Effects of Diazinon and Diazoxon on Astrocyte-Neuronal Interactions: Inhibition of Neurite Outgrowth by Mechanisms of Oxidative Stress

Abstract

Organophosphorus insecticides (OPs) are among the most widely-used class of insecticides in the world. Concern for the developmental neurotoxic potential of OPs has increased in recent years due to mounting in vitro, in vivo, as well as epidemiological evidence showing adverse developmental effects of these compounds. The purpose of this project was to elucidate the neurotoxic mechanisms of a specific OP, diazinon (DZ), and its oxygen metabolite, diazoxon (DZO). Specifically, this work focuses on the ability for these compounds to adversely affect astrocyte function and impair their ability to foster neurite outgrowth in primary hippocampal neurons. The results demonstrate that both DZ and DZO induce oxidative stress in astrocytes, which subsequently modulates their ability to promote neuronal growth in hippocampal neurons, as well as production and expression of the neuritogenic extracellular matrix protein, fibronectin. Furthermore, the mechanistic in vitro studies revealed that these OPs directly inhibit neurite outgrowth in hippocampal neurons. Interestingly, astrocytes protect against such effects of DZ and DZO on neurite outgrowth by increasing neuronal levels of a vital endogenous antioxidant factor, glutathione (GSH). Depleted of GSH, astrocytes are not able to confer protection to neurons against DZ- and DZO-induced inhibition of neurite outgrowth. Ultimately, this work provides strong evidence for an astrocyte-mediated mechanism of toxicity to these OPs in a developmental neurotoxicity model. These results highlight the importance of astrocytes in supporting neuronal growth and development, and their role in a properly functioning antioxidant defense system in the brain. Thus, the impairment of astrocyte function by DZ and DZO shown here supports the concern for these ubiquitous compounds to adversely affect neurodevelopment, which starts in utero and continues on through adolescence.