Current ecotoxicity testing programs are impeded as they predominantly rely on slow and expensive animal tests measuring adverse outcomes. Therefore, new approach methodologies (NAMs) increasingly involve short-term mechanistic assays that employ molecular endpoints to predict adverse outcomes of regulatory relevance. This study aimed to elucidate the application of NAMs in adult fathead minnows using fluoxetine (FLX) as a model compound. Fish were exposed to three FLX concentrations (measured: 2.42, 10.7, and 56.7 μgL-1) and a control. After 96 h, molecular toxicity signatures were characterized using proteomics and transcriptomics analyses in livers and brains of a sub-set of fish. The remaining fish were sampled at 21 days and assessed for liver histopathology and morphometric measurements. Fecundity was monitored throughout the study. In the livers, 56.7 μgL-1 FLX caused enrichment of PPAR signaling in the proteome and fatty acid-related pathways in the transcriptome, potential upstream responses that led to lipid-type vacuolation of hepatocytes, observed via histopathology. Upregulated genes in the brain suggested alterations in serotonin-related signaling processes and reproductive behaviour, which may explain the observed significant decrease in fecundity. While the relationships between molecular responses and adverse outcomes remain complex, this research provided important insights into the mechanistic toxicity of FLX.

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic; National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 Brno 625 00 Czech Republic

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic; RECETOX Masaryk University Brno 625 00 Czech Republic

Environment and Climate Change Canada National Wildlife Research Centre Ottawa ON K1A 0H3 Canada

Faculty of Agricultural and Environmental Sciences McGill University Montreal QC H9X 3V9 Canada

Faculty of Agricultural and Environmental Sciences McGill University Montreal QC H9X 3V9 Canada; Computer Science Department St Francis Xavier University Antigonish NS B2G 2W5 Canada

Toxicology Centre University of Saskatchewan Saskatoon SK S7N 5B3 Canada

Toxicology Centre University of Saskatchewan Saskatoon SK S7N 5B3 Canada; Department of Animal and Poultry Science College of Agriculture and Bioresources University of Saskatchewan Saskatoon SK S7N 5A8 Canada

Toxicology Centre University of Saskatchewan Saskatoon SK S7N 5B3 Canada; School of the Environment and Sustainability University of Saskatchewan Saskatoon SK S7N 5C8 Canada

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