{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T19:48:18Z","timestamp":1782503298029,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010197","name":"Norwegian Seafood Research Fund","doi-asserted-by":"publisher","award":["901472"],"award-info":[{"award-number":["901472"]}],"id":[{"id":"10.13039\/501100010197","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Although chemotherapeutics are used to treat infections in farmed fish, knowledge on how they alter host physiology is limited. Here, we elucidated the physiological consequences of repeated exposure to the potent oxidative chemotherapeutic peracetic acid (PAA) in Atlantic salmon (Salmo salar) smolts. Fish were exposed to the oxidant for 15 (short exposure) or 30 (long exposure) minutes every 15 days over 45 days. Unexposed fish served as the control. Thereafter, the ability of the remaining fish to handle a secondary stressor was investigated. Periodic chemotherapeutic exposure did not affect production performance, though survival was lower in the PAA-treated groups than in the control. Increased ventilation, erratic swimming, and a loss of balance were common behavioural manifestations during the oxidant exposure. The plasma reactive oxygen species levels increased in the PAA-treated groups, particularly after the third exposure, suggesting an alteration in the systemic oxidative stress status. Plasma indicators for internal organ health were affected to a certain degree, with the changes mainly observed after the second and third exposures. Metabolomics disclosed that the oxidant altered several circulating metabolites. Inosine and guanosine were the two metabolites significantly affected by the oxidative stressor, regardless of exposure time. A microarray analysis revealed that the gills and liver were more responsive to the oxidant than the skin, with the gills being the most sensitive. Moreover, the magnitude of the transcriptomic modifications depended on the exposure duration. A functional analysis showed that genes involved in immunity and ribosomal functions were significantly affected in the gills. In contrast, genes crucial for the oxidation-reduction process were mainly targeted in the liver. Skin mucus proteomics uncovered that the changes in the mucosal proteome were dependent on exposure duration and that the oxidant interfered with ribosome-related processes. Mucosal mapping revealed gill mucous cell hypertrophy after the second and third exposures, although the skin morphological parameters remained unaltered. Lastly, repeated oxidant exposures did not impede the ability of the fish to mount a response to a secondary stressor. This study provides insights into how a chemical oxidative stressor alters salmon physiology at both the systemic and mucosal levels. This knowledge will be pivotal in developing an evidence-driven approach to the use of oxidative therapeutics in fish, with some of the molecules and pathways identified as potential biomarkers and targets for assessing the physiological cost of these treatments.<\/jats:p>","DOI":"10.3390\/antiox10121931","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T20:29:27Z","timestamp":1638304167000},"page":"1931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multiomics Provide Insights into the Key Molecules and Pathways Involved in the Physiological Adaptation of Atlantic Salmon (Salmo salar) to Chemotherapeutic-Induced Oxidative Stress"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2823-2669","authenticated-orcid":false,"given":"Carlo C.","family":"Lazado","sequence":"first","affiliation":[{"name":"Nofima, Norwegian Institute of Food, Fisheries and Aquaculture Research, 1433 \u00c5s, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"Timmerhaus","sequence":"additional","affiliation":[{"name":"Nofima, Norwegian Institute of Food, Fisheries and Aquaculture Research, 1433 \u00c5s, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette W.","family":"Breiland","sequence":"additional","affiliation":[{"name":"Nofima, Norwegian Institute of Food, Fisheries and Aquaculture Research, 9019 Troms\u00f8, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Pittman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Bergen, 5006 Bergen, Norway"},{"name":"Quantidoc AS, 5006 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigurd","family":"Hytter\u00f8d","sequence":"additional","affiliation":[{"name":"Norwegian Veterinary Institute, P.O. Box 750, Sentrum, 0106 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"736038","DOI":"10.1016\/j.aquaculture.2020.736038","article-title":"Survey findings of disinfection strategies at selected Norwegian and North American land-based RAS facilities: A comparative insight","volume":"532","author":"Lazado","year":"2021","journal-title":"Aquaculture"},{"key":"ref_2","unstructured":"Kibenge, F.S.B., and Powell, M.D. (2020). 7\u2013Functional diets in fish health management. Aquaculture Health Management, Academic Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.fsi.2019.04.066","article-title":"Progress, challenges and opportunities in fish vaccine development","volume":"90","author":"Adams","year":"2019","journal-title":"Fish Shellfish. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41586-021-03308-6","article-title":"A 20-year retrospective review of global aquaculture","volume":"591","author":"Naylor","year":"2021","journal-title":"Nature"},{"key":"ref_5","unstructured":"Inglis, V. (1996, January 20\u201322). Antibacterial chemotherapy in aquaculture: Review of practice, associated risks and need for action. Proceedings of the Meeting on the Use of Chemicals in Aquaculture in Asia, Iloilo, Philippines."