There is a pressing need to identify the molecular mechanisms underlying the, often magnifying, interactive effects between contaminants and natural stressors. We here test our hypothesis that lower general stress defense responses contribute to synergistic interactions between stressors. We focus on the widespread pattern that many contaminants are more toxic at higher temperatures. Specifically, we tested the effects of an environmentally realistic low-effect and high-effect concentration of the pesticide chlorpyrifos under warming at the gene expression level in the Northern house mosquito Culex pipiens molestus (Forskal, 1775). By applying the independent action model for combined stressors on RNA-seq data, we identified interactive gene expression patterns under combined exposure to chlorpyrifos and warming for general stress defense responses: protection of macromolecules, antioxidant processes, detoxification, and energy metabolism/allocation. Most of these general stress defense response genes showed upregulated antagonistic interactions, i.e. were less upregulated than expected under the independent action model. This indicates that when pesticide exposure was combined with warming the general stress defense responses were no longer buffering increased stress levels, which may contribute to a higher sensitivity to toxicants under warming. These upregulated antagonistic interactions were stronger for the high-effect chlorpyrifos concentration, indicating that exposure to this concentration under warming was most stressful. Our results highlight that quantitative analysis of the frequency and strength of the interaction types of general stress defense response genes, specifically focusing on antagonistic upregulations and synergistic downregulations, may advance understanding of how natural stressors modify the toxicity of contaminants.

Please see section '2. Materials and Methods' in the manuscript 'Reduced stress defense responses contribute to the higher toxicity of a pesticide under warming' in Molecular Ecology (Authors: Delnat V., Swaegers J., Asselman J. & Stoks R.).

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