The increased toxicity of UV-degraded nitroguanidine and IMX-101 to zebrafish larvae: Evidence implicating oxidative stress

Gust, Kurt A.; Stanley, Jacob K.; Wilbanks, Mitchell S.; Mayo, Michael L.; Chappell, Pornsawan; Jordan, Shinita M.; Moores, Lee C.; Kennedy, Alan J.; Barker, Natalie D.

doi:10.1016/j.aquatox.2017.07.004

Cited by 24 publications

(20 citation statements)

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“…In agreement with published results, our data also indicated that DNAN and NTO account for the majority of toxicity exerted by IMX-101 with DNAN being more toxic than NTO. Nevertheless, mode-of-action results for the three IM constituents are only now beginning to emerge, e.g., in fish species [24, 25], but a significant knowledge gap remains. In order to fill this knowledge gap, we launched the present toxicogenomics study to investigate the toxicological mechanisms of IM constituents, where we hypothesized that the three chemicals would act independently on different molecular targets and affect different biological pathways in Caenorhabditis elegans .…”

Section: Introductionmentioning

confidence: 99%

Comparative toxicogenomics of three insensitive munitions constituents 2,4-dinitroanisole, nitroguanidine and nitrotriazolone in the soil nematode Caenorhabditis elegans

et al. 2018

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BackgroundEcotoxicological studies on the insensitive munitions formulation IMX-101 and its components 2,4-dinitroanisole (DNAN), nitroguanidine (NQ) and nitrotriazolone (NTO) in various organisms showed that DNAN was the main contributor to the overall toxicity of IMX-101 and suggested that the three compounds acted independently. These results motivated this toxicogenomics study to discern toxicological mechanisms for these compounds at the molecular level.MethodsHere we used the soil nematode Caenorhabditis elegans, a well-characterized genomics model, as the test organism and a species-specific, transcriptome-wide 44 K-oligo probe microarray for gene expression analysis. In addition to the control treatment, C. elegans were exposed for 24 h to 6 concentrations of DNAN (1.95–62.5 ppm) or NQ (83–2667 ppm) or 5 concentrations of NTO (187–3000 ppm) with ten replicates per treatment. The nematodes were transferred to a clean environment after exposure. Reproduction endpoints (egg and larvae counts) were measured at three time points (i.e., 24-, 48- and 72-h). Gene expression profiling was performed immediately after 24-h exposure to each chemical at the lowest, medium and highest concentrations plus the control with four replicates per treatment.ResultsStatistical analyses indicated that chemical treatment did not significantly affect nematode reproduction but did induce 2175, 378, and 118 differentially expressed genes (DEGs) in NQ-, DNAN-, and NTO-treated nematodes, respectively. Bioinformatic analysis indicated that the three compounds shared both DEGs and DEG-mapped Reactome pathways. Gene set enrichment analysis further demonstrated that DNAN and NTO significantly altered 12 and 6 KEGG pathways, separately, with three pathways in common. NTO mainly affected carbohydrate, amino acid and xenobiotics metabolism while DNAN disrupted protein processing, ABC transporters and several signal transduction pathways. NQ-induced DEGs were mapped to a wide variety of metabolism, cell cycle, immune system and extracellular matrix organization pathways.ConclusionDespite the absence of significant effects on apical reproduction endpoints, DNAN, NTO and NQ caused significant alterations in gene expression and pathways at 1.95 ppm, 187 ppm and 83 ppm, respectively. This study provided supporting evidence that the three chemicals may exert independent toxicity by acting on distinct molecular targets and pathways.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0636-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Comparative toxicogenomics of three insensitive munitions constituents 2,4-dinitroanisole, nitroguanidine and nitrotriazolone in the soil nematode Caenorhabditis elegans

et al. 2018

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“…The UV treatment degraded only 3.3% of the MeNQ, indicating that MeNQ degradation products have much higher toxicity than the parent compound. The molecular effects of this exposure to UVtreated MeNQ in larval fathead minnows tended to differ from the molecular responses to UV-treated NQ in zebrafish larvae observed by Gust et al (2017), where oxidative stress mitigation responses were predominant in the transcriptional expression profiles. The results suggest either differences in species responses or differences in toxicological mechanisms between the UV-breakdown products of MeNQ versus NQ.…”

Section: Discussionmentioning

confidence: 65%

“…Moores et al () demonstrated the greatest increase in toxicity yet observed for UV‐degraded NQ, where 90% UV degradation of NQ elicited a 1240‐fold increase in toxicity in Daphnia pulex . Comparatively, the effect of UV‐degraded NQ was perhaps less severe in fish compared with cladocerans, where 69.2% UV degradation of NQ caused a 17‐fold increase in toxicity in larval zebrafish (Gust et al ), whereas 7% UV degradation of NQ elicited an 85‐fold increase in toxicity for D. pulex (Kennedy et al ).…”

