Journal of Kerman University of Medical Sciences

Histopathological Evaluation of the Effect of Metronidazole on the Embryo Skin and Integument Tissues using a Chicken Embryo Model

Document Type : Original Article

Authors

Hadi Tavakkoli 1
Reza Kheirandish 2
Zeynab Moradi 3

1 Associate Professor of Avian Medicine, Department of Clinical Science, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran

2 Professor, of Pathobiology, Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran

3 Student of Veterinary Medicine, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran

Abstract
Background: Metronidazole is categorized in pharmacological group C and few researches have been conducted about its pathological effects on the human fetus. Since the embryogenesis in chicken is similar to that in human beings, in the current study, the toxic effects of this drug on embryo skin and integument tissues were assessed using a chicken embryo model.
Method: The experiment was done on 36 fertilized Ross 308 eggs with the mean egg-weight of (54.4 ± 0.8g). The embryos of the control group received sterile phosphate buffered saline solution into the yolk sac on day 4 of the growing period. The embryos of the two treatment groups received metronidazole at dosages of 50 and 100 mg per Kg body-weight, respectively. The pathological effects of the drug on the embryos’ skin and integument tissues were evaluated using macroscopic and histopathologic studies.
Results: According to the results, metronidazole has adverse effects on the embryo skin and integument tissues during embryonic development. Macroscopic evaluation of the organs revealed white nodules, of about 1mm in diameter, on the skin surface of the embryos. Histopathological effects of the drug consisted of hyperkeratosis, degeneration of the integument tissues and detachment from the epidermis.
Conclusion: Based on the obtained results, it is concluded that consumption of metronidazole during pregnancy can cause adverse effects on the skin and integument tissues of the human fetus. Therefore, the drug should only be given during pregnancy when benefits outweigh its risks.
 

