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| Status |
Public on Mar 01, 2018 |
| Title |
Transcriptomics Provides Mechanistic Indicators of Mixture Toxicology for IMX-101 and IMX-104 Formulations in Fathead Minnows (Pimephales promelas) [DNAN] |
| Organism |
Pimephales promelas |
| Experiment type |
Expression profiling by array
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| Summary |
Abstract — Within the US military, new insensitive munitions (IMs) are rapidly replacing conventional munitions improving safety from unintended detonation. Toxicity data for IM chemicals are expanding rapidly, however IM constituents are typically deployed in mixture formulations, and very little is known about their mixture toxicology. In the present study we sought to characterize the mixture effects and toxicology of the two predominant IM formulations IMX-101 and IMX-104 in acute (48 h) larval fathead minnow (Pimephales promelas) exposures. IMX-101 consists of a mixture of 2,4-dinitroanisole (DNAN), 3-nitro-1,2,4-triazol-5-one (NTO), and nitroguanidine (NQ) while IMX-104 is composed of DNAN, NTO, and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). DNAN was the most potent constituent in IMX-101 eliciting an LC50 of 36.1 mg/L, whereas NTO and NQ did not elicit significant mortality in exposures up to 1040 and 2640 mg/L, respectively. Toxic unit calculations indicated that IMX-101 elicited toxicity representative of the component concentration of DNAN within the mixture. Toxicogenomic responses for the individual constituents of IMX-101 indicated unique transcriptional expression and functional responses characteristic of: oxidative stress, impaired energy metabolism, tissue damage and inflammatory responses in DNAN exposures; impaired steroid biosynthesis and developmental cell-signaling in NQ exposures; and altered mitogen-activated protein kinase signaling in NTO exposures. Transcriptional responses to the IMX-101 mixture were driven by the effects of DNAN where expression and functional responses were nearly identical comparing DNAN alone versus the fractional equivalent of DNAN within IMX-101. Given that each individual constituent of the IMX-101 mixture elicited unique functional responses, and NTO and NQ did not interact with DNAN within the IMX-101 mixture exposure, the overall toxicity and toxicogenomic responses within acute exposures to the IMX-101 formulation are indicative of "independent" mixture toxicology. Alternatively, in the IMX-104 exposure both DNAN and RDX were each present at concentrations sufficient to elicit lethality (RDX LC50 = 28.9 mg/L). Toxic-unit calculations for IMX-104 mixture formulation exposures indicated slight synergistic toxicity (ΣTU LC50 = 0.82, 95% confidence interval = 0.73-0.90). Unique functional responses relative to DNAN were observed in the IMX-104 exposure including responses characteristic of RDX exposure. Based on previous transcriptomics responses to acute RDX exposures in fathead minnow larvae, we hypothesize that the potentially synergistic responses within the IMX-104 mixture are related to interactive effects of each DNAN and RDX on oxidative stress mitigation pathways.
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| Overall design |
Five separate microarray analyses were conducted within this study. The five experiments investigated 5 unique chemical exposures in dose-series assays including: 1. DNAN , 2. NTO, 3. NQ, 4. IMX-101, and 5. IMX-104. This GEO entry represents analysis number 1. DNAN: Fathead minnow larvae were exposed to DNAN at 0 (control), 0.37, 0.81, 1.6, 3.3, 6.6, 13.2, 26.5, 53.0 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. Fathead minnow larvae were exposed in static nonrenewal acute 48-h bioassays. Exposure chambers were 250 mL beakers with a test solution volume of 200 ml. Ten larvae were exposed in each beaker, and 4 replicate beakers were tested per treatment. Fish were fed <24-h old Artemia nauplii prior to test initiation. Surviving fish were enumerated daily and any fish found to be deceased were promptly removed from exposure chambers. All animal testing was conducted using methods and protocols approved by the US Army, Engineer Research and Development Center’s Institutional Animal Care and Use Committee (IACUC Protocol #EL-6009-2014-1).
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| Contributor(s) |
Gust KA, Lotufo GR, Stanley JK, Wilbanks MS, Chappell P, Barker ND |
| Citation(s) |
29625381 |
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| Submission date |
Jul 25, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Kurt A Gust |
| E-mail(s) |
[email protected]
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| Phone |
601-634-3593
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| Organization name |
US Army ERDC
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| Department |
Environmental Laboratory
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| Lab |
Environmental Genomics and Systems Biology Team
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| Street address |
3909 Halls Ferry Rd.
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| City |
Vicksburg |
| State/province |
MS |
| ZIP/Postal code |
39180 |
| Country |
USA |
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| Platforms (1) |
| GPL17098 |
Agilent-036574 FHM_8x60K_V2 [Probe name version] |
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| Samples (12)
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| GSM2717425 |
DNAN, 0.81, Rep 4 |
| GSM2717426 |
DNAN, 26.5, Rep 1 |
| GSM2717427 |
DNAN, 26.5, Rep 2 |
| GSM2717428 |
DNAN, 26.5, Rep 3 |
| GSM2717429 |
DNAN, 26.5, Rep 4 |
| GSM2717430 |
DNAN, CON, Rep 1 |
| GSM2717431 |
DNAN, CON, Rep 2 |
| GSM2717432 |
DNAN, CON, Rep 3 |
| GSM2717433 |
DNAN, CON, Rep 4 |
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| This SubSeries is part of SuperSeries: |
| GSE101890 |
Transcriptomics Provides Mechanistic Indicators of Mixture Toxicology for IMX-101 and IMX-104 Formulations in Fathead Minnows (Pimephales promelas) |
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| Relations |
| BioProject |
PRJNA395894 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE101870_RAW.tar |
34.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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