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Advances in Clinical Toxicology Research Article 18 min read

A Mini Review on Reproductive Toxicity of Cyclosporine in Male Animals

Oyovwi Mega O*
* Corresponding author
ISSN: 2577-4328  10.23880/act-16000307  Received: April 23, 2024  Published: May 09, 2024
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Keywords
Reproduction Toxicity Cyclosporine Oxidative Stress Inflammation Immunosuppression
Abstract

Cyclosporine is an immunosuppressive drug that is widely used in organ transplantation and autoimmune diseases. However, its potential reproductive toxicity in male animals is not fully understood. This mini-review aims to provide an overview of the current knowledge on the reproductive toxicity of cyclosporine in male animals, focusing on its effects on spermatogenesis, sperm quality, and fertility. A literature search was conducted using PubMed, Google Scholar, and other databases to identify relevant studies. Studies have shown that cyclosporine can have various adverse effects on spermatogenesis in male animals, including decreased sperm production, impaired sperm motility, and increased sperm abnormalities. Cyclosporine can also affect sperm quality by reducing sperm concentration, viability, and DNA integrity. These effects may result in decreased fertility in male animals. The available evidence suggests that cyclosporine has reproductive toxic effects in male animals. Further research is needed to fully elucidate the mechanisms of action and to develop strategies to mitigate these effects.

Introduction

Cyclosporine is a potent immunosuppressive drug used to prevent rejection in organ transplantation, treat autoimmune diseases such as rheumatoid arthritis and psoriasis, and manage severe allergic reactions [1]. Its discovery revolutionized organ transplantation, significantly improving patient outcomes. However, concerns have emerged regarding cyclosporine’s potential reproductive effects. This review aims to summarize the current knowledge on the reproductive effects of cyclosporine in male animals.

Evidence from Research from Animal studies has shown that cyclosporine inhibits spermatogenesis, reducing sperm count and motility [2, 3, 4]. In humans, cyclosporine therapy has been associated with azoospermia (absence of sperm) and decreased sperm quality [5, 6]. Cyclosporine can disrupt the menstrual cycle, causing irregular periods or amenorrhea (absence of periods) [7]. It may also damage ovarian follicles, leading to premature ovarian failure and infertility.

Cyclosporine exerts its reproductive toxicity primarily through its effects on the hypothalamus-pituitary-gonadal (HPG) axis [4, 8]. It inhibits the release of gonadotropin- releasing hormone (GnRH) from the hypothalamus, which in turn suppresses the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland [4]. As a result, testosterone production by the testes is decreased [9]. In addition to its effects on the HPG axis, Cyclosporine has also been shown to directly affect testicular function [10]. It can induce apoptosis (programmed cell death) in Leydig cells, which are responsible for testosterone production Drobnis, et al. Cyclosporine can also disrupt spermatogenesis, leading to reduced sperm count and motility [4]. Cyclosporine is known to inhibit calcineurin, a key enzyme involved in immune cell signaling [11]. Calcineurin inhibition can disrupt cellular processes in the testes, leading to impaired spermatogenesis and sperm function [12].

Cyclosporine and Male Reproductive System

Cyclosporine is primarily metabolized by cytochrome P450 enzymes, particularly CYP3A4, in the liver [13]. The main metabolite is M17 (AMO1), which is further metabolized to M21 (AMO2) [13]. Both M17 and M21 have immunosuppressive activity, but to a lesser extent than cyclosporine. Studies have shown that cyclosporine and its metabolites distribute to various tissues and organs, including the male reproductive system [3, 14]. In the testes, cyclosporine concentrates in the seminiferous tubules, where spermatogenesis occurs [15]. It also accumulates in the epididymis and seminal vesicles.

Cyclosporine has been shown to inhibit spermatogenesis, the process of sperm production. Studies have demonstrated a dose-dependent decrease in sperm count and seminiferous tubule diameter in men treated with cyclosporine [16, 17]. This inhibition is believed to occur through various mechanisms, including: Inhibition of testosterone synthesis, Induction of oxidative stress, and Alteration of Sertoli cell function [4]. In addition to impaired spermatogenesis, cyclosporine can also affect sperm morphology and motility [4]. Although, Men treated with cyclosporine have been found not to have an incidence of abnormal sperm quality [18].

