Transcriptomics provides mechanistic indicators of mixture toxicology for IMX-101 and IMX-104 formulations in fathead minnows (Pimephales promelas)

Gust, Kurt A.; Lotufo, Guilherme R.; Stanley, Jacob K.; Wilbanks, Mitchell S.; Chappell, Pornsawan; Barker, Natalie D.

doi:10.1016/j.aquatox.2018.03.019

Cited by 18 publications

(11 citation statements)

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“…Other data from ongoing investigations in our laboratory suggest that DNAN, NTO and NQ elicited independent toxicity to test organisms including fathead minnow larvae [24], the fresh-water amphipod Hyallela azteca (Lotufo et al Unpublished data) and the earthworm Eisenia fetida (Gong et al Unpublished data). 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.…”

Section: Introductionmentioning

confidence: 99%

“…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%

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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%

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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“…• fish-e.g., P. promelas (Saari et al 2017;Gust et al 2018); Rainbow Trout (Oncorhynchus mykiss, Berthelot et al 2014) • invertebrates-e.g., Daphnia spp. (Colbourne et al 2005;Orsini et al 2016), Hyalella azteca (Christie et al 2018;Poynton et al 2018), Chironomus spp.…”

Section: 'Omic Tools and Data Sets Of Direct Relevance To The Bay−deltamentioning

confidence: 99%

Review of and Recommendations for Monitoring Contaminants and their Effects in the San Francisco Bay−Delta

Connon

Hasenbein

Brander

et al. 2019

SFEWS

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Legacy and current-use contaminants enter into and accumulate throughout the San Francisco Bay−Delta (Bay−Delta), and are present at concentrations with known effects on species important to this diverse watershed. There remains major uncertainty and a lack of focused research able to address and provide understanding of effects across multiple biological scales, despite previous and ongoing emphasis on the need for it. These needs are challenging specifically because of the established regulatory programs that often monitor on a chemical-by-chemical basis, or in which decisions are grounded in lethality-based endpoints. To best address issues of contaminants in the Bay−Delta, monitoring efforts should consider effects of environmentally relevant mixtures and sub-lethal impacts that can affect ecosystem health. These efforts need to consider the complex environment in the Bay−Delta including variable abiotic (e.g., temperature, salinity) and biotic (e.g., pathogens) factors. This calls for controlled and focused research, and the development of a multi-disciplinary contaminant monitoring and assessment program that provides information across biological scales. Information gained in this manner will contribute toward evaluating parameters that could alleviate ecologically detrimental outcomes. This review is a result of a Special Symposium convened at the University of California−Davis (UCD) on January 31, 2017 to address critical information needed on how contaminants affect the Bay−Delta. The UCD Symposium focused on new tools and approaches for assessing multiple stressor effects to freshwater and estuarine systems. Our approach is similar to the recently proposed framework laid out by the U.S. Environmental Protection Agency (USEPA) that uses weight of evidence to scale toxicological responses to chemical contaminants in a laboratory, and to guide the conservation of priority species and habitats. As such, we also aimed to recommend multiple endpoints that could be used to promote a multi-disciplinary understanding of contaminant risks in Bay−Delta while supporting management needs.

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“…Among the chemicals suitable for use as constituents in IM formulations, 1-methyl-3nitroguanidine (MeNQ) (Aubert and Roos 2014;Reinke 2016) has had relatively little characterization of potential health and ecotoxicological hazard. While the ecotoxicity of dinitroanisole (DNAN), nitroguanidine (NQ), and nitrotriazolone (NTO), the components of IMX-101, a principal TNT replacement, has been widely investigated (Lent et al 2015(Lent et al , 2016(Lent et al , 2018Lotufo et al 2018;Gust et al 2018Gust et al , 2021Johnson et al 2017;Kennedy et al 2015Kennedy et al , 2017Quinn et al 2014;Stanley et al 2015), only two studies describing MeNQ toxicity in mammalian exposures (Kinkead et al 1993;Reinke 2016) and our laboratory's three recent MeNQ ecotoxicological evaluations (Lotufo et al 2020(Lotufo et al , 2021Gust et al 2021) are the only studies presently available. In these ecotoxicology studies, the lethal effects of MeNQ in both acute and chronic aquatic exposures were only observed at high exposure concentrations (≥ 2186 mg/ L) for a broad range of target species including both aquatic invertebrates (Daphnia pulex, Chironomus dilutus, Lumbriculus variegatus, Hydra littoralis, Hyalella azteca) and vertebrates (Pimephales promelas, Rana pipiens).…”

Section: Introductionmentioning

confidence: 99%

Mode of action evaluation for reduced reproduction in Daphnia pulex exposed to the insensitive munition, 1-methyl-3-nitro-1-nitroguanidine (MeNQ)

et al. 2021

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The US Department of Defense (DOD) is developing insensitive munitions (IMs) that are resistant to unintended detonation to protect warfighters. To enable material life-cycle analysis for the IM, 1-methyl-3-nitro-1-nitroguanidine (MeNQ), ecotoxicological impacts assessment was required. A previous investigation of MeNQ exposures in Daphnia pulex revealed concentration-responsive decreases in reproduction relative to controls (0 mg/L) across a 174, 346, 709, 1385, and 2286 mg/L exposure range. The present study used those exposures to conduct global transcriptomic expression analyses to establish hypothetical mode(s) of action underlying inhibited reproduction. The number of significantly affected transcripts and the magnitude of fold-change differences relative to controls tended to increase with increasing MeNQ concentration where hierarchical clustering analysis identified separation among the “low” (174 and 346 mg/L) and “high” (709, 1385, and 2286 mg/L) exposures. Vitellogenin is critical to Daphnia reproductive processes and MeNQ exposures significantly decreased transcriptional expression for vitellogenin-1 precursor at the lowest exposure level (174 mg/L) with benchmark dose (BMD) levels closely tracking concentrations that caused inhibited reproduction. Additionally, juvenile hormone-inducible protein, chorion peroxidase, and high choriolytic enzyme transcriptional expression were impacted by MeNQ exposure having potential implications for egg production / maturation and overall fecundity. In concert with these effects on specific genes involved in Daphnia reproductive physiology, MeNQ exposures caused significant enrichment of several canonical-pathways responsible for metabolism of cellular energy substrates where BMD levels for transcriptional expression were observed at ≤100 mg/L. These observations imply possible effects on whole-organism energy budgets that may also incur indirect costs on reproduction.

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Transcriptomics provides mechanistic indicators of mixture toxicology for IMX-101 and IMX-104 formulations in fathead minnows (Pimephales promelas)

Cited by 18 publications

References 76 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

Review of and Recommendations for Monitoring Contaminants and their Effects in the San Francisco Bay−Delta

Mode of action evaluation for reduced reproduction in Daphnia pulex exposed to the insensitive munition, 1-methyl-3-nitro-1-nitroguanidine (MeNQ)

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