Abstract
Objectives
The increase in pharmaceutical drug consumption and the presence of these drugs in the environment causes concern about their effects. Due to the prevalence of metformin in surface and waste waters, this study investigated its 7 day chronic toxicity. Typically, metformin is prescribed with other medications to control blood sugar levels and achieve healthy HbA1c (hemoglobin) levels for people with type 2 diabetes (T2D).
Methods
Accordingly, the effect of metformin on catfish (Clarias gariepinus) following exposure and post-exposure recovery was evaluated using blood indices as biomarkers for hematotoxicity, electrolytes imbalance, oxidative stress, and immunosuppression. The first group was a control group, the second group was exposed to 10 mg/L of metformin, and the third group was exposed to 50 mg/L of metformin for 7 days, followed by a 15-day recovery period. Hemotoxic effects of the metformin residue on fish were reported.
Results
A significant decrease in the most of antioxidants and electrolytes concentrations was observed in the present study. Low- and high- dose metformin suppressed the immunity of the exposed treated fish could be through the activation of lymphocytes and monocytes compared to control fish. Also, high dose of metformin induces cell oxidative stress through the reduction of super oxide dismutase (SOD) antioxidant enzyme and total antioxidant capacity (TAC). In addition, metformin increased the expression of inflammatory mediators as interleukin-6 (IL-6) and interleukin-1 beta (IL-1 β). However, some parameters were returned to their normal levels after 15 days post- exposure such as urea, uric acid, superoxide dismutase, chloride and IL-1 β especially with high- dose metformin exposure.
Conclusion
We conclude that our findings contribute to the current eco-toxicological knowledge regarding commonly consumed drugs and have provided additional data for research into these drugs.
Similar content being viewed by others
References
Ambrosio-Albuquerque EP, Cusioli LF, Bergamasco R, Gigliolli AAS, Lupepsa L, Paupitz BR, Barbieri PA, Borin-Carvalho LA, De Brito Portela-Castro AL (2021) Metformin environmental exposure: a systematic review. Environ Toxicol Pharmacol 83:103588
Attia ZI, Hegazi MM, Mourad MH, Ashour OA (2016) Antioxidant enzymes status in liver and white muscle of Nile Tilapia exposed to different hypoxic levels and durations. The Egypt J Exp Biol (Zoology) 11:71–71
Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, Fahey JW, Derry JM, Wollheim CB, Wierup N (2017) Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci Transl Med 9:eaah4477
Badawy MA, Yasseen BA et al (2021) Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality. Elife 10:e69417. https://doi.org/10.7554/eLife.69417
Bailey CJ (2017) Metformin: historical overview. Diabetologia 60:1566–1576
Bailey CJ, Gwilt M (2022) Diabetes, metformin and the clinical course of Covid-19: outcomes, mechanisms and suggestions on the therapeutic use of metformin. Front Pharmacol 13:784459. https://doi.org/10.3389/fphar.2022.784459
Beavers WN, Skaar EP (2016) Neutrophil-generated oxidative stress and protein damage in Staphylococcus aureus. Pathog Dis 74
Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F (2010) Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 9:1092–1099
Besse J-P, Garric J (2008) Human pharmaceuticals in surface waters: implementation of a prioritization methodology and application to the French situation. Toxicol Lett 176:104–123
Cho K, Chung JY, Cho SK, Shin H-W, Jang I-J, Park J-W, Yu K-S, Cho J-Y (2015) Antihyperglycemic mechanism of metformin occurs via the AMPK/LXRα/POMC pathway. Sci Rep 5:1–7
Corremans R, Neven E, Maudsley S, Leysen H, de Broe ME, D’Haese PC, Vervaet BA, Verhulst A (2022) Progression of established non-diabetic chronic kidney disease is halted by metformin treatment in rats. Kidney Int 101:929–944
Costa F, Lago A, Rocha VN, Barros OS, Costa L, Vipotnik Z, Silva B, Tavares T (2019) A review on biological processes for pharmaceuticals wastes abatement—a growing threat to modern society. Environ Sci Technol 53:7185–7202
Currie CJ, Poole CD, Gale E (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777
Didion SP (2017) Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature. Int J Mol Sci 18:2563
El-Naggar SA, Elwan M et al (2021) Metformin causes hepato-renal dysfunctions in obese male rats. Braz Arch Biol Technol 64. https://doi.org/10.1590/1678-4324-2021210188