Cyclosporine inhibits the synthesis of testosterone by Leydig cells [19, 20]. This effect is dose-dependent, with higher doses leading to more pronounced suppression. The reduced testosterone levels can result in hypogonadism, a condition characterized by low testosterone levels and its associated symptoms, such as decreased libido, erectile dysfunction, and infertility [4, 21]. Cyclosporine disrupts the steroidogenesis pathway in Leydig cells, which is responsible for the synthesis of testosterone [3, 10]. It inhibits the activity of enzymes involved in the production of precursors to testosterone, such as cholesterol and pregnenolone [4]. This disruption leads to a decline in testosterone production and an accumulation of intermediates in the steroidogenesis pathway. In addition to reducing testosterone production and impairing steroidogenesis, cyclosporine has been associated with other effects on Leydig cells, including: Decreased cell viability, Alterations in gene expression and Reduced responsiveness to luteinizing hormone (LH), the hormone that stimulates testosterone production.

Animal Studies on Cyclosporine’s Reproductive Toxicity

Studies in rats and mice have demonstrated that cyclosporine administration leads to dose-dependent alterations in spermatogenesis [4, 10, 22, 23]. High doses of cyclosporine (e.g., 50-100 mg/kg/day) result in significant reductions in sperm count, motility, and normal morphology [24, 25]. These effects are attributed to cyclosporine’s inhibition of spermatid maturation and Sertoli cell function. Animal studies have also explored the impact of cyclosporine on fertility and reproductive parameters [3]. Administration of cyclosporine has been shown to decrease fertility rates in male rodents Oyovwi, et al. [26, 27]. This is associated with impaired sperm quality and reduced sperm transport. Additionally, cyclosporine can alter hormone levels (e.g., testosterone, luteinizing hormone) involved in reproductive function [28, 29, 30]. Beyond its effects on spermatogenesis and fertility, cyclosporine has been linked to other reproductive abnormalities in rodents. These include testicular atrophy, decreased libido, and alterations in epididymal sperm maturation [4]. The mechanisms underlying these effects are not fully understood but may involve oxidative stress, inflammation, impaired androgenic hormones and enzymes and immune dysregulation [3, 4, 31].

Mechanism of Cyclosporine-Induced reproductive Toxicity

Immunosuppressive Effects

Cyclosporine primarily targets T lymphocytes, inhibiting their activation and proliferation [32]. This immunosuppressive action can disrupt the immune tolerance required for successful reproduction. It may impair the development of regulatory immune cells, leading to an imbalance between pro- and anti-inflammatory responses. Notably, Cyclosporine exerts its immunosuppressive action by inhibiting calcineurin, a phosphatase that plays a crucial role in T-cell activation [33, 34, 35, 36]. By blocking calcineurin, cyclosporine suppresses the production of interleukin-2 (IL-2), a cytokine essential for T-cell proliferation and differentiation [37]. This immunosuppressive effect has implications for reproductive function.

Oxidative Stress

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the body’s antioxidant defenses. Cyclosporine increases the production of reactive oxygen species (ROS) in the reproductive organs [38, 39]. Cyclosporine can impair mitochondrial function, leading to increased ROS production [40, 41]. Cyclosporine activates NADPH oxidase, an enzyme that generates ROS in immune cells [42, 43]. Excessive ROS can damage cellular components, including DNA, proteins, and lipids [44]. This oxidative stress can impair gamete function, embryo development, and placental integrity [45, 46]. Cyclosporine can reduce the activity of antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase, making cells more susceptible to oxidative damage [4, 47]. Oxidative stress can damage sperm, oocytes, and reproductive tissues [4]. In male rats, cyclosporine-induced oxidative stress has been associated with decreased sperm motility, morphology, and viability [4].

