microRNA Expression Profile in Different Rat Brain Regions Following Exposure to Soman
Authors: Feng Xiaorong , Gautam Aarti , Kumar Raina , Dimitrov George , Sowe Bintu , Meyerhoff James , Pham Michael , Hammamieh Rasha , Lumley Lucille A , Jett Marti 
Published: November 2023

Soman, or GD (systematic name: O‐pinacolyl methylphosphonofluoridate), is an extremely toxic man‐made chemical substance. It belongs to a class of chemicals known as organophosphorus (OP) nerve agents, which may cause seizures, respiratory failure, and death. GD interferes with normal functioning of the mammalian nervous system by inhibiting the cholinesterase enzyme. Exposure to GD can consequently result in neuropathological abnormalities in various regions of the rat brain. Small microRNAs are (~22 nt) non‐coding RNAs that regulate the expression of target mRNAs at the post‐transcriptional level. Experimental evidence has demonstrated that miRNAs are involved in heterogeneous brain functions including neuro‐inflammation, synaptic remodeling, and neuronal death. The purpose of the current study was to investigate if exposure to soman results in significant molecular changes in different brain tissues on the miRNA level. The experiments were conducted at the U.S. Army Medical Research Institute of Chemical Defense where rats were exposed to either 0.8 LD50 GD or 1.0 LD50 GD versus a saline control group and then evaluated for seizure activity. We carried out miRNA profiling studies in brain tissues (hippocampus, hypothalamus, piriform, thalamus, amygdala and medial prefrontal cortex) collected from rats exposed to GD at 72 hours post‐exposure. Compared to the control group, there were 74 differentially expressed (DE) miRNAs (54 downregulated and 20 upregulated) in the hypothalamus at a dose of 0.8 LD50 of GD exposure. In addition, we found 105 DE miRNAs (62 downregulated and 43 upregulated) in the hypothalamus at a dose of 1.0 LD50 of GD exposure when compared to the control group. We used false discovery rate (FDR) correction for DE miRNAs data and then filtered for experimentally validated miRNAs in ingenuity pathway analysis (IPA). We observed 12 miRNA with 357 gene targets, some of which play roles in neurotransmitter and nervous system signaling pathways. IPA revealed 31 miRNAs passing the experimental validated filter with 591 gene targets. Twenty‐eight miRNAs of these target 101 genes were involved in neurological pathways. Among the pathways targeted by differentially expressed miRNAs are: IL‐8 signaling, axonal guidance signaling, NF‐kB signaling, PTEN signaling and B‐cell receptor signaling. Among top toxicity pathways, aryl‐hydro carbon receptor was highly activated. Changes in miRNAs expression profile of other brain regions were also observed and will be discussed. These data provide important insights into the molecular mechanisms involved in soman‐induced neuropathology and a basis for generating hypotheses about the mechanisms of soman‐induced brain damage. Comprehensive investigations are currently underway to further elucidate the exposure related changes in different tissues of the brain.

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DISCLAIMERS: Research was conducted in compliance with the Animal Welfare Act and all other Federal Requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.