Elliott SM, Brigham ME, Lee KE, Banda JA, Choy SJ, Gefell DJ, Minarik TA, Moore JN, Jorgenson ZG (2017) Contaminants of emerging concern in tributaries to the Laurentian Great Lakes: I. Patterns of occurrence. PLoS ONE 12:e0182868
Fabbri E, Franzellitti S (2016) Human pharmaceuticals in the marine environment: focus on exposure and biological effects in animal species. Environ Toxicol Chem 35:799–812
Filippatos T, Tzavella E, Rizos C, Elisaf M, Liamis G (2017) Acid-base and electrolyte disorders associated with the use of antidiabetic drugs. Expert Opin Drug Saf 16:1121–1132
Fish U, Service W (2010) American Fisheries Society–Fish Health Section (AFS-FHS): 2010, Standard procedures for aquatic animal health inspections. AFS-FHS blue book: suggested procedures for the detection and identification of certain finfish and shellfish pathogens
Foretz M, Guigas B, Viollet B (2019) Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 15:569–589
Foster LB, Dunn RT (1974) Single-antibody technique for radioimmunoassay of cortisol in unextracted serum or plasma. Clin Chem 20:365–368
Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15:1583–1606
Gabr RQ, El-Sherbeni AA, Ben-Eltriki M, El-Kadi AO, Brocks DR (2017) Pharmacokinetics of metformin in the rat: assessment of the effect of hyperlipidemia and evidence for its metabolism to guanylurea. Can J Physiol Pharmacol 95:530–538
García-Ayllón M-S, Small DH, Avila J, Sáez-Valero J (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22
Gaweł S, Wardas M, Niedworok E, Wardas P (2004) Malondialdehyde (MDA) as a lipid peroxidation marker. Wiadomosci Lekarskie (Warsaw, Poland: 1960) 57:453–455
Gnudi L and Ricciardi CA (2022) Diabetes and kidney disease: metformin. Diabetes and Kidney Disease. Springer
Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE (2012) Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 22:820–827
Gormsen LC, Søndergaard E, Christensen NL, Brøsen K, Jessen N, Nielsen S (2019) Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia 62:1251–1256
Grenni P, Ancona V, Caracciolo AB (2018) Ecological effects of antibiotics on natural ecosystems: a review. Microchem J 136:25–39
Hamed M, Soliman HA, Osman AG, Sayed AE-DH (2019) Assessment the effect of exposure to microplastics in Nile Tilapia (Oreochromis niloticus) early juvenile: I. blood biomarkers. Chemosphere 228:345–350
Hamed M, Soliman HA, Osman AG, Sayed AE-DH (2020) Antioxidants and molecular damage in Nile Tilapia (Oreochromis niloticus) after exposure to microplastics. Environ Sci Pollut Res 27:14581–14588
Hanington PC, Belosevic M (2007) Interleukin-6 family cytokine M17 induces differentiation and nitric oxide response of goldfish (Carassius auratus L.) macrophages. Dev Comp Immunol 31:817–829
Huang X-J, Choi Y-K, Im H-S, Yarimaga O, Yoon E, Kim H-S (2006) Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) detection techniques. Sensors 6:756–782
Khadre S, Ibrahim H, Shabana M, El-Seady N (2011) Effect of metformin and glimepiride on liver and kidney functions in alloxan-induced diabetic rats. J High Inst Publ Health 41:282–310
Knedel M, Böttger R (1967) A kinetic method for determination of the activity of pseudocholinesterase (acylcholine acyl-hydrolase 3.1. 1.8.). Klin Wochenschr 45:325–327
Lazarus B, Wu A, Shin J-I, Sang Y, Alexander GC, Secora A, Inker LA, Coresh J, Chang AR, Grams ME (2018) Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 178:903–910
Maclaren RD, Wisniewski K, Maclaren C (2018) Environmental concentrations of metformin exposure affect aggressive behavior in the Siamese fighting fish. Betta splendens PloS one 13:e0197259
Massima Mouele ES, Tijani JO, Badmus KO, Pereao O, Babajide O, Zhang C, Shao T, Sosnin E, Tarasenko V, Fatoba OO (2021) Removal of pharmaceutical residues from water and wastewater using dielectric barrier discharge methods—a review. Int J Environ Res Publ Health 18:1683
Meador JP, Yeh A, Gallagher EP (2018) Adverse metabolic effects in fish exposed to contaminants of emerging concern in the field and laboratory. Environ Pollut 236:850–861
Mekkawy IA, Mahmoud UM, Sayed AE-DH (2011) Effects of 4-nonylphenol on blood cells of the African catfish Clarias gariepinus (Burchell, 1822). Tissue Cell 43:223–229
Niemuth NJ, Jordan R, Crago J, Blanksma C, Johnson R, Klaper RD (2015) Metformin exposure at environmentally relevant concentrations causes potential endocrine disruption in adult male fish. Environ Toxicol Chem 34:291–296
Niemuth NJ, Klaper RD (2018) Low-dose metformin exposure causes changes in expression of endocrine disruption-associated genes. Aquat Toxicol 195:33–40
