Ameliorating the Developmental Neurotoxicity of Chlorpyrifos: A Mechanisms-Based Approach in PC12 Cells

Abstract

BackgroundOrganophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation.ObjectivesWe evaluated mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons.ResultsIn undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication.ConclusionsOur results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects.

Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic synaptic function and cognition

“…Indeed, we previously found that nicotine can protect neuronotypic cells in culture from the direct antimitotic and oxidative effects of chlorpyrifos (Qiao et al, 2003, 2005; Slotkin et al, 2007a). Nevertheless, using the same in vivo treatment model as in the present study, we found that prolonged prenatal nicotine exposure actually worsened the impact of chlorpyrifos on the development of cholinergic synaptic function (Slotkin and Seidler, 2015), reflecting the fact that nicotine itself is a developmental neurotoxicant (Slotkin, 2008).…”

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

“…In this series of experiments, mecamylamine and atropine (nicotinic and muscarinic acetylcholine receptor antagonists, respectively) were coincubated with CPF and CPO, and the effects on axonal transport and mitochondrial dynamics were assessed. The concentrations of mecamylamine and atropine were based on previously published neuronal culture studies (Heppner and Fiekers, 1992;Slotkin et al, 2007;Ueda et al, 2008).…”

Alleviating effects of melatonin on oxidative changes in the testes and pituitary glands evoked by subacute chlorpyrifos administration in Wistar rats

“…However, toxicity has been reported at doses that do not inhibit AChE [14,15] . Therefore, other mechanisms including the induction of oxidative stress have been implicated in CPF-induced toxicity [16][17][18][19][20][21][22][23] .…”