Mechanisms of Organophosphorus (OP) Injury: Sarin-Induced Hippocampal Gene Expression Changes and Pathway Perturbation.

摘要

This project aimed to investigate the molecular mechanism(s) of organ injury following exposure to sublethal doses of the organophosphorus agent, sarin. The lethal toxic effect of sarin exposure is caused by irreversible inhibition of acetylcholinesterase (AChE) and subsequently excessive stimulation of postsynaptic cholinergic receptors. However, much less is known about the effects of low-dose sarin exposure on functions of critical brain regions. Neurotoxicity caused by sarin exposure can be mediated by pathways independent of the cholinergic system. Since the hippocampus plays an important role in cognitive functions (including learning and memory), and is one of the most sensitive brain regions to sarin-induced injury, the focus of this study is to investigate differential gene expression and pathway perturbation in this brain region, using microarray technology combined with advanced bioinformatics. Sarin treatment resulted in differential expression of a large number of genes. Most of these genes showed increased expression, especially at the 6-hour and 25-day time points. However, significant gene repression was observed at the 10-day time point. Pathway analysis revealed that one of the direct effects of sarin cellular toxicity could be related to DNA damage and inhibition of the glutathione antioxidant system, which triggered the up-regulation of the apoptotic pathways at early time points.