Gene Expression and Pathway Analysis in Rat Brain and Liver after Exposure to Royal Demolition Explosive (Hexahydro-1,3,5-trinitro-1,3,5-triazine)

The nitramine explosive, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is associated with acute and chronic toxicity in mammals and targets both the central nervous system and liver. After a single oral dose of RDX in male rats, the systemic distribution of RDX and the toxicodynamic response was measured using clinical chemistry and Affymetrix Rat Genome® 230 2.0 gene expression arrays, respectively. Nominal doses of 0, 9 and 36 mg/kg pure RDX were administered to animals followed by liver, cerebral cortex, and hippocampus gene expression analysis at 0, 3.5, 24, and 48 hours. RDX quickly entered the liver and brain, increasing up to 24 hours. For the 36 mg/kg dose, RDX was still measurable in liver and brain at 48 hours, but was non-detectible for the 9 mg/kg dose. At 3.5 hours, the time within which most convulsions reportedly occur after RDX ingestion, the hippocampus displayed the highest response for both gene expression and pathways, while the cortex was relatively non-responsive. The top 2 impacted pathways, primarily involved in neurotransmission, were the GABAergic and glutamatergic pathways. High numbers of genes also responded to RDX in the liver with P450 metabolism pathways significantly involved. Compared to the liver, the hippocampus displayed more consistent biological effects across dose and time with neurotransmission pathways predominating. Overall, based on gene expression data, RDX responses were high in both the hippocampus and liver, but were minimal in the cerebral cortex. These results identify the hippocampus as an important target for RDX based on gene expression.