Percellome toxicogenomics project: newly designed repeated dose study

Abstract

Chlorpyrifos (CPF) is an organophosphate insecticide reported to induce, both after acute and repeated exposure, learning and memory dysfunctions, although the mechanism is not completely known. CPF produces basal forebrain cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. This effect was reported to be induced through apoptotic process, partially mediated by AChE overexpression, although neuronal necrosis was also described after CPF exposure. Accordingly, we hypothesized that CPF induces apoptotic and necrotic basal forebrain cholinergic cell death. We evaluated, in septal SN56 basal forebrain cholinergic neurons, the CPF effect after 24 h and 14 days exposure on apoptosis and necrosis induction and the apoptotic and necrotic gene expression pathways. This study shows that CPF induces, after acute and long-term exposure, apoptosis and necrosis, partially mediated through AChE overexpression. Evaluation of cell death pathways supports the necrosis and apoptosis data and revealed that some genes are altered at lower concentrations than those at which the effects observed are produce and below the No Observed Adverse Effect Level (NOAEL). The present finding suggests that the use of gene expression profile could be a more sensitive and accurate way to determine the CPF's NOAEL.