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Metabolic effects of diclofenac on the aquatic food chain – 1 H-NMR study of water flea-zebrafish system

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Abstract

In the environment, aquatic organisms are not only directly exposed to pollutants, but the effects can be exacerbated along the food chain. In this study, we investigated the effect of the food (water flea) on the secondary consumer (zebrafish) with the exposure diclofenac (DCF) Both organisms were exposed to an environmentally relevant concentrations (15 µg/L) of diclofenac for five days, and zebrafish were fed exposed and non-exposed water fleas, respectively. Metabolites of the water fleas were directly analyzed using HRMAS NMR, and for zebrafish, polar metabolite were extracted and analyzed using liquid NMR. Metabolic profiling was performed and statistically significant metabolites which affected by DCF exposure were identified. There were more than 20 metabolites with variable importance (VIP) score greater than 1.0 in comparisons in fish groups, and identified metabolites differed depending on the effect of exposure and the effect of food. Specifically, exposure to DCF significantly increased alanine and decreased NAD + in zebrafish, which means energy demand was increased. Additionally, the effects of exposed food decreased in guanosine, a neuroprotective metabolite, which explained that the neurometabolic pathway was perturbated by the feeding of exposed food. Our results which short-term exposed primary consumers to pollutants indirectly affected the metabolism of secondary consumers suggest that the long-term exposure further study remains to be investigated.

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References

  1. Nkwunonwo UC, Odika PO, Onyia NI (2020) A review of the Health Implications of Heavy Metals in Food Chain in Nigeria. Sci World J 2020:6594109. https://doi.org/10.1155/2020/6594109

    Article  CAS  Google Scholar 

  2. Wang W, Gao H, Jin S, Li R, Na G (2019) The ecotoxicological effects of microplastics on aquatic food web, from primary producer to human: a review. Ecotoxicol Environ Saf 173:110–117. https://doi.org/10.1016/j.ecoenv.2019.01.113

    Article  CAS  PubMed  Google Scholar 

  3. Chae Y, An YJ (2016) Toxicity and transfer of polyvinylpyrrolidone-coated silver nanowires in an aquatic food chain consisting of algae, water fleas, and zebrafish. Aquat Toxicol 173:94–104. https://doi.org/10.1016/j.aquatox.2016.01.011

    Article  CAS  PubMed  Google Scholar 

  4. Tang Y, Liu Y, Chen Y, Zhang W, Zhao J, He S et al (2021) A review: Research progress on microplastic pollutants in aquatic environments. Sci Total Environ 766:142572. https://doi.org/10.1016/j.scitotenv.2020.142572

    Article  CAS  PubMed  Google Scholar 

  5. Elliott PN (2010) Non-steroidal anti-inflammatory drugs. Drugs in Sport. 317

  6. Fatta-Kassinos D, Hapeshi E, Achilleos A, Meric S, Gros M, Petrovic M et al (2011) Existence of pharmaceutical compounds in tertiary treated urban wastewater that is utilized for reuse applications. Water Resour Manage 25:1183–1193. https://doi.org/10.1007/s11269-010-9646-4

    Article  Google Scholar 

  7. Fent K, Weston AA, Caminada D (2006) Ecotoxicology of human pharmaceuticals. Aquat Toxicol 78:207. https://doi.org/10.1016/j.aquatox.2006.02.006

  8. Bonnefille B, Gomez E, Courant F, Escande A, Fenet H (2018) Diclofenac in the marine environment: a review of its occurrence and effects. Mar Pollut Bull 131:496–506. https://doi.org/10.1016/j.marpolbul.2018.04.053

    Article  CAS  PubMed  Google Scholar 

  9. Jux U, Baginski RM, Arnold HG, Kronke M, Seng PN (2002) Detection of pharmaceutical contaminations of river, pond, and tap water from Cologne (Germany) and surroundings. Int J Hyg Environ Health 205:393–398. https://doi.org/10.1078/1438-4639-00166

    Article  CAS  PubMed  Google Scholar 

  10. Hanif H, Waseem A, Kali S, Qureshi NA, Majid M, Iqbal M et al (2020) Environmental risk assessment of diclofenac residues in surface waters and wastewater: a hidden global threat to aquatic ecosystem. Environ Monit Assess 192:204. https://doi.org/10.1007/s10661-020-8151-3

