Transcriptomics,Genomics

Dataset Information

31

The Increased Toxicity of UV-Degraded Nitroguanidine and IMX-101 Exposures in Zebrafish Larvae: Evidence Implicating Oxidative Stress [1]


ABSTRACT: Abstract — Insensitive munitions (IMs) improve soldier safety by decreasing sympathetic detonation during training and use in theatre. The environmental effects of IM constituents such as nitroguanidine (NQ) and IM mixture formulations such as IMX-101 remain largely unknown. In the present study, we investigated the acute (96h) toxicity of NQ and IMX-101 to zebrafish larvae, both in the parent IMs and in IMs irradiated with environmentally-relevant levels of ultraviolet (UV) energy. Zebrafish were exposed to control and ten concentrations of NQ ranging from 1 to 732 mg/L (measured concentrations) or seven concentrations of IMX-101 ranging from 2 to 122 mg/L (measured concentrations) of the parent material or material that had been UV-irradiated (UV-treated) at the equivalent of 24 hours of sunlight. The UV-treatment increased the toxicity of NQ by 17-fold, indicated by a decreased LC50 from 1323 mg/L (parent compound) to 77.2 mg/L. Similarly, UV-treatment increased the toxicity of IMX-101 by nearly two fold (LC50 decreased from 131.3 to 67.6 mg/L). Molecular responses to parent and UV-treated IMs were assessed using global transcript expression assays. Both gene set enrichment analysis (GSEA) and differential transcript expression analysis coupled with pathway and annotation cluster enrichment were conducted to provide functional interpretations of expression results and hypothetical modes of toxicity. The parent NQ exposure caused significant enrichment of functions related to immune responses and proteasome-mediated protein metabolism occurring primarily at low, sublethal exposure levels (5.5 and 45.6 mg/L). Enriched functions in the IMX-101 exposure were indicative of increased xenobiotic metabolism, oxidative stress mitigation, protein degradation, and anti-inflammatory responses, each of which displayed predominantly positive concentration-response relationships. UV-treated NQ had a fundamentally different transcriptomic expression profile relative to parent NQ where positive concentration-response relationships were observed for genes involved in oxidative-stress mitigation pathways whereby we hypothesize that the increased toxicity of UV-treated NQ resulted from increased oxidative stress. This hypothesis was supported by transcriptomic responses indicative of oxidative-stress responses involved in zebrafish development, especially neurological development of visual systems and the brain. Transcriptomic profiles were similar between UV-treated versus parent IMX-101 exposures, however, more significant and diverse enrichment as well as greater magnitudes of differential expression for oxidative stress responses were observed in UV-treated IMX-101 exposures. Further, transcriptomics indicated potential for cytokine signaling suppression providing potential connections between oxidative stress and anti-inflammatory responses. Given these result, we hypothesize that the increased toxicity of UV-irradiated NQ and the IMX-101 mixture result from breakdown products with increased potential to elicit oxidative stress. Overall design: Six separate microarray analyses were conducted within this study. The 6 designs were conduced as follows: 1. NQ parent compound, 2. UV-Treated NQ, 3. Two-way design, NQ Parent x UV-Treated NQ, 4. IMX-101 parent material, 5. UV-treated IMX-101, 6. Two way design, IMX-101 parent x UV-Treated IMX-101. This GEO entry represents analysis number 1. - NQ parent compound: Zebrafish larvae were exposed to NQ at 0 (control), 1.4, 2.8, 5.5, 11.0, 22.7, 45.6, 90.4, 181, 348, and 732 mg/L (measured concentrations). Exposure and control water was dechlorinated tap water (Vicksburg, MS USA municipal dechlorinated via activated carbon filtration) amended with artificial sea salts (Instant Ocean, Blacksburg, VA, USA) to a conductivity of 600 µS/cm. Danio rerio larvae were exposed in static nonrenewal acute 96-h bioassays. Exposure chambers were 300-ml high-form lipless beakers with a test solution volume of 250 ml. Eight larval fish per beaker were exposed in the parent or UV-treated NQ treatments each including 4 exposure replicates and 6 control replicates. Larval zebrafish were fed newly hatched Artemia nauplii two hours before the initiation of exposures and at the 48-h timepoint. Surviving fish were enumerated daily and any fish found to be deceased were promptly removed from exposure chambers.

INSTRUMENT(S): Agilent.SingleColor.36575, Commercial Zebrafish, 8x 60k, 60mer Microarray

SUBMITTER: Kurt Gust  

PROVIDER: GSE94614 | GEO | 2017-08-25

SECONDARY ACCESSION(S): PRJNA371834

REPOSITORIES: GEO

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Publications

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

Gust Kurt A KA   Stanley Jacob K JK   Wilbanks Mitchell S MS   Mayo Michael L ML   Chappell Pornsawan P   Jordan Shinita M SM   Moores Lee C LC   Kennedy Alan J AJ   Barker Natalie D ND  

Aquatic toxicology (Amsterdam, Netherlands) 20170721


Insensitive munitions (IMs) improve soldier safety by decreasing sympathetic detonation during training and use in theatre. IMs are being increasingly deployed, although the environmental effects of IM constituents such as nitroguanidine (NQ) and IM mixture formulations such as IMX-101 remain largely unknown. In the present study, we investigated the acute (96h) toxicity of NQ and IMX-101 to zebrafish larvae (21d post-fertilization), both in the parent materials and after the materials had been  ...[more]

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