Inflammatory Responses

Cyclosporine triggers inflammatory responses by activating pro-inflammatory cytokines and suppressing anti-inflammatory mediators [48]. Chronic inflammation in the reproductive organs can damage tissues, disrupt hormonal balance, and inhibit reproductive processes [49]. Cyclosporine inhibits the nuclear factor kappa B (NF- κB), a transcription factor that regulates the expression of pro-inflammatory cytokines [50, 51]. By inhibiting NF- κB, cyclosporine promotes the release of inflammatory mediators. Cyclosporine activates mitogen-activated protein kinase (MAPK) pathways, which are involved in the production of inflammatory cytokines and chemokines [51]. Cyclosporine also activates signal transducer and activator of transcription (STAT) proteins, which regulate the expression of genes involved in inflammation and immune responses [52]. Cyclosporine treatment increases the levels of pro- inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interferon-gamma (IFN-γ) [53]. Cyclosporine also stimulates the production of chemokines, which attract immune cells to the site of inflammation [54]. Cyclosporine-induced inflammation is associated with increased production of ROS, which can damage cellular components and contribute to oxidative stress [4]. Cyclosporine-induced inflammation leads to testicular damage, including germ cell apoptosis, Leydig cell dysfunction, and impaired spermatogenesis [4]. Cyclosporine has been linked to ovarian toxicity, including follicular atresia, disruption of ovulation, and reduced fertility [55]. More so, Cyclosporine treatment can cause endometrial inflammation, which may interfere with implantation and pregnancy maintenance [56].

Hormonal Imbalances

Cyclosporine can interfere with the hypothalamic- pituitary-gonadal axis, leading to hormonal imbalances [4]. It may suppress the release of gonadotropins (LH and FSH), which are essential for fertility [3]. Additionally, it can alter the production of sex hormones (estrogen, progesterone, and testosterone), affecting fertility [3, 57]. In male rats, cyclosporine has been shown to inhibit the synthesis of testosterone by Leydig cells in the testes [16]. This leads to decreased serum testosterone levels, resulting in impaired spermatogenesis and reduced sperm counts [3, 4]. Cyclosporine can affect the pituitary-gonadal axis, which regulates hormone production [58, 59]. It has been found to inhibit the hypothalamic hypophyseal gonadal axis in transplant patients Watkins PB, et al. [60] which may alter the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, leading to decreased LH and FSH secretion from the pituitary gland. This disruption of the axis further contributes to gonadal hormone imbalances. Cyclosporine has been shown to interfere with steroidogenesis, the process of hormone production in the gonads [3]. It inhibits the activity of key enzymes involved in steroid synthesis, such as cytochrome P450 enzymes [61]. This impairment can lead to decreased production of testosterone, estrogen, and other sex hormones. Cyclosporine’s immunosuppressive effects can also contribute to reproductive toxicity [4]. It suppresses the immune system, which can lead to inflammation and damage to reproductive tissues. This inflammation can disrupt hormone production and impair fertility [56]. In addition to hormonal imbalances, cyclosporine has been linked to other mechanisms of reproductive toxicity, such as oxidative stress, mitochondrial dysfunction, and changes in gene expression [62, 63, 64]. These mechanisms can further contribute to impaired spermatogenesis, oogenesis, and fertility.

Mitochondrial Dysfunction

Mitochondria are the energy powerhouses of cells and play a crucial role in spermatogenesis. Cyclosporine has been shown to impair mitochondrial function in reproductive tissues [63]. Mitochondria are responsible for energy production and play a crucial role in gamete maturation, fertilization, and embryo development [65]. Mitochondrial dysfunction can lead to reduced ATP levels, and oxidative stress .ATP depletion and oxidative stress impair sperm maturation and motility. Mitochondrial damage triggers apoptotic pathways in developing sperm. Oxidative stress damages sperm DNA, compromising fertility.

Conclusion

Cyclosporine exhibits reproductive toxicity in male animals, primarily affecting testicular function, sexual behavior, and the prostate gland. These effects are likely mediated by the inhibition of steroidogenesis, alterations in hormonal balance, and oxidative stress. Further research is needed to fully understand the mechanisms of cyclosporine’s reproductive toxicity and to develop strategies to mitigate its adverse effects.

Ethical Clearance Statement

This article does not contain any studies with animals performed by any of the authors. Informed consent was obtained from all authors included in the study.

Funding

This research was not funded

Author Contribution

Oyovwi Mega Obukohwo participated in sorting and conceptualizing the manuscript and wrote the manuscript. Oyovwi Mega Obukohwo Tang organized the literature and presented ideas. Oyovwi Mega Obukohwo read and approved the submitted version. Oyovwi Mega Obukohwo is responsible for the contribution. The author contributed to the revision of the manuscript, read and approved the submitted version.

CRediT Authorship Contribution Statement

Oyovwi Mega Obukohwo: Resources. Oyovwi Mega Obukohwo: Investigation. Oyovwi Mega Obukohwo: Writing – review & editing. Oyovwi Mega Obukohwo: Writing – review & editing. Oyovwi Mega Obukohwo: Writing – original draft. Oyovwi Mega Obukohwo: Writing – original draft Oyovwi Mega Obukohwo: Writing – review & editing.

