Skip to main content

Advertisement

Log in

Behavioral and immunotoxic effects of Prograf® (tacrolimus) in the male Siamese fighting fish

  • Published:
Ecotoxicology Aims and scope Submit manuscript

Abstract

Siamese fighting fish (Betta splendens) has been extensively exploited in the behavioral and physiological toxicology studies of drugs. Tacrolimus is an immunosuppressant drug largely used in liver and renal transplantations. Here we found that a 7-day exposure of male B. splendens to concentrations of 0.05 and 0.1 µg/mL Prograf® (tacrolimus) caused alterations in aggression and immunity indexes. Tacrolimus exposed fish presented lower opercular display in a mirror test which is indicative of reduced aggression. In addition, serum levels of lysozyme, IgM, alternative complement, and bactericidal activity of subjects exposed to 0.1 µg/mL tacrolimus were lower than those from the control treatment. These results showed the behavioral impairment and immunotoxic impacts of tacrolimus in a model of aquatic toxicology. The results suggest fishes provide a possible model for better understanding of the drug action in vertebrates, and possible consequences for the environment via its effects on non-target organisms in an ecotoxicology context.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Alexander JB, Ingram GA (1992) Noncellular nonspecific defence mechanisms of fish. Annu Rev Fish Dis 2:249–279

    Article  Google Scholar 

  • Alton LA, Portugal SJ, White CR (2013) Balancing the competing requirements of air-breathing and display behaviour during male–male interactions in Siamese fighting fish Betta splendens. Comp Biochem Physiol A Mol Integr Physiol 164:363–367

    Article  CAS  Google Scholar 

  • Bahi A, Guardiola FA, Messina C, Mahdhi A, Cerezuela R, Santulli A, Esteban MA (2017) Effects of dietary administration of fenugreek seeds, alone or in combination with probiotics, on growth performance parameters, humoral immune response and gene expression of gilthead seabream (Sparus aurata L.). Fish Shellfish Immunol 60:50–58

    Article  CAS  Google Scholar 

  • Busse M, Traeger T, Potschke C, Billing A, Dummer A, Friebe E, Broker BM (2008) Detrimental role for cd4+ t lymphocytes in murine diffuse peritonitis due to inhibition of local bacterial elimination. Gut 57:188–195

    Article  CAS  Google Scholar 

  • Castro N, Ros AF, Becker K, Oliveira RF (2006) Metabolic costs of aggressive behaviour in the Siamese fighting fish, Betta splendens. Aggress Behav 32:474–480

    Article  Google Scholar 

  • Chopra A, Das P, Rai A, Kuppuswamy PS, Li X, Huston J, Sola C (2012) Catatonia as a manifestation of tacrolimus-induced neurotoxicity in organ transplant patients: a case series. Gen Hosp Psychiatry 34:209–e9

    Google Scholar 

  • Dehoux JP, Gianello P (2007) The importance of large animal models in transplantation. Front Biosci 12:4864–4880

    Article  CAS  Google Scholar 

  • Dzieweczynski TL, Campbell BA, Marks JM, Logan B (2014) Acute exposure to 17α-ethinylestradiol alters boldness behavioral syndrome in female Siamese fighting fish. Horm Behav 66:577–584

    Article  CAS  Google Scholar 

  • Dzieweczynski TL, Hebert OL (2012) Fluoxetine alters behavioral consistency of aggression and courtship in male Siamese fighting fish, Betta splendens. Physiol Behav 107:92–97

    Article  CAS  Google Scholar 

  • Ekberg H, Bernasconi C, Nöldeke J, Yussim A, Mjörnstedt L, Erken U, Navrátil P (2010) Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study. Nephrol Dial Transplant 25:2004–2010

    Article  CAS  Google Scholar 

  • Forsatkar MN, Nematollahi MA, Brown C (2016) The toxicological effect of Ruta graveolens extract in Siamese fighting fish: a behavioral and histopathological approach. Ecotoxicol 25:824–834

    Article  CAS  Google Scholar 

  • Forsatkar MN, Nematollahi MA, Amiri BM, Huang WB (2014) Fluoxetine inhibits aggressive behaviour during parental care in male fighting fish (Betta splendens, Regan). Ecotoxicol 23:1794–1802

    Article  CAS  Google Scholar 

  • Forsatkar MN, Nematollahi MA, Brown C (2017a) Male Siamese fighting fish use gill flaring as the first display towards territorial intruders. J Ethol 35:51–59

    Article  Google Scholar 

  • Forsatkar MN, Safari O, Boiti C (2017b) Effects of social isolation on growth, stress response, and immunity of zebrafish. Acta Ethol 20:255–261

    Article  Google Scholar 

  • Fung JJ (2004) Tacrolimus and transplantation: a decade in review. Transplantation 77:S41–S43

    Article  CAS  Google Scholar 

  • Giebułtowicz J, Nałęcz-Jawecki G (2016) Occurrence of immunosuppressive drugs and their metabolites in the sewage-impacted Vistula and Utrata Rivers and in tap water from the Warsaw region (Poland). Chemosphere 148:137–147

    Article  Google Scholar 

  • Guardiola FA, Porcino C, Cerezuela R, Cuesta A, Faggio C, Esteban MA (2016) Impact of date palm fruits extracts and probiotic enriched diet on antioxidant status, innate immune response and immune-related gene expression of European seabass (Dicentrarchus labrax). Fish Shellfish Immun 52:298–308

    Article  CAS  Google Scholar 

  • Härtel C, Schumacher N, Fricke L, Ebel B, Kirchner H, Müller-Steinhardt M (2004) Sensitivity of whole-blood T lymphocytes in individual patients to tacrolimus (FK 506): impact of interleukin-2 mRNA expression as surrogate measure of immunosuppressive effect. Clin Chem 50:141–151

