97), and cell death (98)(99)(100). Several studies have found an association between mitochondrial dynamics and malathion-induced drop in mitochondrial ATP synthesis in rat liver (9) or quinalphos and acephate effects on liver succinic dehydrogenase (84,85,101) and ATPase activities (87) -all of them the key enzymes for oxidative phosphorylation.…”

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

“…Specifically, cortical neurons were coincubated (for 24 hours) with either atropine (50 mM) or mecamylamine (10 mM) and a representative concentration of DFP shown to impair axonal transport (10 nM) in the first set of experiments (see Results). The representative concentrations of atropine or mecamylamine were based on previous in vitro studies (Middlemore-Risher et al, 2011).…”