Project description: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.

Project description:Mosquitoes function as important vectors for many diseases globally and can have substantial negative economic, environmental, and health impacts. Specifically, West Nile virus (WNv) is a significant and increasing threat to wildlife populations and human health throughout North America. Mosquito control is an important means of controlling the spread of WNv, as the virus is primarily spread between avian and mosquito vectors. This is of particular concern for avian host species such as the Greater sage-grouse (Centrocercus urophasianus), in which WNv negatively impacts fitness parameters. Most mosquito control methods focus on the larval stages. In North America, control efforts are largely limited to larvicides, which require repeated application and have potentially negative ecological impacts. There are multiple potential advantages to using indigenous fish species as an alternative for larval control including lowered environmental impact, decreased costs in terms of time and financial inputs, and the potential for the establishment of self-sustaining fish populations. We tested the efficacy of using fathead minnows (Pimephales promelas) as biological control for mosquito populations in livestock reservoirs of semiarid rangelands. We introduced minnows into 10 treatment reservoirs and monitored an additional 6 non-treated reservoirs as controls over 3 years. Adult mosquitoes of species known to transmit WNv (e.g., Culex tarsalis) were captured at each site and mosquito larvae were also present at all sites. Stable isotope analysis confirmed that introduced fathead minnows were feeding at the mosquito larvae trophic level in all but one treatment pond. Treatment ponds demonstrated suppressed levels of mosquito larva over each season compared to controls with a model-predicted 114% decrease in larva density within treatment ponds. Minnows established self-sustaining populations throughout the study in all reservoirs that maintained sufficient water levels. Minnow survival was not influenced by water quality. Though minnows did not completely eradicate mosquito larvae, minnows are a promising alternative to controlling mosquito larvae density within reservoirs. We caution that careful site selection is critical to avoid potential negative impacts, but suggest the introduction of fathead minnows in reservoirs can dramatically reduce mosquito larva abundance and potentially help mitigate vector-borne disease transmission.

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Transcriptomics Provides Mechanistic Indicators of Mixture Toxicology for IMX-101 and IMX-104 Formulations in Fathead Minnows (Pimephales promelas)

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