    Article  Google Scholar 

  • HedayatiRad M, Nematollahi MA, Forsatkar MN, Brown C (2017) Prozac impacts lateralization of aggression in male Siamese fighting fish. Ecotoxicol Environ Saf 140:84–88

    Article  CAS  Google Scholar 

  • Hisatomi A, Sakuma S, Fujiwara M, Seki J (2008) Effect of tacrolimus on the cauda epididymis in rats: analysis of epididymal biochemical markers or antioxidant defense enzymes. Toxicol 243:23–30

    Article  CAS  Google Scholar 

  • Hwang H, Ghee JY, Song JH, Piao S, Yang CW (2012) Comparison of adverse drug reaction profiles of two tacrolimus formulations in rats. Immunopharmacol Immunotoxicol 34:434–442

    Article  CAS  Google Scholar 

  • Kari G, Rodeck U, Dicker AP (2007) Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharm Ther 82:70–80

    Article  CAS  Google Scholar 

  • Kindt MV, Kemp R, Allen HL, Jensen RD, Patrick DH (1999) Tacrolimus toxicity in rhesus monkey: model for clinical side effects. Transpl Proc 31:3393–3396

    Article  CAS  Google Scholar 

  • Kujawski S, Lin W, Kitte F, Börmel M, Fuchs S, Arulmozhivarman G, Antos CL (2014) Calcineurin regulates coordinated outgrowth of zebrafish regenerating fins. Dev Cell 28:573–587

    Article  CAS  Google Scholar 

  • Lopes CT, Gallo AP, Palma PVB, Cury PM, Bueno V (2008) Skin allograft survival and analysis of renal parameters after FTY720+ tacrolimus treatment in mice. In. Transpl Proc 40:856–60

    Article  CAS  Google Scholar 

  • MacRae CA, Peterson RT (2015) Zebrafish as tools for drug discovery. Nat Rev Drug Discov 14:721

    Article  CAS  Google Scholar 

  • Magnadóttir B (2006) Innate immunity of fish (overview). Fish Shellfish Immun 20:137–151

    Article  Google Scholar 

  • McDaid J, Scott CJ, Kissenpfennig A, Chen H, Martins PN (2015) The utility of animal models in developing immunosuppressive agents. Eur J Pharm 759:295–302

    Article  CAS  Google Scholar 

  • McDonald MD, Gonzalez A, Sloman KA (2011) Higher levels of aggression are observed in socially dominant toadfish treated with the selective serotonin reuptake inhibitor, fluoxetine. Comp Biochem Physiol C Toxicol Pharm 153:107–112

    Article  Google Scholar 

  • Montgomery TM, Brown AC, Gendelman HK, Ota M, Clotfelter ED (2014) Exposure to 17α‐ethinylestradiol decreases motility and ATP in sperm of male fighting fish Betta splendens. Environ Toxicol 29:243–252

    Article  CAS  Google Scholar 

  • Patel P, Patel H, Panchal S, Mehta T (2012) Formulation strategies for drug delivery of tacrolimus: an overview. Int J Pharm Invest 2(4):169–175

    Article  CAS  Google Scholar 

  • Rao YV, Das BK, Jyotyrmayee P, Chakrabarti R (2006) Effect of Achyranthes aspera on the immunity and survival of Labeo rohita infected with Aeromonas hydrophila. Fish Shellfish Immun 20:263–273

    Article  Google Scholar 

  • Saaristo M, Lagesson A, Bertram MG, Fick J, Klaminder J, Johnstone CP, Brodin T (2019) Behavioural effects of psychoactive pharmaceutical exposure on European perch (Perca fluviatilis) in a multi-stressor environment. Sci Total Environ 655:1311–1320

    Article  CAS  Google Scholar 

  • Stevenson LM, Brown AC, Montgomery TM, Clotfelter ED (2011) Reproductive consequences of exposure to waterborne phytoestrogens in male fighting fish Betta splendens. Arch Environ Contam Toxicol 60:501–510

    Article  CAS  Google Scholar 

  • Swain P, Dash S, Sahoo PK, Routray P, Sahoo SK, Gupta SD, Sarangi N (2007) Non-specific immune parameters of brood Indian major carp Labeo rohita and their seasonal variations. Fish Shellfish Immunol 22:38–43

    Article  CAS  Google Scholar 

  • Theodoridi A, Tsalafouta A, Pavlidis M (2017) Acute exposure to fluoxetine alters aggressive behavior of zebrafish and expression of genes involved in serotonergic system regulation. Front Neurosci 11:223

    Article  Google Scholar 

  • Tilahun AY, Karau MJ, Clark CR, Patel R, Rajagopalan G (2012) The impact of tacrolimus on the immunopathogenesis of staphylococcal enterotoxin-induced systemic inflammatory response syndrome and pneumonia. Microbes Infect 14:528–536

    Article  CAS  Google Scholar 

  • Venkatasubramanian H, Selvaraj V, Ramasamy M, Santhakumar K (2018) Effect of Fadrozole exposure on socioreproductive behaviors and neurochemical parameters in Betta splendens. Zebrafish https://doi.org/10.1089/zeb.2018.1595.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was partly funded by the Young Researchers and Elite Club, Karaj Branch, Islamic Azad University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammad Navid Forsatkar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Javanshir Khoei, A., Forsatkar, M.N. & Brown, C. Behavioral and immunotoxic effects of Prograf® (tacrolimus) in the male Siamese fighting fish. Ecotoxicology 28, 1032–1037 (2019). https://doi.org/10.1007/s10646-019-02103-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10646-019-02103-4

Keywords

Navigation