    Article  CAS  PubMed  Google Scholar 

  11. Tkaczyk A, Bownik A, Dudka J, Kowal K, Ślaska B (2021) Daphnia magna model in the toxicity assessment of pharmaceuticals: a review. Sci Total Environ 763:143038. https://doi.org/10.1016/j.scitotenv.2020.143038

    Article  CAS  PubMed  Google Scholar 

  12. Roper C, Tanguay RL (2018) Chapter 12 - Zebrafish as a model for developmental biology and toxicology. In: Slikker W, Paule MG, Wang C (eds) Handbook of developmental neurotoxicology, 2nd edn. Academic Press;, pp 143–151. https://doi.org/10.1016/B978-0-12-809405-1.00012-2

  13. Emwas AH, Roy R, McKay RT, Tenori L, Saccenti E, Gowda GAN et al (2019) NMR spectroscopy for metabolomics research. Metabolites 9:123. https://doi.org/10.3390/metabo9070123

  14. Gowda GN, Raftery D (2019) NMR-Based metabolomics: methods and protocols. Springer. https://doi.org/10.1007/978-1-4939-9690-2

  15. Kim S, Lee S, Lee W, Lee Y, Choi J, Lee H et al (2021) Comparison of metabolic profiling of Daphnia magna between HR-MAS NMR and solution NMR techniques. J Korean Magn Reson Soc 25:12–16. https://doi.org/10.6564/JKMRS.2021.25.2.012

    Google Scholar 

  16. David RM, Jones HS, Panter GH, Winter MJ, Hutchinson TH, Chipman JK (2012) Interference with xenobiotic metabolic activity by the commonly used vehicle solvents dimethylsulfoxide and methanol in zebrafish (Danio rerio) larvae but not Daphnia magna. Chemosphere 88:912–917. https://doi.org/10.1016/j.chemosphere.2012.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Weber CI (Ed.) (1991) Methods for measuring the acute toxicity of effluents and receiving waters to freshwater and marine organisms (p. 197).

  18. Wu H, Southam AD, Hines A, Viant MR (2008) High-throughput tissue extraction protocol for NMR-and MS-based metabolomics. Anal Biochem 372:204–212. https://doi.org/10.1016/j.ab.2007.10.002

    Article  CAS  PubMed  Google Scholar 

  19. Westerhuis JA, van Velzen EJ, Hoefsloot HC, Smilde AK (2010) Multivariate paired data analysis: multilevel PLSDA versus OPLSDA. Metabolomics 6:119–128. https://doi.org/10.1007/s11306-009-0185-z

    Article  CAS  PubMed  Google Scholar 

  20. Sathishkumar P, Meena RAA, Palanisami T, Ashokkumar V, Palvannan T, Gu FL (2020) Occurrence, interactive effects and ecological risk of diclofenac in environmental compartments and biota - a review. Sci Total Environ 698:134057. https://doi.org/10.1016/j.scitotenv.2019.134057

    Article  CAS  PubMed  Google Scholar 

  21. Mehinto AC, Hill EM, Tyler CR (2010) Uptake and Biological Effects of environmentally relevant concentrations of the nonsteroidal anti-inflammatory Pharmaceutical Diclofenac in Rainbow Trout (Oncorhynchus mykiss). Environ Sci Technol 44:2176–2182. https://doi.org/10.1021/es903702m

    Article  CAS  PubMed  Google Scholar 

  22. Muñoz-Peñuela M, Moreira RG, Gomes ADO, Tolussi CE, Branco GS, Pinheiro JPS et al (2022) Neurotoxic, biotransformation, oxidative stress and genotoxic effects in Astyanax altiparanae (Teleostei, Characiformes) males exposed to environmentally relevant concentrations of diclofenac and/or caffeine. Environ Toxicol Pharmacol 91:103821. https://doi.org/10.1016/j.etap.2022.103821

    Article  CAS  PubMed  Google Scholar 

  23. Letzel M, Metzner G, Letzel T (2009) Exposure assessment of the pharmaceutical diclofenac based on long-term measurements of the aquatic input. Environ Int 35:363–368. https://doi.org/10.1016/j.envint.2008.09.002

    Article  CAS  PubMed  Google Scholar 

  24. Lee J, Ji K, Lim Kho Y, Kim P, Choi K (2011) Chronic exposure to diclofenac on two freshwater cladocerans and japanese medaka. Ecotoxicol Environ Saf 74:1216–1225. https://doi.org/10.1016/j.ecoenv.2011.03.014

