title: Identifying health impacts of exposure to copper using transcriptomics and metabolomics in a fish model.
abstract: Copper (Cu) is a micronutrient essential for the biochemical functioning of numerous processes in vertebrates but is also often present in the aquatic environment at concentrations able to cause adverse health effects in aquatic organisms. This study investigated the signaling pathways mediating the effects of exposure to Cu using a toxicogenomic approach in a fish model, the stickleback ( Gasterosteus aculeatus ). Freshwater-acclimated male fish were exposed via the water to Cu, including at environmentally relevant concentrations (3.2-128 microg of Cu/L for 4 days), and the biological responses explored through analyses of the hepatic transcriptome and metabolome and phenotypic end points, including assessment of DNA damage in blood cells. The Cu exposures resulted in DNA strand breaks in blood cells at all exposure concentrations and alterations in hepatic gene expression and metabolite concentrations in a concentration-dependent manner (from 10 microg of Cu/L). Genes associated with the cholesterol biosynthesis pathway were significantly over-represented and consistently down-regulated (at 128 microg of Cu/L), similar to that occurring in a mouse model for Wilson's disease. Additionally, inductions in metallothionein and catalase were also observed. The concentrations of NAD(+) and lactate increased significantly with the Cu exposure, consistent with a shift toward anaerobic metabolism, and these aligned closely with changes observed in gene expression. The pathways of Cu toxicity identified in our study support the conserved mechanisms of Cu toxicity from lower vertebrates to mammals, provide novel insights into the deleterious effects of Cu in fish, and further demonstrate the utility of fish as environmental sentinels for chemical impacts on both environmental and human health.
authors.affiliation: School of Biosciences, University of Exeter, Exeter, Devon EX4 4PS, United Kingdom. e.santos@exeter.ac.uk
authors.forename: Eduarda M
authors.initials: EM
authors.lastname: Santos
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Ball
authors.forename: Tim D
authors.initials: TD
authors.lastname: Williams
authors.forename: Huifeng
authors.initials: H
authors.lastname: Wu
authors.forename: Fernando
authors.initials: F
authors.lastname: Ortega
authors.forename: Ronny
authors.initials: R
authors.lastname: van Aerle
authors.forename: Ioanna
authors.initials: I
authors.lastname: Katsiadaki
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
authors.forename: Mark R
authors.initials: MR
authors.lastname: Viant
authors.forename: James K
authors.initials: JK
authors.lastname: Chipman
authors.forename: Charles R
authors.initials: CR
authors.lastname: Tyler
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003300:Copper / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D023701:Smegmamorpha; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D003300:Copper; D002784:Cholesterol