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Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

ABSTRACT: 2,4-Dinitroanisole (DNAN) is an emerging insensitive munitions compound that readily undergoes anaerobic nitro-group reduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN), followed by formation of unique azo dimers. Currently there is little knowledge on the ecotoxicity of DNAN (bio)transformation products. In the present study, mortality, development, and behavioral effects of DNAN (bio)transformation products were assessed using zebrafish (Danio rerio) embryos. The authors tested individual products, MENA and DAAN, as well as dimer and trimer surrogates. As pure compounds, 3-nitro-4-methoxyaniline and 2,2'-dimethoxy-4,4'-azodianiline caused statistically significant effects, with lowest-observable-adverse effect levels (LOAEL) at 6.4??M on 1 or 2 developmental endpoints, respectively. The latter had 6 additional statistically significant developmental endpoints with LOAELs of 64??M. Based on light-to-dark swimming behavioral tests, DAAN (640??M) caused reduction in swimming, suggestive of neurotoxicity. No statistically significant mortality occurred (?64??M) for any of the individual compounds. However, metabolite mixtures formed during different stages of MENA (bio)transformation in soil were characterized using high-resolution mass spectrometry in parallel with zebrafish embryo toxicity assays, which demonstrated statistically significant mortality during the onset of azo-dimer formation. Overall the results indicate that several DNAN (bio)transformation products cause different types of toxicity to zebrafish embryos. Environ Toxicol Chem 2016;35:2774-2781. © 2016 SETAC.

SUBMITTER: Olivares CI

PROVIDER: S-EPMC5052101 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

Olivares Christopher I CI Sierra-Alvarez Reyes R Abrell Leif L Chorover Jon J Simonich Michael M Tanguay Robert L RL Field Jim A JA

Environmental toxicology and chemistry 20160628 11

2,4-Dinitroanisole (DNAN) is an emerging insensitive munitions compound that readily undergoes anaerobic nitro-group reduction to 2-methoxy-5-nitroaniline (MENA) and 2,4-diaminoanisole (DAAN), followed by formation of unique azo dimers. Currently there is little knowledge on the ecotoxicity of DNAN (bio)transformation products. In the present study, mortality, development, and behavioral effects of DNAN (bio)transformation products were assessed using zebrafish (Danio rerio) embryos. The authors ...[more]

PMID: 27058972

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Project description: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.

Dataset Information

Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

Publications

Zebrafish embryo toxicity of anaerobic biotransformation products from the insensitive munitions compound 2,4-dinitroanisole.

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