    Article  CAS  PubMed  Google Scholar 

  25. Gomez-Olivan LM, Galar-Martinez M, Garcia-Medina S, Valdes-Alanis A, Islas-Flores H, Neri-Cruz N (2014) Genotoxic response and oxidative stress induced by diclofenac, ibuprofen and naproxen in Daphnia magna. Drug Chem Toxicol 37:391–399. https://doi.org/10.3109/01480545.2013.870191

    Article  CAS  PubMed  Google Scholar 

  26. Tkachenko A, Nesterova L, Pshenichnov M (2001) The role of the natural polyamine putrescine in defense against oxidative stress in Escherichia coli. Arch Microbiol 176:155–157. https://doi.org/10.1007/s002030100301

    Article  CAS  PubMed  Google Scholar 

  27. Lenis YY, Elmetwally MA, Maldonado-Estrada JG, Bazer FW (2017) Physiological importance of polyamines. Zygote 25:244–255. https://doi.org/10.1017/S0967199417000120

    Article  CAS  PubMed  Google Scholar 

  28. Lin H-Y, Lin H-J (2019) Polyamines in Microalgae: something borrowed, something New. Mar Drugs 17:1. https://doi.org/10.3390/md17010001

    Article  Google Scholar 

  29. Miller-Fleming L, Olin-Sandoval V, Campbell K, Ralser M (2015) Remaining Mysteries of Molecular Biology: the role of polyamines in the cell. J Mol Biol 427:3389–3406. https://doi.org/10.1016/j.jmb.2015.06.020

    Article  CAS  PubMed  Google Scholar 

  30. Habte-Tsion H-M, Ren M, Liu B, Ge X, Xie J, Chen R (2016) Threonine modulates immune response, antioxidant status and gene expressions of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream (Megalobrama amblycephala). Fish Shellfish Immunol 51:189–199. https://doi.org/10.1016/j.fsi.2015.11.033

    Article  CAS  PubMed  Google Scholar 

  31. Duarte IA, Reis-Santos P, Novais SC, Rato LD, Lemos MFL, Freitas A et al (2020) Depressed, hypertense and sore: long-term effects of fluoxetine, propranolol and diclofenac exposure in a top predator fish. Sci Total Environ 712:136564. https://doi.org/10.1016/j.scitotenv.2020.136564

    Article  CAS  PubMed  Google Scholar 

  32. Sarojnalini C, Hei A (2019) Fish as an important functional food for quality life. U: Functional Foods, (Lagouri, V, Ured) 77–97.

  33. Penberthy WT (2009) Editorial [hot topic: nicotinamide adenine dinucleotide biology and disease (executive editor: w. todd penberthy)]. Curr Pharm Design 15:1–2. https://doi.org/10.2174/138161209787185779

    Article  Google Scholar 

  34. James EL, Lane JA, Michalek RD, Karoly ED, Parkinson EK (2016) Replicatively senescent human fibroblasts reveal a distinct intracellular metabolic profile with alterations in NAD + and nicotinamide metabolism. Sci Rep 6:38489. https://doi.org/10.1038/srep38489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ma Y, Bao Y, Wang S, Li T, Chang X, Yang G et al (2016) Anti-inflammation effects and potential mechanism of saikosaponins by regulating nicotinate and nicotinamide metabolism and arachidonic acid metabolism. Inflammation 39:1453–1461. https://doi.org/10.1007/s10753-016-0377-4

    Article  CAS  PubMed  Google Scholar 

  36. Cittolin-Santos GF, de Assis AM, Guazzelli PA, Paniz LG, da Silva JS, Calcagnotto ME et al (2017) Guanosine exerts neuroprotective effect in an experimental model of Acute Ammonia Intoxication. Mol Neurobiol 54:3137–3148. https://doi.org/10.1007/s12035-016-9892-4

    Article  CAS  PubMed  Google Scholar 

  37. Bettio LE, Gil-Mohapel J, Rodrigues ALS (2016) Guanosine and its role in neuropathologies. Purinergic Signalling 12:411–426. https://doi.org/10.1007/s11302-016-9509-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jiang S, Fischione G, Giuliani P, Romano S, Caciagli F, Di Iorio P (2008) Metabolism and distribution of guanosine given intraperitoneally: implications for spinal cord injury. Nucleosides Nucleotides Nucleic Acids 27:673–680. https://doi.org/10.1080/15257770802143962

