There is increasing pressure to develop alternative ecotoxicological risk assessment approaches that do not rely on expensive, time-consuming, and ethically questionable live animal testing. This study aimed to develop a comprehensive early life stage toxicity pathway model for the exposure of fish to estrogenic chemicals that is rooted in mechanistic toxicology. Embryo-larval fathead minnows (FHM; Pimephales promelas) were exposed to graded concentrations of 17α-ethinylestradiol (water control, 0.01% DMSO, 4, 20, and 100 ng/L) for 32 days. Fish were assessed for transcriptomic and proteomic responses at 4 days post-hatch (dph), and for histological and apical end points at 28 dph. Molecular analyses revealed core responses that were indicative of observed apical outcomes, including biological processes resulting in overproduction of vitellogenin and impairment of visual development. Histological observations indicated accumulation of proteinaceous fluid in liver and kidney tissues, energy depletion, and delayed or suppressed gonad development. Additionally, fish in the 100 ng/L treatment group were smaller than controls. Integration of omics data improved the interpretation of perturbations in early life stage FHM, providing evidence of conservation of toxicity pathways across levels of biological organization. Overall, the mechanism-based embryo-larval FHM model showed promise as a replacement for standard adult live animal tests.

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

Computer Science Department St Francis Xavier University Antigonish Nova Scotia B2G 2W5 Canada

Department of Animal and Poultry Science College of Agriculture and Bioresources University of Saskatchewan Saskatoon Saskatchewan S7N 5A8 Canada

Department of Environment and Geography York University York YO10 5NG United Kingdom

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

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

Global Institute for Food Security University of Saskatchewan Saskatoon Saskatchewan S7N 0W9 Canada

Global Institute for Water Security University of Saskatchewan Saskatoon Saskatchewan S7N 3H5 Canada

RECETOX Masaryk University Brno 625 00 Czech Republic

School of the Environment and Sustainability University of Saskatchewan Saskatoon Saskatchewan S7N 5C8 Canada

Toxicology Centre University of Saskatchewan Saskatoon Saskatchewan S7N 5B3 Canada

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