Declaration of Competing Interest

The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank the reviewers for their helpful comments.

Data Availability

No data was used for the research described in the article.

References

  1. Hussain Y, Khan H (2022) Immunosuppressive drugs. Encyclopedia of infection and immunity, pp: 726- 740.
  2. Baykalir BG, Seven PT, Gur S, Seven I (2018) The effects of propolis on sperm quality, reproductive organs and testicular antioxidant status of male rats treated with cyclosporine-A. Animal Reproduction 13(2): 105-111.
  3. Oyovwi MO, Ben-Azu B, Edesiri TP, Arientare RR, Emojevwe V, et al. (2022) Lutein attenuates cyclosporin-induced testicular impairment in male rats through modulation of androgenic hormones and enzymes.  Pharmacology and Toxicology of Natural Medicines 2(1): 12-24.
  4. Oyovwi OM, Ben-Azu B, Tesi EP, Emojevwe V, Rotu RA, et al. (2024) Possible mechanisms involved in the protective effect of lutein against cyclosporine-induced testicular damage in rats. Heliyon 10(3): e24989.
  5. Drobnis EZ, Nangia AK (2017) Immunosuppressants and male reproduction. Adv Exp Med Biol 1034: 179-210.
  6. Shenuka S, Thiyagarajan T, Kumar RS (2019) A Review on the Effect of Immunosuppressants on Fertility. Research Journal of Pharmacy and Technology 12(3): 1441-1447.
  7. Nonato DR, Barbosa VS, Rodrigues DL, Amaral PC, Assis MR, et al. (2010) Menstrual disturbances in systemic lupus erythematosus patients using immunossuppressants.  Bras J Rheumatol  50(5): 501- 515.
  8. Akintunde JK, Farouk AA, Mogbojuri O (2019) Metabolic treatment of syndrome linked with Parkinson’s disease and hypothalamus pituitary gonadal hormones by turmeric curcumin in Bisphenol-A induced neuro- testicular dysfunction of wistar rat.  Biochemistry and biophysics reports 17: 97-107.
  9. Oyovwi MO, Kingsley NE, Rume RA, Victor E (2021) The concept of male reproductive anatomy.  Male Reproductive anatomy.
  10. He Z, Qiu J, Li J, Zhao D, Chen G, et al. (2013, March) Long-term effects of conversion from cyclosporine to rapamycin on testicular function and morphology in a rat transplantation model. In  Transplantation proceedings 45(2): 763-769.
  11. Jørgensen KA, Koefoed‐Nielsen PB, Karamperis N (2003) Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus. Scandinavian journal of immunology 57(2): 93-98.
  12. Liu Y, Zhang C, Wang S, Hu Y, Jing J, et al. (2020) Dependence of sperm structural and functional integrity on testicular calcineurin isoform PPP3R2 expression.  Journal of Molecular Cell Biology 12(7): 515-529.
  13. Picard N, Djebli N, Sauvage FL, Marquet P (2007) Metabolism of sirolimus in the presence or absence of cyclosporine by genotyped human liver microsomes and recombinant cytochromes P450 3A4 and 3A5. Drug metabolism and disposition 35(3): 350-355.
  14. Patocka J, Nepovimova E, Kuca K, Wu W (2021) Cyclosporine A: chemistry and toxicity–a review. Current medicinal chemistry 28(20): 3925-3934.
  15. Abdul-Hamid M, Abdella EM, Galaly SR, Ahmed RH (2016) Protective effect of ellagic acid against cyclosporine A-induced histopathological, ultrastructural changes, oxidative stress, and cytogenotoxicity in albino rats. Ultrastructural Pathology 40(4): 205-221.
  16. Turk G, Atessahin A, Sonmez M, Yuce A, Ceribasi AO (2007) Lycopene protects against cyclosporine A-induced testicular toxicity in rats.  Theriogenology  67(4): 778- 785.
  17. Turk G, Sonmez M, Ceribasi AO, Yuce A, Atessahin A (2010) Attenuation of cyclosporine A-induced testicular and spermatozoal damages associated with oxidative stress by ellagic acid.  International immunopharmacology 10(2): 177-182.
  18. Haberman J, Karwa G, Greenstein SM, Soberman R, Glicklich D, et al. (1991) Male fertility in cyclosporine- treated renal transplant patients.  The Journal of urology 145(2): 294-296.