    Article  CAS  PubMed  Google Scholar 

  39. Lanznaster D, Dal-Cim T, Piermartiri TC, Tasca CI (2016) Guanosine: a neuromodulator with therapeutic potential in Brain Disorders. Aging Dis 7:657–679. https://doi.org/10.14336/AD.2016.0208

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zimmer BM, Barycki JJ, Simpson MA (2021) Integration of sugar metabolism and proteoglycan synthesis by UDP-glucose dehydrogenase. J Histochem Cytochem 69:13–23. https://doi.org/10.1369/0022155420947500

    Article  CAS  PubMed  Google Scholar 

  41. Swiacka K, Szaniawska A, Caban M (2019) Evaluation of bioconcentration and metabolism of diclofenac in mussels Mytilus trossulus - laboratory study. Mar Pollut Bull 141:249–255. https://doi.org/10.1016/j.marpolbul.2019.02.050

    Article  CAS  PubMed  Google Scholar 

  42. Syed M, Skonberg C, Hansen SH (2016) Mitochondrial toxicity of diclofenac and its metabolites via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria: possible role in drug induced liver injury (DILI). Toxicol In Vitro 31:93–102. https://doi.org/10.1016/j.tiv.2015.11.020

    Article  CAS  PubMed  Google Scholar 

  43. Oviedo-Gómez DGC, Galar-Martínez M, García-Medina S, Razo-Estrada C, Gómez-Oliván LM (2010) Diclofenac-enriched artificial sediment induces oxidative stress in Hyalella azteca. Environ Toxicol Pharmacol 29:39–43. https://doi.org/10.1016/j.etap.2009.09.004

    Article  PubMed  Google Scholar 

  44. Stulten D, Zuhlke S, Lamshoft M, Spiteller M (2008) Occurrence of diclofenac and selected metabolites in sewage effluents. Sci Total Environ 405:310–316. https://doi.org/10.1016/j.scitotenv.2008.05.036

    Article  CAS  PubMed  Google Scholar 

  45. Fu Q, Fedrizzi D, Kosfeld V, Schlechtriem C, Ganz V, Derrer S et al (2020) Biotransformation changes bioaccumulation and toxicity of diclofenac in aquatic organisms. Environ Sci Technol 54:4400–4408. https://doi.org/10.1021/acs.est.9b07127

    Article  CAS  PubMed  Google Scholar 

  46. Tian R, Yang C, Chai SM, Guo H, Seim I, Yang G (2022) Evolutionary impacts of purine metabolism genes on mammalian oxidative stress adaptation. Zool Res 43:241–254. https://doi.org/10.24272/j.issn.2095-8137.2021.420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Furuhashi M (2020) New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. Am J Physiol Endocrinol Metab 319:E827–E834. https://doi.org/10.1152/ajpendo.00378.2020

    Article  CAS  PubMed  Google Scholar 

  48. Martinez Y, Li X, Liu G, Bin P, Yan W, Mas D et al (2017) The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids 49:2091–2098. https://doi.org/10.1007/s00726-017-2494-2

    Article  CAS  PubMed  Google Scholar 

  49. Peterson JW, Boldogh I, Popov VL, Saini SS, Chopra AK (1998) Anti-inflammatory and antisecretory potential of histidine in Salmonella-challenged mouse small intestine. Lab Invest 78:523–534. https://doi.org/10.1007/s001090050237

    CAS  PubMed  Google Scholar 

  50. Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C et al (2013) Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Diabetologia 56:985–994. https://doi.org/10.1007/s00125-013-2839-7

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Grant number NRF-2020R1I1A2075016).

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Authors and Affiliations

  1. Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busandaehak-ro 63, Geumjeong-gu, 46241, Busan, Republic of Korea

    Li Youzhen, Kim Seonghye, Lee Sujin & Kim Suhkmann

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  1. Li Youzhen
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  2. Kim Seonghye
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection was performed by Youzhen Li, analysis were performed by Youzhen Li, Seonghye Kim and Sujin Lee. The first draft of the manuscript was written by Suhkmann Kim and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kim Suhkmann.

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All procedures performed in the current work were approved with approval number PNU-2019-2473 and were following the ethical standards of the Department of Chemistry, Pusan National University, Institutional Animal Care and Use Committee (PNU-IACUC).

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Li, Y., Kim, S., Lee, S. et al. Metabolic effects of diclofenac on the aquatic food chain – 1 H-NMR study of water flea-zebrafish system. Toxicol Res. 39, 307–315 (2023). https://doi.org/10.1007/s43188-022-00167-9

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