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

Abstract

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.

DRomics, a workflow to exploit dose-response omics data in ecotoxicology

“…They could identify potential Modes of Action of pollutants (MoAs) at the molecular level, that generally need to be validated in a second step using targeted experiments (Andersen et al 2018). Some authors already used our R package DRomics ("Dose Response for Omics") on transcriptomics and/or metabolomics data on different organisms and pollutants, to help the understanding of the adverse effects, by identifying most sensitive pathways (Larras et al, 2020;Gust et al, 2021;Vokuev et al, 2021). DRomics was also used on community transcriptomics and metabolomics data to provide insights into mechanisms of pollution-induced community tolerance (Lips et al, 2022;Larras et al, 2022).…”