Nimmo IA (1987) The glutathione S-transferases of fish. Fish Physiol Biochem 3(4):163–172. https://doi.org/10.1007/BF02180277
Nishikimi M, Rao NA, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46:849–854
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358
Parra-Saldivar R, Castillo-Zacarías C, Bilal M, Iqbal HMN, Barceló D (2021) Sources of pharmaceuticals in water. In: Perez Solsona S, Montemurro N, Chiron S, Barceló D (eds) Interaction and fate of pharmaceuticals in soil-crop systems: the impact of reclaimed wastewater. Springer International Publishing, Cham
Parrott JL, Restivo VE, Kidd KA, Zhu J, Shires K, Clarence S, Khan H, Sullivan C, Pacepavicius G, Alaee M (2022) Chronic embryo-larval exposure of fathead minnows to the pharmaceutical drug metformin: survival, growth, and microbiome responses. Environ Toxicol Chem 41:635–647
Patel M, Kumar R, Kishor K, Mlsna T, Pittman CU Jr, Mohan D (2019) Pharmaceuticals of emerging concern in aquatic systems: chemistry, occurrence, effects, and removal methods. Chem Rev 119:3510–3673
Pereira A, Silva L, Laranjeiro C, Lino C, Pena A (2020) Selected pharmaceuticals in different aquatic compartments: part II-toxicity and environmental risk assessment. Molecules 25(8):1796. https://doi.org/10.3390/molecules25081796
Reis JS, Amaral CAV, Volpe CMO, Fernandes JS, Borges EA, Isoni CA, Anjos PMFD, Machado JAN (2012) Oxidative stress and interleukin-6 secretion during the progression of type 1 diabetes. Arq Bras de Endocrinol& Metabol 56:441–448
Rena G, Hardie DG, Pearson ER (2017) The mechanisms of action of metformin. Diabetologia 60:1577–1585
Rojas LBA, Gomes MB (2013) Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr 5:1–15
Sayed AH, Hamed M et al (2021) Spirulina platensis alleviated the hemotoxicity, oxidative damage and histopathological alterations of hydroxychloroquine in catfish (Clarias gariepinus). Front Physiol 12. https://doi.org/10.3389/fphys.2021.683669
Shabalina IG, Petrovic N, Kramarova TV, Hoeks J, Cannon B, Nedergaard J (2006) UCP1 and defense against oxidative stress: 4-hydroxy-2-nonenal effects on brown fat mitochondria are uncoupling protein 1-independent. J Biol Chem 281:13882–13893
Sookoian S, Pirola CJ (2012) Alanine and aspartate aminotransferase and glutamine-cycling pathway: their roles in pathogenesis of metabolic syndrome. World J Gastroenterol: WJG 18:3775–3781
Stevens JP (2013) Intermediate statistics: a modern approach. Routledge
Tripathi SS, Singh S, Garg G, Kumar R, Verma AK, Singh AK, Bissoyi A, Rizvi SI (2022) Metformin ameliorates acetaminophen-induced sub-acute toxicity via antioxidant property. Drug Chem Toxicol 45:52–60
Uppal NN, Workeneh BT, Rondon-Berrios H, Jhaveri KD (2022) Electrolyte and acid-base disorders associated with cancer immunotherapy. Clin J Am Soc Nephrol 17:922–933
Yimer EM, Surur A et al (2019) The effect of metformin in experimentally induced animal models of epileptic seizure. Behav Neurol 2019:6234758. https://doi.org/10.1155/2019/6234758
Younus H (2018) Therapeutic potentials of superoxide dismutase. Int J Health Sci 12:88
Goonoo MS, Morris R, Raithatha A, Creagh F (2020) Metformin-associated lactic acidosis: reinforcing learning points. BMJ Case Rep 13(9):e235608. https://doi.org/10.1136/bcr-2020-235608
Blough B, Moreland A, Mora A (2017) Metformin-induced lactic acidosis with emphasis on the anion gap. Bayl Univ Med Cent Proc 28(1):31–33. https://doi.org/10.1080/08998280.2015.11929178
Habig WH, Pabst MJ et al (1974) Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139
Jacob S, Dötsch A, Knoll S, Köhler H-R, Rogall E, Stoll D, Tisler S, Huhn C, Schwartz T, Zwiener C, Triebskorn R (2018) Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)? Environ Sci Eur 30(1):48. https://doi.org/10.1186/s12302-018-0179-4
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Hesham Taher, Mahmoud S. Sabra, Alaa El-Din Salah El-Din, Alaa El-Din H. Sayed declare that we have no conflict of interest.
Ethical statement
Assiut University's Faculty of Science, Zoology Department, Research, Ethical Committee approved the experimental setup and fish handling.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Taher, H., Sabra, M.S., Salah El-Din, A.ED. et al. Hemato-biochemical indices alteration, oxidative stress, and immune suppression in the African catfish (Clarias gariepinus) exposed to metformin. Toxicol. Environ. Health Sci. 14, 361–369 (2022). https://doi.org/10.1007/s13530-022-00150-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13530-022-00150-9