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.3389\/fmicb.2018.01284","article-title":"Current Status of the Use of Antibiotics and the Antimicrobial Resistance in the Chilean Salmon Farms","volume":"9","author":"Miranda","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1038\/s41467-020-15735-6","article-title":"Aquaculture at the crossroads of global warming and antimicrobial resistance","volume":"11","author":"Reverter","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105625","DOI":"10.1016\/j.aquatox.2020.105625","article-title":"Oxidant-induced modifications in the mucosal transcriptome and circulating metabolome of Atlantic salmon","volume":"227","author":"Lazado","year":"2020","journal-title":"Aquat. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1111\/raq.12365","article-title":"Sustainable aquaculture requires environmental-friendly treatment strategies for fish diseases","volume":"12","author":"Lieke","year":"2020","journal-title":"Rev. Aquac."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3354\/aei00354","article-title":"Decay of peracetic acid in seawater and implications for its chemotherapeutic potential in aquaculture","volume":"12","author":"Pedersen","year":"2020","journal-title":"Aquac. Environ. Interact."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.aquaeng.2012.11.011","article-title":"Peracetic acid degradation in freshwater aquaculture systems and possible practical implications","volume":"53","author":"Pedersen","year":"2013","journal-title":"Aquac. Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1093\/jac\/dkq308","article-title":"Mode of action of hydrogen peroxide and other oxidizing agents: Differences between liquid and gas forms","volume":"65","author":"Finnegan","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"734956","DOI":"10.1016\/j.aquaculture.2020.734956","article-title":"Antioxidative, histological and immunological responses of rainbow trout after periodic and continuous exposures to a peracetic acid-based disinfectant","volume":"520","author":"Liu","year":"2020","journal-title":"Aquaculture"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.aquaculture.2012.02.024","article-title":"Acute toxicity and histopathology of channel catfish fry exposed to peracetic acid","volume":"342\u2013343","author":"Straus","year":"2012","journal-title":"Aquaculture"},{"key":"ref_15","unstructured":"Block, S.S. (1991). Peroxygen Compounds, Lippincott Williams & Wilkins."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.ecoenv.2019.05.045","article-title":"Gill damage and delayed mortality of Northern shrimp (Pandalus borealis) after short time exposure to anti-parasitic veterinary medicine containing hydrogen peroxide","volume":"180","author":"Bechmann","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hushangi, R., and Hosseini Shekarabi, S.P. (2018). Effect of a peracetic acid-based disinfectant on growth, hematology and histology of juvenile rainbow trout (Oncorhynchus mykiss). Fishes, 3.","DOI":"10.3390\/fishes3010010"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"735830","DOI":"10.1016\/j.aquaculture.2020.735830","article-title":"Crowding reshapes the mucosal but not the systemic response repertoires of Atlantic salmon to peracetic acid","volume":"531","author":"Lazado","year":"2021","journal-title":"Aquaculture"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lazado, C.C., Voldvik, V., Breiland, M.W., Os\u00f3rio, J., Hansen, M.H., and Krasnov, A. (2020). Oxidative chemical stressors alter the physiological state of the nasal olfactory mucosa of Atlantic salmon. Antioxidants, 9.","DOI":"10.3390\/antiox9111144"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.fsi.2019.08.048","article-title":"Atlantic salmon (Salmo salar) mounts systemic and mucosal stress responses to peracetic acid","volume":"93","author":"Soleng","year":"2019","journal-title":"Fish Shellfish. Immunol."},{"key":"ref_21","unstructured":"Noble, C., Gismervik, K., Iversen, M.H., Kolarevic, J., Nilsson, J., Stien, L.H., and Turnbull, J.F. (2018). Welfare Indicators for Farmed Atlantic Salmon: Tools for Assessing Fish Welfare, Nofima."},{"key":"ref_22","unstructured":"Doneanu, C.E., Chen, W., and Mazzeo, J.R. (2020, May 20). UPLC\/MS Monitoring of Water-Soluble Vitamin Bs in Cell Culture Media in Minutes. Water Appl. Note 2011, 720004042en. Available online: https:\/\/www.waters.com\/waters\/library.htm?locale=en_US&lid=134636355."},{"key":"ref_23","first-page":"31","article-title":"Development and assessment of oligonucleotide microarrays for Atlantic salmon (Salmo salar L.)","volume":"6","author":"Krasnov","year":"2011","journal-title":"Comp. Biochem. Physiol. Part D Genom. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"736076","DOI":"10.1016\/j.aquaculture.2020.736076","article-title":"The optimum velocity for Atlantic salmon post-smolts in RAS is a compromise between muscle growth and fish welfare","volume":"532","author":"Timmerhaus","year":"2021","journal-title":"Aquaculture"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"736315","DOI":"10.1016\/j.aquaculture.2020.736315","article-title":"Dynamic morphometrics of mucous cells reveal the minimal impact of therapeutic doses of peracetic acid on Atlantic salmon gill health","volume":"534","author":"Haddeland","year":"2021","journal-title":"Aquaculture"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/jfd.12002","article-title":"Body site matters: An evaluation and application of a novel histological methodology on the quantification of mucous cells in the skin of Atlantic salmon, Salmo salar L.","volume":"36","author":"Pittman","year":"2013","journal-title":"J. Fish Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/j.1365-2761.2011.01308.x","article-title":"Novel method for quantifying salmonid mucous cells","volume":"34","author":"Pittman","year":"2011","journal-title":"J. Fish Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100368","DOI":"10.1016\/j.aqrep.2020.100368","article-title":"Morphomolecular alterations in the skin mucosa of Atlantic salmon (Salmo salar) after exposure to peracetic acid-based disinfectant","volume":"17","author":"Lazado","year":"2020","journal-title":"Aquac. