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Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) causes seizure activity in larval zebrafish via antagonism of γ-aminobutyric acid type A receptor α1β2γ2.

ABSTRACT: Hexahydro-1,3,5-trinitro-1,3,5-triazine, or Royal Demolition Explosive (RDX), is a major component of plastic explosives such as C-4. Acute exposures from intentional or accidental ingestion are a documented clinical concern, especially among young male U.S. service members in the armed forces. When ingested in large enough quantity, RDX causes tonic-clonic seizures. Previous in silico and in vitro experiments predict that RDX causes seizures by inhibiting α1β2γ2 γ-aminobutyric acid type A (GABA_A) receptor-mediated chloride currents. To determine whether this mechanism translates in vivo, we established a larval zebrafish model of RDX-induced seizures. After a 3 h of exposure to 300 µM RDX, larval zebrafish exhibited a significant increase in motility in comparison to vehicle controls. Researchers blinded to experimental group manually scored a 20-min segment of video starting at 3.5 h post-exposure and found significant seizure behavior that correlated with automated seizure scores. Midazolam (MDZ), an nonselective GABA_AR positive allosteric modulator (PAM), and a combination of Zolpidem (α1 selective PAM) and compound 2-261 (β2/3-selective PAM) were effective in mitigating RDX-triggered behavioral and electrographic seizures. These findings confirm that RDX induces seizure activity via inhibition of the α1β2γ2 GABA_AR and support the use of GABA_AR-targeted anti-seizure drugs for the treatment of RDX-induced seizures.

SUBMITTER: Mundy PC

PROVIDER: S-EPMC10110628 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) causes seizure activity in larval zebrafish via antagonism of γ-aminobutyric acid type A receptor α1β2γ2.

Mundy Paige C PC Werner Alicia A Singh Latika L Singh Vikrant V Mendieta Rosalia R Patullo Caitlyn E CE Wulff Heike H Lein Pamela J PJ

Archives of toxicology 20230313 5

Hexahydro-1,3,5-trinitro-1,3,5-triazine, or Royal Demolition Explosive (RDX), is a major component of plastic explosives such as C-4. Acute exposures from intentional or accidental ingestion are a documented clinical concern, especially among young male U.S. service members in the armed forces. When ingested in large enough quantity, RDX causes tonic-clonic seizures. Previous in silico and in vitro experiments predict that RDX causes seizures by inhibiting α1β2γ2 γ-aminobutyric acid type A (GABA ...[more]

PMID: 36912926

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Project description:UnlabelledKinetic isotopic fractionation of carbon and nitrogen during RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) biodegradation was investigated with pure bacterial cultures under aerobic and anaerobic conditions. Relatively large bulk enrichments in (15)N were observed during biodegradation of RDX via anaerobic ring cleavage (ε(15)N = -12.7‰ ± 0.8‰) and anaerobic nitro reduction (ε(15)N = -9.9‰ ± 0.7‰), in comparison to smaller effects during biodegradation via aerobic denitration (ε(15)N = -2.4‰ ± 0.2‰). (13)C enrichment was negligible during aerobic RDX biodegradation (ε(13)C = -0.8‰ ± 0.5‰) but larger during anaerobic degradation (ε(13)C = -4.0‰ ± 0.8‰), with modest variability among genera. Dual-isotope ε(13)C/ε(15)N analyses indicated that the three biodegradation pathways could be distinguished isotopically from each other and from abiotic degradation mechanisms. Compared to the initial RDX bulk δ(15)N value of +9‰, δ(15)N values of the NO2 (-) released from RDX ranged from -7‰ to +2‰ during aerobic biodegradation and from -42‰ to -24‰ during anaerobic biodegradation. Numerical reaction models indicated that N isotope effects of NO2 (-) production were much larger than, but systematically related to, the bulk RDX N isotope effects with different bacteria. Apparent intrinsic ε(15)N-NO2 (-) values were consistent with an initial denitration pathway in the aerobic experiments and more complex processes of NO2 (-) formation associated with anaerobic ring cleavage. These results indicate the potential for isotopic analysis of residual RDX for the differentiation of degradation pathways and indicate that further efforts to examine the isotopic composition of potential RDX degradation products (e.g., NOx) in the environment are warranted.ImportanceThis work provides the first systematic evaluation of the isotopic fractionation of carbon and nitrogen in the organic explosive RDX during degradation by different pathways. It also provides data on the isotopic effects observed in the nitrite produced during RDX biodegradation. Both of these results could lead to better understanding of the fate of RDX in the environment and help improve monitoring and remediation technologies.

Project description:Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a typical representative of energetic materials, is widely applied in military and industrial fields with its high energy density and excellent detonation performances. However, when used as a raw material for propellants and rocket propellants, RDX poses certain safety concerns due to its high sensitivity to external stimuli such as electrostatic discharge, impact, and friction, which limits its further application. Herein, to reduce the RDX electrostatic spark and mechanical sensitivities and improve safety performances, a conductive polymer of poly(3,4-ethylene-dioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) was introduced into the energetic material system based on a simple suction filtration method. RDX-based energetic composites with varying PEDOT:PSS mass fractions were prepared by both micron-sized RDX and nanosized RDX. The RDX-based energetic composites were characterized, and their response characteristics and performances were tested and compared. The results demonstrated that the conductive interfaces constructed by PEDOT:PSS on the RDX surface significantly reduced the electrostatic spark and mechanical sensitivity. The electrostatic spark sensitivity of μ-RDX-based energetic composites decreased by 40%, while the impact sensitivity and friction sensitivity decreased by 76.47% and 50%, respectively. Compared to micron-sized RDX-based energetic composites, the nano-sized RDX-based energetic composites desensitization effect on electrostatic spark sensitivity was more pronounced. For n-RDX-based energetic composites, the electrostatic spark sensitivity decreased by 66.4%. Furthermore, the assembly and desensitization mechanism of the RDX-based energetic composites were thoroughly investigated. This study not only provides a simple and reliable assembly method for the safe application of RDX but also offers corresponding data and experimental support for future research, which is of significant importance for the application of energetic materials.

Dataset Information

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) causes seizure activity in larval zebrafish via antagonism of γ-aminobutyric acid type A receptor α1β2γ2.

Publications

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) causes seizure activity in larval zebrafish via antagonism of γ-aminobutyric acid type A receptor α1β2γ2.

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