RDX Binds to the GABA _A Receptor–Convulsant Site and Blocks GABA _A Receptor–Mediated Currents in the Amygdala: A Mechanism for RDX-Induced Seizures

Abstract

BackgroundHexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown.ObjectiveWe investigated the mechanism by which RDX induces seizures.Methods and resultsBy screening the affinity of RDX for a number of neurotransmitter receptors, we found that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric acid type A (GABAA) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of spontaneous GABAA receptor–mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents. In extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges.ConclusionsThese results suggest that binding to the GABAA receptor convulsant site is the primary mechanism of seizure induction by RDX and that reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism of RDX action with respect to seizure induction can guide therapeutic strategies, allow more accurate development of safe thresholds for exposures, and help prevent the development of new explosives or other munitions that could pose similar health risks.

Biochemical and Microbial Analysis of Ovine Rumen Fluid Incubated with 1,3,5-Trinitro-1,3,5-triazacyclohexane (RDX)

“…Structurally, RDX is unabsorbed in the soil making it easy for its transportation into ground water aquifers [29,44]. The present US Environmental Protection Agency (EPA) guideline for RDX quantity in drinking water is set at 2 ppm, but actual data suggest RDX prevalence as high as 36 ppm in the United States [2].…”

Conserved toxic responses across divergent phylogenetic lineages: a meta-analysis of the neurotoxic effects of RDX among multiple species using toxicogenomics

“…Impacts on the nervous system have been observed in a variety of species exposed to RDX including humans, dogs, rats, birds and earthworms (Goldberg et al 1992;Talmage et al 1999;Gong et al 2008;Gust et al 2009). Williams et al (2011) recently demonstrated that the molecular initiating event for neurotoxicity is binding of RDX to the GABA A (c-aminobutyric acid) receptor (GABA A R) where it blocks membrane repolarization.…”

“…For example, mechanisms for cell-to-cell communication in pre-metazoan cells also serve as the molecular foundation for the most complex communications network in multicellular organisms, the nervous system (Tsang et al 2007). Given the known impacts of RDX exposure on nervous system processes, investigation of the molecular functions affected by RDX exposure, including GABAergic signaling (Williams et al 2011), constitute a key focus for understanding the impacts of RDX across disparate phylogenetic lineages. GABA receptors have been described in many different phyla such as social amoeba (Dictyostelium discodeum), cnidarians, mollusks, annelids, arthropods, nematodes, and chordates (Kass- Simon and Pierobon 2007;Tsang et al 2007; Kehoe et al 2009;Fountain 2010).…”

Molasses enhanced phyto and bioremediation treatability study of explosives contaminated Hawaiian soils

“…These particles dissolve over an extended period of time and this is the primary mechanism for the transport and dissemination of energetics throughout the environment [6]. EPA (1998) [7] classifies RDX as a possible human carcinogen class C and may cause generalized seizures [8]. HMX may be harmful to the central nervous system [9].…”