  19. Seethalakshmi L, Flores C, Malhotra RK, Pallias JD, Tharakan D, et al. (1992) The Mechanism of Cyclosporine’s Action in the Inhibition of Testosterone Biosynthesis by Rat Leydig Cells in-vitro.  Transplantation  53(1): 190- 194.
  20. Pan X, Wang X, Wang X, Zhang W, Sun Z, et al. (2018) Protective effects of new Wenshen Shengjing Decoction on cyclosporineinduced impairment of testosterone synthesis and spermatogenic apoptosis.  Experimental and Therapeutic Medicine 15(1): 813-821.
  21. Cohen J, Nassau DE, Patel P, Ramasamy R (2020) Low testosterone in adolescents & young adults. Frontiers in endocrinology 10: 494570.
  22. Gawish AM, ElFiky S, Therase M, AbdElraaof A, Khalil W, et al. (2016) Sperm abnormality toxicity due to cyclosporine A and the ameliorative effect of royal jelly in male rats. The Journal of Basic & Applied Zoology 76: 60-73.
  23. Shukry M, Alotaibi SS, Albogami SM, Fathallah N, Farrag F, et al. (2020) Garlic alleviates the injurious impact of cyclosporine-A in male rats through modulation of fibrogenic and steroidogenic genes. Animals 11(1): 64.
  24. Olshan AF, Mattison DR, Zwanenburg TSB (1994) Cyclosporine A: Review of genotoxicity and potential for adverse human reproductive and developmental effects: Report of a working group on the genotoxicity of cyclosporine A, August 18, 1993. Mutation Research/ Reviews in Genetic Toxicology 317(2): 163-173.
  25. de Lion Siervo GEM, Mariani NAP, Silva AAS, Punhagui- Umbelino APF, da Costa IR, et al. (2023) Low dose of cyclosporine A disrupts sperm parameters and testosterone levels reversibly in mice.  Toxicology and Applied Pharmacology 460: 116374.
  26. Srinivas M, Agarwala S, Gupta SD, Das SN, Jha P, et al. (1998) Effect of cyclosporine on fertility in male rats. Pediatric surgery international 13: 388-391.
  27. Krueger BA, Trakshel GM, Sluss PM, Maines MD (1991) Cyclosporin-mediated depression of luteinizing hormone receptors and heme biosynthesis in rat testes: a possible mechanism for decrease in serum testosterone. Endocrinology 129(5): 2647-2654.
  28. Shin WY, Li SZ, Chung SS, Lee HC, Huh KB, et al. (2000) Effects of cyclosporin A on sex hormone and estrogen receptor in male rat with special reference to cyclosporin A-induced osteoporosis.  Yonsei medical journal  41(1): 61-67.
  29. Adebayo AA, Babatola LJ, Fasanya CB, Oboh G (2022) Persea americana seed extract restores defective sperm quality and biochemical parameters relevant to reproduction in male wistar rats treated with cyclosporine A.  Journal of Food Biochemistry  46(11): e14220.
  30. Yazdani I, Majdani R, Ghasemnejad-Berenji M, Dehpour AR (2022) Beneficial effects of Cyclosporine A in combination with Nortriptyline on germ cell-specific apoptosis, oxidative stress and epididymal sperm qualities following testicular ischemia/reperfusion in rats: a comparative study.  BMC Pharmacology and Toxicology 23(1): 59.
  31. Miroux C, Morales O, Ghazal K, Othman SB, de Launoit Y, et al. (2012) In vitro effects of cyclosporine A and tacrolimus on regulatory T-cell proliferation and function. Transplantation 94(2): 123-131.
  32. Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, et al. (1996) The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol 80(3): S40-S45.
  33. Batiuk TD (1996) Cyclosporine immunosuppression: the role of calcineurin phosphatase inhibition.
  34. Rovira P, Mascarell L, Truffa-Bachi P (2000) The impact of immunosuppressive drugs on the analysis of T-cell activation. Current medicinal chemistry 7(7): 673-692.
  35. Hamawy MM, Knechtle SJ (2003) An overview of the actions of cyclosporine and FK506.  Transplantation Reviews 17(4): 165-171.
