Abstract
The aim of this study was to investigate the beneficial effects of vitamin K relate to protection against detrimental effects of bromadiolone. Wistar rats (n = 30) were divided in three groups (n = 10): control group and two groups treated with bromadiolone (0.12 mg/kg) and bromadiolone + vitamin K (0.12 mg/kg + 100 mg/kg) over the period of four days. The main findings in the bromadiolone-exposed rats, such as damaged hepatocytes, high levels of globulin, total proteins and lymphocytes, and altered albumin/globulin ratio, collectively indicate an acute inflammatory process. Morphological changes in erythrocytes include microcytosis, hypochromia, hyperchromia, hemolysis, stomatocytosis, and spherocytosis. Significantly low values of RBC, Hct, and hemoglobin concentrations indicate impairments of the hematopoietic pathway causing combined anemia. The selected dose of bromadiolone caused a non-significant increase of catalase activity and a significant increase of the total protein content in brain tissue homogenates. Vitamin K supplementation reduced many of the harmful effects of bromadiolone. The cytoprotective role of vitamin K was proved to be of great importance for the preservation of structural changes on the membranes of hepatocytes and erythrocytes, in addition to the known role in the treatment of coagulopathies. The results of the study suggest valuable properties of vitamin K in the prevention and treatment of various types of anemia caused by bromadiolone toxicity. Future research is necessary to determine the adequate dose and treatment duration with vitamin K in disorders caused by the cumulative action of bromadiolone and possibly other pesticides.
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Lefebvre S, Fourel I, Queffélec S, Vodovar D, Mégarbane B, Benoit E, Siguret V, Lattard V (2017) Poisoning by anticoagulant rodenticides in humans and animals: Causes and consequences. In: Malangu N (ed) Poisoning - from specific toxic agents to novel rapid and simplified techniques for analysis. IntechOpen. https: //doi.org/ https://doi.org/10.5772/intechopen.69955.
Marangoni MN, Martynowycz MW, Kuzmenko I, Braun D, Polak PE, Weinberg G, Rubinstein I, Gidalevitz D, Feinstein DL (2016) Membrane cholesterol modulates superwarfarin toxicity. Biophys J 110:1777–1788. https://doi.org/10.1016/j.bpj.2016.03.004
Fisher P, Campbell KJ, Howald GR, Warburton B (2019) Anticoagulant rodenticides. Islands and animal welfare accountancy Animals (Basel) 9:919. https://doi.org/10.3390/ani9110919
Radi ZA, Thompson LJ (2004) Renal subcapsular hematoma associated with brodifacoum toxicosis in a dog. Vet Hum Toxicol 46:83–84
Lefebvre S, Benoit E, Lattard V (2016) Comparative biology of the resistance to vitamin K antagonists: An overview of the resistance mechanisms. In: Basaran O, Biteker M (ed) Anticoagulation therapy. https://doi.org/10.5772/64204
Damin-Pernik M, Espana B, Lefebvre S, Fourel I, Caruel H, Benoit E, Lattard V (2017) Management of rodent populations by anticoagulant rodenticides: toward third-generation anticoagulant rodenticides. Drug Metab Dispos 45:160–165. https://doi.org/10.1124/dmd.116.073791
Vandenbroucke V, Bousquet-Melou A, De Backer P, Croubels S (2008) Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration. J Vet Pharmacol Ther 31:437–445. https: //doi.org/ https://doi.org/10.1111/j.1365-2885.2008.00979.x
Damin-Pernik M, Espana B, Besse S, Fourel I, Caruel H, Popowycz F, Benoit E, Lattard V (2016) Development of an ecofriendly anticoagulant rodenticide based on the stereochemistry of Difenacoum. Drug Metab Dispos 44:1872–1880. https://doi.org/10.1124/dmd.116.071688
Boettcher S, Wacker A, Moerike K, Kopp HG, Jaschonek K, Grobosch T, Kanz L, Salih HR (2011) Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen. Eur J Haematol 86:173–175. https://doi.org/10.1111/j.1600-0609.2010.01550.x
Pitt WC, Higashi M, Primus TM (2011) The effect of cooking on diphacinone residues related to human consumption of feral pig tissues. Food Chem Toxicol 49:2030–2034. https://doi.org/10.1016/j.fct.2011.05.014
Kammerer M, Pouliquen H, Pinault L, Loyau M (1998) Residues depletion in egg after warfarin ingestion by laying hens. Vet Hum Toxicol 40:273–275
De Swiet M, Lewis PJ (1977) Excretion of anticoagulants in human milk. N Engl J Med 297:1471. https://doi.org/10.1056/nejm197712292972614
Serieys LEK, Armenta TC, Moriarty JG, Boydston EE, Lyren LM, Poppenga RH, Crooks KR, Wayne RK, Riley SP (2015) Anticoagulant rodenticides in urban bobcats: exposure, risk factors and potential effects based on a 16-year study. Ecotoxicol 24:844–862. https://doi.org/10.1007/s10646-015-1429-5
Hughes J, Sharp E, Taylor MJ, Melton L, Hartley G (2013) Monitoring agricultural rodenticide use and secondary exposure of raptors in Scotland. Ecotoxicology 22:974–984. https://doi.org/10.1007/s10646-013-1074-9
Thomas PJ, Mineau P, Shore RF, Champoux L, Martin PA, Wilson LK, Fitzgerald G, Elliott JE (2011) Second generation anticoagulant rodenticides in predatory birds: Probabilistic characterisation of toxic liver concentrations and implications for predatory bird populations in Canada. Environ Int 37: 914–920 Doi: https://doi.org/10.1016/j.envint.2011.03.010
Christensen TK, Lassen P, Elmeros M (2012) High exposure rates of anticoagulant rodenticides in predatory bird species in intensively managed landscapes in Denmark. Arch Environ Contam Toxicol 63:437–444. https://doi.org/10.1007/s00244-012-9771-6
Ruiz-Suárez N, Henríquez-Hernández LA, Valerón PF, Boada LD, Zumbado M, Camacho M, Almeida-González M, Luzardo OP (2014) Assessment of anticoagulant rodenticide exposure in six raptor species from the Canary Islands (Spain). Sci Total Environ 485:371–376. https://doi.org/10.1016/j.scitotenv.2014.03.094
United States Environmental Protection Agency. Pesticide Fact Sheet. Name of Chemical: Difenacoum reason for issuance: New rodenticide. Off. Prev. Pestic. Toxic Subst. 2007, 7501C. Available online: https: //www 3.epa.gov/pesticides/chem_search/reg_actions/registration/fs_PC-011901_01-Sep-07.pdf
Revathi K, Yoganonda M (2006) Effect of bromadiolone on haematology, liver and kidney in Mus musculus. J Environ Biol 27:135–140
Jeantet AY, Truchet M, Naulleau G, Martoja R (1991) Effects of bromadiolone on some organs and tissues (liver, kidney, spleen, blood) of coypu (Myocastor coypus). CR Acad Sci 312:149–156
World Health Organization & Food and Agriculture Organization of the United Nations (1996) WHO/FAO data sheet on pesticides. no.88, Bromadiolone. World Health Organization. https: //apps.who.int/iris/handle/10665/63287.
Haffa A, Krueger D, Bruner J, Engelke J, Gundberg C, Akhter M, Binkley N (2000) Diet or warfarin-induced vitamin K insufficiency elevates circulating undercarboxylated osteocalcin without altering skeletal status in growing female rats. J Bone Miner Res 15:872–878. https://doi.org/10.1359/jbmr.2000.15.5.872
Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market. http: //data.europa.eu/eli/dir/1998/8/oj.
Frankova M, Stejskal V, Aulicky R (2019) Efficacy of rodenticide baits with decreased concentrations of brodifacoum: validation of the impact of the new EU anticoagulant regulation. Sci Rep 9:16779. https://doi.org/10.1038/s41598-019-53299-8
AVMA Guidelines for the Euthanasia of Animals. 2020 ed. https: //www.avma.org/sites/default/files/2020-01/2020-Euthanasia-Final-1-17-20.pdf.
UNESCO - Universal Declaration of Animal Rights 17–10–1978. http: //www.esdaw.eu/unesco.html.
World Society for the Protection of Animals 2020. Universal Declaration on Animal Welfare. https: //europaregina.eu/business-ethics/animal-ethics/universal-declaration-on-animal-welfare/
Suljević D, Sulejmanović J, Fočak M, Halilović E, Pupalović D, Hasić A, Alijagic A (2021) Assessing hexavalent chromium tissue-specific accumulation patterns and induced physiological responses to probe chromium toxicity in Coturnix japonica quail. Chemosphere 266:129005. https://doi.org/10.1016/j.chemosphere.2020.129005
Suljevic D, Corbic A, Islamagic E, Focak M, Filipic F, Alijagic A (2019) Impairments of bone marrow hematopoietic cells followed by the sever erythrocyte damage and necrotic liver as the outcome of chronic in vivo exposure to cadmium: novel insights from quails. Environ Toxicol Pharmacol 72:103250. https://doi.org/10.1016/j.etap.2019.103250
Suljevic D, Focak M, Filipic F, Hamzic N, Zubcevic N, Alijagic A (2018) Haematopoiesis in the European common toad Bufo bufo (Linnaeus, 1758): new methodological insights to study general, seasonal, and sexual haematopoietic distribution and maturation pattern. Turk J Zoo 42:198–206. https://doi.org/10.3906/zoo-1706-18
Ibragić S, Fehratović E, Suljević D, Mitrašinović-Brulić M (2021) Artificial sweeteners elicit oxidative stress in rat brain and development of microcytic anemia: Promising protective effects of vitamin C. J Res Pharm 25:117–123 Doi: https://doi.org/10.29228/jrp.2
Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177:751–766
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126
Gül N, Yiğit N, Saygılı F, Demirel E, Geniş C (2016) Comparison of the effects of difenacoum and brodifacoum on the ultrastructure of rat liver cells. Arh Hig Rada Toksikol 67:204–209. https://doi.org/10.1515/aiht-2016-67-2783
El-Daly AA, Nassar SA (2014) Anticogulant Difenacoum-induced histological and ultrastructural alterations in liver of albino rats. Int J Adv Res 2:782–792
Binev RG, Valchev I, Groseva N, Lazarov L, Hristov T, Uzunova K (2012) Morphological investigations of experimental acute intoxication with the anticoagulant rodenticide bromadiolone in pheasants. İstanbul Üniv Vet Fak Derg 38:161–173
DuVall M, Murphy M, Ray A, Reagor J (1989) Case studies on second-generation anticoagulant rodenticide toxicities in nontarget species. J Vet Diagn Invest 1: 66–68 Doi: https://doi.org/10.1177/104063878900100118
Bachmann KA, Sullivan TJ (1983) Dispositional andpharmacodynamic characteristics of brodifacoum in warfarin-sensitive rats. Pharmacol 27: 281–288. https://doi.org/10.1159/000137881
Mosterd JJ, Thijssen HH (1991) The long-term effects of the rodenticide, brodifacoum, on blood coagulation and vitamin K metabolism in rats. Br J Pharmacol 104:531–535. https://doi.org/10.1111/j.1476-5381.1991.tb12463.x
Suttie JW (1987) Recent advances in hepatic vitamin K metabolism and function. Hepatology 7:367–376. https://doi.org/10.1002/hep.1840070226
Zuo W, Zhang X, Chang JB, Ma WB, Wei JJ (2019) Bromadiolone poisoning leading to subarachnoid haemorrhage: A case report and review of the literature. J Clin Pharm Ther 44:958–962. https://doi.org/10.1111/jcpt.13005
Lee HJ, You MR, Moon WR, Sul H, Chung CH, Park CY, Park SG (2014) Evaluation of risk factors in patients with vitamin K-dependent coagulopathy presumed to be caused by exposure to brodifacoum. Korean J Intern Med 29:498–508. https://doi.org/10.3904/kjim.2014.29.4.498.
Wadelius M, Pirmohamed M (2007) Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 7:99–111. https://doi.org/10.1038/sj.tpj.6500417.
Eason CT, Murphy EC, Wright GR, Spurr EB (2002) Assessment of risks of brodifacoum to non-target birds and mammals in New Zealand. Ecotoxicology 11:35–48. https://doi.org/10.1023/a:1013793029831
Hattori SM, Makkai HPS, Becker K (1990) Feed value of some browse plants. Central Zone of Delta State, Nigeria 39:97–104
Kaneko JJ (1997) Serum proteins and the dysproteinemias. In: Kaneko JJ (ed) Clinical biochemistry of domestic animals. Academic press, San Diego (CA), pp 117–138
Zaias J, Mineau M, Cray C, Yoon D, Altman NH (2009) Reference values for serum proteins of common laboratory rodent strains. J Am Assoc Lab Anim Sci 48:387–390
Olfert ED, Godson DL (2000) Humane endpoints for infectious disease animal models. ILAR J 41:99–104. https://doi.org/10.1093/ilar.41.2.99
Card DJ, Francis S, Deuchande K, Harrington DJ (2014) Superwarfarin poisoning and its management. BMJ Case Rep Article ID bcr2014206360. https://doi.org/10.1136/bcr-2014-206360.
Altay S, Cakmak HA, Boz GC, Koca S, Velibey Y (2012) Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning. Cardiovasc J Afr 23:9–11. https://doi.org/10.5830/CVJA-2012-051
Binev R, Petkov P, Rusenov A (2005) Intoxication with anticoagulant rodenticide bromadiolone in a dog - a case report. Vet Arhiv 75:273–282
Kalinin S, Marangoni N, Kowal K, Dey A, Lis K, Brodsky S, van Breemen R, Hauck Z, Ripper R, Rubinstein I, Weinberg G, Feinstein DL (2017) The long-lasting rodenticide brodifacoum induces neuropathology in adult male rats. Toxicol Sci 159:224–237. https://doi.org/10.1093/toxsci/kfx134
Jang W, Kim J, Chae H, Kim M, Koh KN, Park CJ, Kim Y (2019) Hereditary spherocytosis caused by copy number variation in SPTB gene identified through targeted next-generation sequencing. Int J Hematol 10:250–254. https://doi.org/10.1007/s12185-019-02630-0
Manciu S, Matei E, Trandafir B (2017) Hereditary spherocytosis - diagnosis, surgical treatment and outcomes. A literature review. Chirurgia (Bucur) 112:110–116. https://doi.org/10.21614/chirurgia.
Sawhney A, Johal M (2000) Erythrocyte Alterations Induced by Malathion in Channa punctatus (Bloch). Bull Environ Contam Toxicol 64:398–405. https://doi.org/10.1007/s001280000014
Agrawal D, Gupta GSD, Shukla JS, Dutta KK, Ray PK (1990) Effect of methyl isocyanate (MIC) on rat erythrocytes. Arch Toxicol 64:332–335. https://doi.org/10.1007/BF01972995
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84. https://doi.org/10.1016/j.biocel.2006.07.001
Mansour SA, Mossa AH (2009) Lipid peroxidation and oxidative stress in rat erythrocytes induced by chlorpyrifos and the protective effect of zinc. Pestic Biochem Physiol 93:34–39. https://doi.org/10.1016/j.pestbp.2008.09.004
Abdel-Daim MM, Samak DH, El-Sayed YS, Aleya L, Alarifi S, Alkahtani S (2019) Curcumin and quercetin synergistically attenuate subacute diazinon-induced inflammation and oxidative neurohepatic damage, and acetylcholinesterase inhibition in albino rats. Environ Sci Pollut Res Int 26:3659–3665. https://doi.org/10.1007/s11356-018-3907-9
Sodhi S, Brar RS, Banga HS (2017) Bromadiolone induced oxidative stress and cytological damage in layer birds. Int J Adv Vet Sci Tech. 6:340–345. https://doi.org/10.23953/cloud.ijavst.272.
Akbel E, Arslan-Acaroz D, Demirel HH, Kucukkurt I, Ince S (2018) The subchronic exposure to malathion, an organophosphate pesticide, causes lipid peroxidation, oxidative stress, and tissue damage in rats: the protective role of resveratrol. Toxicol Res (Camb) 7:503–512. https://doi.org/10.1039/c8tx00030a
Ghasemnejad-Berenji M, Nemati M, Pourheydar B, Gholizadeh S, Karimipour M, Mohebbi I, Jafari A (2021) Neurological effects of long-term exposure to low doses of pesticides mixtures in male rats: biochemical, histological, and neurobehavioral evaluations. Chemosphere 264:128464. https://doi.org/10.1016/j.chemosphere.2020.128464
Jafari M, Salehi M, Ahmadi S, Asgari A, Abasnezhad M, Hajigholamali M (2012) The role of oxidative stress in diazinon-induced tissues toxicity in Wistar and Norway rats. Toxicol Mech Methods 22:638–647. https://doi.org/10.3109/15376516.2012.716090
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Damir Suljević involved in conceptualization, methodology, validation, formal analysis, data curation, writing – original draft, and writing – review and editing. Saida Ibragić participated in formal analysis, methodology, data curation, writing – original draft, and writing – review and editing. Maja Mitrašinović-Brulić took part in methodology, validation, and formal analysis. Muhamed Fočak involved in methodology, validation, formal analysis, and writing – original draft editing.
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Suljević, D., Ibragić, S., Mitrašinović-Brulić, M. et al. Evaluating the effects of anticoagulant rodenticide bromadiolone in Wistar rats co-exposed to vitamin K: impact on blood–liver axis and brain oxidative status. Mol Cell Biochem 477, 525–536 (2022). https://doi.org/10.1007/s11010-021-04303-1
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DOI: https://doi.org/10.1007/s11010-021-04303-1