Keywords

skin
Fetus
Histopathologic
Chicken
Metronidazole
  1. Pasupuleti V, Escobedo AA, Deshpande A, Thota P, Roman Y, Hernandez AV. Efficacy of 5-Nitroimidazoles for the Treatment of Giardiasis: A Systematic Review of Randomized Controlled Trials. PLoS Negl Trop Dis 2014; 8(3):2733 -9.
  2. Mombelli A, Almaghlouth A, Cionca N, Courvoisier DS, Giannopoulou C. Differential benefits of amoxicillin–metronidazole in different phases of periodontal therapy in a randomized controlled crossover clinical trial. J Periodontol 2015; 86(3):367-75.
  3. Nishizawa T, Maekawa T, Watanabe N, Harada N, Hosoda Y, Yoshinaga M, et al. Clarithromycin versus metronidazole as first-line Helicobacter pylori eradication: a multicenter, prospective, randomized controlled study in Japan. J Clin Gastroenterol 2015; 49(6):468-71.
  4. Taieb A, Ortonne J, Ruzicka T, Roszkiewicz J, Berth‐Jones J, Peirone M, et al. Superiority of ivermectin 1% cream over metronidazole 0· 75% cream in treating inflammatory lesions of rosacea: a randomized, investigator blinded trial. Br J Dermatol 2015; 172(4):1103-10.
  5. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infection–Results from a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis 2016; 62(11):1380-9.
  6. Williams C, Vacca A, Dunham L, Lloyd D, Coogan MP, Evans G, et al. The redox-active drug metronidazole and thiol-depleting garlic compounds act synergistically in the protist parasite Spironucleus vortens. Mol Biochem Parasitol 2016; 206(1):20-8.
  7. Hobbs K, Stern-Nezer S, Buckwalter MS, Fischbein N, Caulfield AF. Metronidazole-Induced Encephalopathy: Not Always a Reversible Situation. Neurocrit Care 2015; 22(3):429-36.
  8. Wu N, Nguyen J, Ahmed A. A Case Report of Metronidazole-Induced Central Nervous System Complications (P4. 396). Neurology 2016; 86(16 ):396-401.
  9. Thompson KE, Newcomb DL, Moffat GJ, Zalikowski J, Chellman GJ, McNerney ME. Evaluation of early fetal exposure to vaginally-administered metronidazole in pregnant cynomolgus monkeys. Reprod Toxicol 2016; 59:17-21.
  10. Karamanakos P. The possibility of serotonin syndrome brought about by the use of metronidazole. Minerva Anestesiol 2008; 74(11):679-83.
  11. Kazy Z, Puho E, Czeizel AE. Teratogenic potential of vaginal metronidazole treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2005; 123(2):174-8.
  12. Gürcü B, Koca YB, Özkut M, Tuğlu Mİ. Matrix changes due to the toxic effects of metronidazole in intestinal tissue of fish (Onchorhynchus mykiss). Chemosphere 2016; 144:1605-10.
  13. Tiboni GM, Marotta F, Castigliego AP. Teratogenic effects in mouse fetuses subjected to the concurrent in utero exposure to miconazole and metronidazole. Reprod Toxicol 2008; 26(3-4):254-61.
  14. Kołodziejska M, Maszkowska J, Białk-Bielińska A, Steudte S, Kumirska J, Stepnowski P, et al. Aquatic toxicity of four veterinary drugs commonly applied in fish farming and animal husbandry. Chemosphere 2013; 92(9):1253-9.
  15. Heisterberg L. Placental transfer of metronidazole in the first trimester of pregnancy. J Perinat Med 1984; 12(1):43-5.
  16. Sweetman SC, Pharm B, PharmS F. Martindale: The Complete Drug Reference. 36 ed, London, Pharmaceutical Press, 2009.
  17. Männer J, Seidl W, Heinicke F, Hesse H. Teratogenic effects of suramin on the chick embryo. Anat Embryol (Berl) 2003; 206(3):229-37.
  18. Singroha R, Srivastava S, Chhikara P. Effect of Gentamicin on kidney in developing chicks. Eur J Anat 2012; 16(2):119-26.
  19. Cheled-Shoval S, Amit-Romach E, Barbakov M, Uni Z. The effect of in ovo administration of mannan oligosaccharide on small intestine development during the pre-and posthatch periods in chickens. Poult Sci 2011; 90(10):2301-10.
  20. Li X-G, Sui W-G, Yan H-C, Jiang Q-Y, Wang X-Q. The in ovo administration of L-trans pyrrolidine-2, 4-dicarboxylic acid regulates small intestinal growth in chicks. Animal 2014; 8(10):1677-83.
  21. Liu H, Wang J, Chen X, Zhang R, Yu H, Jin H, et al. In ovo administration of rhIGF-1 to duck eggs affects the expression of myogenic transcription factors and muscle mass during late embryo development. J Appl Physiol 2011; 111(6):1789-97.
  22. Kulesa PM, McKinney MC, McLennan R. Developmental imaging: the avian embryo hatches to the challenge. Birth Defects Research Part C: Embryo Today: Reviews 2013; 99(2):121-33.
  23. Jacobsen ID, Grosse K, Hube B. Embryonated chicken eggs as alternative infection model for pathogenic fungi. Methods Mol Biol 2012; 845:487-96.
  24. García-Rubio I, Martínez-Cócera C, Magadán SS, Rodríguez-Jiménez B, Vázquez-Cortés S. Hypersensitivity reactions to metronidazole. Allergol Immunopathol (Madr) 2006; 34(2):70-2.
  25. Reich A, Stander S, Szepietowski JC. Drug-induced pruritus: a review. Acta Derm Venereol 2009; 89(3):236-44.
  26. Riviere JE, Papich MG. Veterinary pharmacology and therapeutics, John Wiley & Sons, 2013.
  27. McClain RM, Downing JC, Edgcomb JE. Effect of metronidazole on fertility and testicular function in male rats. Fundam Appl Toxicol 1989; 12(3):386-96.
  28. Asín-Prieto E, Soraluce A, Trocóniz IF, Cimarras EC, de Ugarte Sobrón JS, Rodríguez-Gascón A, et al. Population pharmacokinetic models for cefuroxime and metronidazole used in combination as prophylactic agents in colorectal surgery: Model-based evaluation of standard dosing regimens. Int J Antimicrob Agents 2015; 45(5):504-11.
  29. Workman P, Twentyman PR, Lee FY, Walton MI. Drug metabolism and chemosensitization. Nitroimidazoles as inhibitors of drug metabolism. Biochem Pharmacol 1983; 32(5):857-64.
  30. Duchêne M. Metronidazole and the Redox Biochemistry of Entamoeba histolytica.  Amebiasis, Springer, 2015. pp. 523-41.
  31. Khan AAP, Khan A, Asiri AM, Azum N, Rub MA, Khan SB, et al. Study of the base-catalysed oxidation of the anti-bacterial and anti-protozoal agent metronidazole by permanganate ion in alkaline medium. Res Chemic Intermed 2014; 40(4):1703-14.
  32. Adams G, Flockhart I, Smithen C, Stratford I, Wardman P, Watts M. Electron-Affinic Sensitization VII. A Correlation between Structures, One-Electron Reduction Potentials, and Efficiencies of Nitroimidazoles as Hypoxic Cell Radiosensitizers. Radiat Res 2012; 178(2):183-9.
  33. Hong CR, Wang J, Hicks KO, Hay MP. Efficient Protocol for the Identification of Hypoxic Cell Radiosensitisers.  Tumor Microenvironment, Springer, 2016. pp. 269-90.

Journal of Kerman University of Medical Sciences
Volume 24, Issue 3
2017
Pages 190-199

Home

Editorial Board

Guide for Authors

Submit Manuscript

Guide for Reviewers

Contact Us