Comprehensive Biomarkers of Soman (GD)-induced Chronic Toxicity: Proinflammatory Cytokines, Oxidative Stress, and Organ Function Parameters

Background: Organophosphate (OP) nerve agents, such as Soman (GD), pose a serious risk to neurological health due to their ability to inhibit acetylcholinesterase, which can result in seizures, epilepsy, and behavioral deficits. Despite acute treatments, the long-term consequences of exposure to OP agents, particularly neuroinflammation and systemic toxicity, remain inadequately understood. Methods: This study used a Sprague dawley rat model to investigate the long-term effects of acute soman exposure (132 µg/kg, s.c) on neuroinflammation and systemic toxicity. Following exposure, animals were treated immediately with atropine sulfate (2 mg/kg, i.m) and oxime HI-6 (125 mg/kg, i.m) to control peripheral effects, and behavioral seizures were managed with midazolam (3 mg/kg, i.m) one hour later. The development of epilepsy was monitored through handling-induced seizures and EEG. At 18 weeks post-exposure, brain, serum, and cerebrospinal fluid (CSF) were collected under terminal anesthesia to assess neuroinflammatory markers and proinflammatory cytokines' gene expression in the brain, as well as cytokine protein levels in serum and CSF. Results: All soman-exposed animals developed epilepsy, as confirmed by handling-induced seizures or EEG. Significant elevations of proinflammatory cytokines (TNF-α, IL-6, IL-1α, IL-18, IL-17A, and MCP1) were found in both serum and CSF, and corresponding gene expression increases were observed in the brain. Reactive nitrogen species (RNS) and reactive oxygen species (ROS) were significantly elevated in the serum of soman-exposed animals, though other blood biochemical parameters were similar to age-matched controls. No hematological changes were observed, indicating the inflammatory response originated in the brain. Elevated serum bilirubin and BUN levels indicated potential liver and kidney dysfunction, although no significant structural changes were detected in these organs. Conclusions: This study identified key biomarkers of the chronic effects of soman exposure on the brain, blood, CSF, liver, and kidney. The findings suggest that monitoring liver and kidney function is crucial for survivors of nerve agent exposure or OP pesticide exposure suicides, and the identified biomarkers may assist in developing diagnostic and therapeutic strategies to mitigate long-term public health impacts.