Proinflammatory cytokines, oxidative stress, and organ function as biomarkers of soman (GD) chronic neurotoxicity

Abstract

Organophosphate (OP) nerve agents, such as soman (GD), pose great risk to neurological health by inhibiting acetylcholinesterase, leading to seizures, epilepsy, and behavioral deficits. While acute treatment may alleviate immediate symptoms, the long-term consequences, particularly those involving neuroinflammation and systemic toxicity, remain poorly understood. This study used adult male and female Sprague Dawley rats to investigate the chronic effects of a single acute exposure to soman (132 µg/kg, s.c., 1.2 × LD50) on neuroinflammation, behavioral comorbidity, and systemic toxicity. Following exposure, animals were treated with atropine sulfate (2 mg/kg, i.m.) and oxime HI-6 (125 mg/kg, i.m.) to mitigate peripheral cholinergic effects, and with midazolam (3 mg/kg, i.m., 1 h post-exposure) to control seizures. Spontaneously recurring seizures were monitored during handling and with video electroencephalogram (vEEG). Neurobehavioral deficits were assessed 4–8 weeks post-exposure. At 18 weeks post-exposure, brain, serum, and cerebrospinal fluid (CSF) were analyzed for inflammatory and nitro-oxidative stress markers, and the liver and kidney function biomarkers were evaluated. Soman-exposed animals developed epilepsy, confirmed by handling-induced seizures and/or continuous vEEG monitoring. Behavioral assessments revealed significant memory deficits following soman exposure. Proinflammatory cytokines (TNF-α, IL-6, IL-1α, IL-18, IL-17A, and MCP-1) were significantly elevated in both serum and CSF, alongside corresponding increases in their gene expression in the brain. Elevated reactive oxygen/nitrogen species were detected in the serum. Although hematological parameters remained unchanged, a significant increase in total bilirubin and an upward trend in serum blood urea nitrogen (BUN) levels and BUN: Creatinine ratio indicated potential liver and kidney dysfunction. However, no significant structural changes in these organs at the cellular level were observed in histological analyses. This study identifies critical chronic biomarkers of soman exposure affecting the brain, serum, CSF, liver, and kidney. The findings highlight the critical need to monitor systemic and neurological impacts, as well as organ function, to develop effective diagnostic and therapeutic strategies for survivors of nerve agent exposure or OP pesticide poisoning. Behavioral deficits and EEG changes in soman-exposed animals further emphasize the long-term neurological consequences of exposure.