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_30","first-page":"1","article-title":"Behavioural responses in effect to chemical stress in fish: A review Madhu Sharma","volume":"7","author":"Sharma","year":"2019","journal-title":"Int. J. Fish. Aquat. Stud."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1111\/jwas.12475","article-title":"Toxicity of Peracetic Acid to Fish: Variation among Species and Impact of Water Chemistry","volume":"49","author":"Straus","year":"2018","journal-title":"J. World Aquac. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1139\/m92-104","article-title":"Bactericidal properties of peracetic acid and hydrogen peroxide, alone and in combination, and chlorine and formaldehyde against bacterial water strains","volume":"38","author":"Alasri","year":"1992","journal-title":"Can. J. Microbiol."},{"key":"ref_33","first-page":"456","article-title":"Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress","volume":"8","author":"Spiers","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.3390\/ijms12106469","article-title":"Metabolomics of oxidative stress in recent studies of endogenous and exogenously administered intermediate metabolites","volume":"12","author":"Liu","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.redox.2017.08.009","article-title":"Short overview on metabolomics approach to study pathophysiology of oxidative stress in cancer","volume":"14","author":"Andrisic","year":"2018","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1667\/RR3552.1","article-title":"Guanosine and Inosine Display Antioxidant Activity, Protect DNA In Vitro from Oxidative Damage Induced by Reactive Oxygen Species, and Serve as Radioprotectors in Mice","volume":"165","author":"Gudkov","year":"2006","journal-title":"Radiat. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1111\/anu.12463","article-title":"Inosine supplementation effectively provokes the growth, immune response, oxidative stress resistance and intestinal morphology of juvenile red sea bream, Pagrus major","volume":"23","author":"Hossain","year":"2017","journal-title":"Aquac. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s10695-019-00669-8","article-title":"Impact of acute handling stress, anaesthesia, and euthanasia on fish plasma biochemistry: Implications for veterinary screening and metabolomic sampling","volume":"45","author":"Young","year":"2019","journal-title":"Fish Physiol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Stiller, K.T., Kolarevic, J., Lazado, C.C., Gerwins, J., Good, C., Summerfelt, S.T., Mota, V.C., and Espmark, \u00c5.M. (2020). The effects of ozone on Atlantic salmon post-smolt in brackish water\u2014Establishing welfare indicators and thresholds. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145109"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1590\/0001-3765201820170730","article-title":"Oxidative stress and fish immune system: Phagocytosis and leukocyte respiratory burst activity","volume":"90","author":"Biller","year":"2018","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549319","DOI":"10.3389\/fimmu.2020.549319","article-title":"Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response","volume":"11","author":"Yamaguchi","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7715","DOI":"10.1007\/s11033-014-3665-9","article-title":"Protective effect of myokine IL-15 against H2O2-mediated oxidative stress in skeletal muscle cells","volume":"41","author":"Li","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/mi.2008.5","article-title":"Mucins in the mucosal barrier to infection","volume":"1","author":"Linden","year":"2008","journal-title":"Mucosal Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Shcherbik, N., and Pestov, D.G. (2019). The Impact of Oxidative Stress on Ribosomes: From Injury to Regulation. Cells, 8.","DOI":"10.3390\/cells8111379"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1095-8649.1988.tb05341.x","article-title":"Normal ranges of some blood chemistry parameters in adult farmed Atlantic salmon, Salmo salar","volume":"32","author":"Sandnes","year":"1988","journal-title":"J. Fish Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/jfd.12476","article-title":"Technical pre-analytical effects on the clinical biochemistry of Atlantic salmon (Salmo salar L.)","volume":"40","author":"Braceland","year":"2017","journal-title":"J. Fish Dis."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/12\/1931\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:38:05Z","timestamp":1760168285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/12\/1931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,30]]},"references-count":46,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["antiox10121931"],"URL":"https:\/\/doi.org\/10.3390\/antiox10121931","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,30]]}}}