  36. Fellman CL, Archer TM, Wills RW, Mackin AJ (2019) Effects of cyclosporine and dexamethasone on canine T cell expression of interleukin-2 and interferon-gamma. Veterinary immunology and immunopathology 216: 109-892.
  37. Baykalir BG, Seven PT, Gur S, Seven IJAR (2018) The effects of propolis on sperm quality, reproductive organs and testicular antioxidant status of male rats treated with cyclosporine-A. Animal Reproduction (AR) 13(2): 105-111.
  38. Ghazipour AM, Shirpoor A, Ghiasi R, Pourheydar B, Khalaji N, et al. (2020) Cyclosporine A induces testicular injury via mitochondrial apoptotic pathway by regulation of mir-34a and sirt-1 in male rats: The rescue effect of curcumin. Chem Biol Interact 327:109180.
  39. DeHornedo JP, De Arriba G, Fernández MC, Benito S, Cid TP (2007) Cyclosporin A causes oxidative stress and mitochondrial dysfunction in renal tubular cells. Nefrologia 27(5): 565-573.
  40. Illsinger S, Janzen N, Lücke T, Bednarczyk J, Schmidt KH, et al. (2011) Cyclosporine A: impact on mitochondrial function in endothelial cells.  Clinical transplantation 25(4): 584-593.
  41. Lee J (2010) Use of antioxidants to prevent cyclosporine a toxicity. Toxicol Res 26(3): 163-170.
  42. Wu Q, Wang X, Nepovimova E, Wang Y, Yang H, et al. (2018) Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings. Food Chem Toxicol 118: 889-907.
  43. Juan CA, Pérez de la Lastra JM, Plou FJ, Pérez-Lebeña E (2021) The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies. Int J Mol Sci 22(9): 4642.
  44. Gualtieri R, Kalthur G, Barbato V, Longobardi S, Di Rella F, et al. (2021) Sperm Oxidative Stress during In Vitro Manipulation and Its Effects on Sperm Function and Embryo Development. Antioxidants (Basel) 10(7): 1025.
  45. Deluao JC, Winstanley Y, Robker RL, Pacella-Ince L, Gonzalez MB, et al. (2022) Oxidative Stress and Reproductive Function: Reactive Oxygen Species in the Mammalian Pre-Implantation Embryo. Reproduction 164(6): F95-F108.
  46. Ergüder IB, Cetin R, Devrim E, Kiliçoğlu B, Avci A, et al. (2005) Effects of cyclosporine on oxidant/antioxidant status in rat ovary tissues: protective role of black grape extract. Int Immunopharmacol (7-8): 1311-1315.
  47. Gui Q, Jiang Z, Zhang L (2021) Insights into the modulatory role of cyclosporine A and its research advances in acute inflammation.  International Immunopharmacology 93: 107420.
  48. Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, et al. (2016) Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Human reproduction update 22(1): 104-115.
  49. Ge Y, Xu Y, Sun W, Man Z, Zhu L, et al. (2012) The molecular mechanisms of the effect of Dexamethasone and Cyclosporin A on TLR4/NF-κB signaling pathway activation in oral lichen planus. Gene 508(2): 157-164.
  50. Arab HH, Ashour AM, Alqarni AM, Arafa ESA, Kabel AM (2021) Camel milk mitigates cyclosporine-induced renal damage in rats: targeting p38/ERK/JNK MAPKs, NF-κB, and matrix metalloproteinases. Biology 10(5): 442.
  51. Khattri S, Shemer A, Rozenblit M, Dhingra N, Czarnowicki T, et al. (2014) Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. Journal of Allergy and Clinical Immunology 133(6): 1626-1634.
  52. Cataldi C, Mari NL, Lozovoy MAB, Martins LMM, Reiche EMV, et al. (2019) Proinflammatory and anti-inflammatory cytokine profiles in psoriasis: use as laboratory biomarkers and disease predictors. Inflammation Research 68: 557-567.
  53. Kountouras J, Zavos C, Chatzopoulos D (2004) Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease.  Journal of cellular and molecular medicine 8(3): 317-328.
  54. Leroy C, Rigot JM, Leroy M, Decanter C, Le Mapihan K, et al. (2015) Immunosuppressive drugs and fertility. Orphanet journal of rare diseases 10: 1-15.
  55. Janssen NM, