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Wastewater treatment plant (WWTP) effluent often releases pharmaceuticals like venlafaxine (a serotonin–norephinephrine reuptake inhibitor antidepressant) to freshwater ecosystems at levels causing adverse metabolic effects on fish. Changes to fish metabolism can be regulated by epigenetic mechanisms like microRNA (small RNA molecules that regulate mRNA translation), including regulating mitochondrial mRNAs. Nuclear‐encoded microRNAs regulate mitochondrial gene expression in mammals, and have predicted effects in fish. We aimed to identify whether venlafaxine exposure changed mitochondrial respiration and resulted in differentially abundant mitochondrial microRNA (mitomiRs) in zebrafish brains. In vitro exposure of brain homogenate to below environmentally relevant concentrations of venlafaxine (<1 µg/L) caused a decrease in mitochondrial respiration, although this was not driven by changes to mitochondrial Complex I or II function. To identify whether these effects occur in vivo, zebrafish were exposed to 1 µg/L venlafaxine for 0, 1, 6, 12, 24, and 96 h. In vivo, venlafaxine exposure had no significant effects on brain mitochondrial respiration; however, select mitomiRs (dre‐miR‐301a‐5p, dre‐miR‐301b‐3p, and dre‐miR‐301c‐3p) were also measured, because they were bioinformatically predicted to regulate mitochondrial cytochrome c oxidase subunit I (COI) abundance. These mitomiRs were differentially regulated based on venlafaxine exposure (with miR‐301c‐3p abundance differing during the day and miR‐301b‐3p being lower in exposed fish at night), and with respect to sex and time sampled. Overall, the results demonstrated that in vitro venlafaxine exposure to zebrafish brain caused a decrease in mitochondrial respiration, but these effects were not seen after acute in vivo exposure. Results may have differed because in vivo exposure allows for fish to mitigate effects through mechanisms that could include mitomiR regulation, and because fish were only acutely exposed. Environ Toxicol Chem 2024;43:1569–1582. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Micro ribonucleic acids (miRNAs) are recently discovered small regulatory molecules that control messenger RNA (mRNA) translation in plants and animals and have been implicated in a variety of hormone-related physiological pathways. Estrogens, thyroid hormones, and gonadotropins are all known to act on miRNA abundance to cause major shifts in cellular activity, physiology, and homeostatic control mechanisms. Research on cancer biology has also recently considered miRNA as therapeutic targets, because the deregulation of specific miRNAs in various tissues has been correlated with tumorigenesis and other carcinogenic responses. Because many pharmaceuticals are considered to be endocrine-disrupting chemicals (EDCs), their effects on miRNAs may be important to our understanding of basic physiological control and phenotypic outcomes of wildlife exposed to EDCs. Presented is a brief overview of the synthesis, control, and action of miRNAs, focusing on endocrine systems. The antidepressant fluoxetine will be used as an example for miRNA studies in aquatic species, one of the few examples in ecotoxicology. Given the mounting evidence that miRNAs are regulated by hormones, a clear need exists to investigate the potential for environmental EDCs to deregulate miRNA expression and action. Environ Toxicol Chem 2016;35:788-793. © 2015 SETAC [ABSTRACT FROM AUTHOR]