Chemical Warfare Nerve Agent-Induced Effects on Gene Expression in Human Neuron and Astrocyte Cultures
Abstract
Acute exposure to organophosphorus nerve agents such as soman and VX cause neuronal degeneration, astrocytic activation and cell death in specific brain regions. Although in vivo neuronal cell death is readily observed after agent exposure, cell death has been difficult to observe in cultured neurons. Reports of VX-exposed primary rat neuron cultures indicate attenuation of cell death by N-methyl-D-aspartate receptor antagonism, but not by acetylcholinesterase activity protection or muscarinic receptor antagonism. To further investigate direct molecular effects, we examined gene expression changes induced by nerve agent exposure in primary cultures of human neurons and astrocytes. Cultured human astrocytes and neurons were exposed to soman or VX and harvested 24 h later for RNA isolation and microarray processing. Principal component analysis indicated neuronal gene expression changes in response to soman, but not VX exposure. Neuronal genes differentially expressed in response to soman exposure mapped to canonical pathways containing inflammatory molecules. Functional analysis of the soman-exposed neuronal dataset identified neurological disease and inflammatory response. In addition, gene networks associated with significant neurological disease function and inflammatory response demonstrate overlapping involvement of several transcripts, including TNFRSF1A and IL1R1. These data suggest a non-cholinergic effect of soman that induces transcriptional expression of inflammatory molecules.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2020
- Accession Number
- AD1091958
Entities
People
- Cristin Rothwell
- Heidi M. Hoard-fruchey
- James F. Dillman
- Robert K. Kan