Section: Discussionmentioning

confidence: 99%

Comparative Toxicological Evaluation of UV‐Degraded versus Parent‐Insensitive Munition Compound 1‐Methyl‐3‐Nitroguanidine in Fathead Minnow

Lotufo

Gust

Ballentine

et al. 2020

Enviro Toxic and Chemistry

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The US Army is replacing traditional munitions with insensitive munitions resistant to accidental detonation. Although the parent insensitive munition compound nitroguanidine (NQ) is generally not acutely toxic at concentrations >1000 mg/L in aquatic exposures, products formed by intensive ultraviolet (UV) degradation resulted in multiple‐order of magnitude increases in toxicity. A methylated congener of NQ, 1‐methyl‐3‐nitroguanidine (MeNQ), is also being assessed for potential use in insensitive munition explosive formulations; therefore, the present study investigated the hazard of parent versus UV‐degraded MeNQ using fathead minnows (Pimephales promelas). Although up to 716 mg/L parent MeNQ caused no significant mortality or effects on growth in larval P. promelas fish in 7‐d exposures, a similar concentration of MeNQ subjected to UV treatment resulted in 85% mortality. The UV treatment degraded only 3.3% of the MeNQ (5800 mg/L stock, UV‐treated for 6 h), indicating that MeNQ degradation products have potentially high toxicity. The parent MeNQ exposure caused significantly decreased transcriptional expression of genes within the significantly enriched insulin metabolic pathway, suggesting antagonism of bioenergetics pathways, which complements observed, although nonsignificant, decreases in body weight. Significant differential transcriptional expression in the UV‐degraded MeNQ treatments resulted in significant enrichment of pathways and functions related to the cell cycle, as well as erythrocyte function involved in O2/CO2 exchange. These functions represent potential mechanistic sources of increased toxicity observed in the UV‐degraded MeNQ exposures, which are distinct from previously observed mechanisms underlying increased toxicity of UV‐degraded NQ in fish. Environ Toxicol Chem 2020;39:612–622. © 2019 SETAC

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“…For example, nitroguanidine (NQ) is an insensitive munition that has a very similar structure and chemical properties as MeNQ. NQ was found to be relatively harmless to fish and aquatic invertebrates [3], but after photolysis, its toxicity is multiple orders of magnitude higher [3–5]. The LC50 of NQ towards Ceriodaphnia dubia was found to be 1,170 mg/L before photolysis and 0.76 mg/L after extensive photolytic degradation [3].…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Parameters of Insensitive Munition Constituent Methylnitroguanidine (MeNQ) of Importance to Environmental Fate and Transport

George

Jones²,

Alberts

et al. 2021

Propellants Explo Pyrotec

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1‐methyl‐3‐nitroguandine (MeNQ) is being pursued as an insensitive munition to replace legacy munitions such as TNT and RDX. This study was intended to determine the basic physicochemical properties of MeNQ as well as potential environmental fate pathways. The solubility of MeNQ was determined to be 12.92±0.52 g/L and aqueous photolysis was found to efficiently degrade the munition, where its quantum yield and half‐life were found to be 0.009 and 0.59 days, respectively. Hydrolysis was an insignificant degradation pathway resulting in 8.1 % degradation at pH 4, 2.6 % at pH 7, and 6.2 % at pH 9 after five days at an elevated temperature. Volatilization at environmentally relevant conditions was found to be insignificant as the molecule thermally degrades, leading to an inability to calculate Henry's Constant for volatilization from water. Spectroscopic (UV‐vis, FTIR, NMR) and analytical (HPLC) studies were undertaken and are shown alongside the parent molecule, NQ, for comparison to characterize the emerging munition.

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The increased toxicity of UV-degraded nitroguanidine and IMX-101 to zebrafish larvae: Evidence implicating oxidative stress

Cited by 24 publications

References 58 publications

Comparative toxicogenomics of three insensitive munitions constituents 2,4-dinitroanisole, nitroguanidine and nitrotriazolone in the soil nematode Caenorhabditis elegans

Comparative toxicogenomics of three insensitive munitions constituents 2,4-dinitroanisole, nitroguanidine and nitrotriazolone in the soil nematode Caenorhabditis elegans

Comparative Toxicological Evaluation of UV‐Degraded versus Parent‐Insensitive Munition Compound 1‐Methyl‐3‐Nitroguanidine in Fathead Minnow

Physicochemical Parameters of Insensitive Munition Constituent Methylnitroguanidine (MeNQ) of Importance to Environmental Fate and Transport

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