Journal Article

Tolerance and dose-response assessment of subchronic dietary ethoxyquin exposure in Atlantic salmon (Salmo salar L.)

Lundebye, Anne-Katrine, Ørnsrud, Robin, Berntssen, Marc H. G., Rasinger, Josef D., Caballero, Maria José, Betancor, Monica B., Bernhard, Annette

2019

Overview

Ethoxyquin (EQ; 6-Ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline) has been used as an antioxidant in feed components for pets, livestock and aquaculture. However, possible risks of EQ used in aquafeed for fish health have not yet been characterized. The present study investigated the toxicity and dose-response of subchronic dietary EQ exposure at doses ranging from 41 to 9666 mg EQ/kg feed in Atlantic salmon (Salmo salar L.). Feed at concentrations higher than 1173 mg EQ/kg were rejected by the fish, resulting in reduced feed intake and growth performance. No mortality was observed in fish exposed to any of the doses. A multi-omic screening of metabolome and proteome in salmon liver indicated an effect of dietary EQ on bioenergetics pathways and hepatic redox homeostasis in fish fed concentrations above 119 mg EQ/kg feed. Increased energy expenditure associated with an upregulation of hepatic fatty acid β-oxidation and induction and carbohydrate catabolic pathways resulted in a dose-dependent depletion of intracytoplasmic lipid vacuoles in liver histological sections, decreasing whole body lipid levels and altered purine/pyrimidine metabolism. Increased GSH and TBARS in the liver indicated a state of oxidative stress, which was associated with activation of the NRF2-mediated oxidative stress response and glutathione-mediated detoxification processes. However, no oxidative DNA damage was observed. As manifestation of altered energy metabolism, the depletion of liver intracytoplasmic lipid vacuoles was considered the critical endpoint for benchmark dose assessment, and a BMDL10 of 243 mg EQ/kg feed was derived as a safe upper limit of EQ exposure in Atlantic salmon.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal Feed / Animals / Antioxidants / Antioxidants (Nutrients) / Aquaculture / Atlantic salmon / Bioenergetics / Biology and Life Sciences / Carbohydrates / Deoxyribonucleic acid / Depletion / Detoxification / Diet / DNA / DNA Damage / Dose-response relationship / Dose-Response Relationship, Drug / Eating - drug effects / Energy expenditure / Energy metabolism / Energy Metabolism - drug effects / Ethoxyquin / Ethoxyquin - pharmacology / Exposure / Fatty acids / Fatty liver / Feeds / Fish / Food safety / Glutathione / Growth rate / Homeostasis / Lipid Metabolism - drug effects / Lipid peroxidation / Lipids / Liver / Liver - metabolism / Livestock / Medicine and Health Sciences / Metabolism / Oxidation / Oxidative stress / Pets / Physical Sciences / Physiological aspects / Proteomes / Research and Analysis Methods / Salmo salar / Salmo salar - metabolism / Salmon / Studies / Toxicity / Vacuoles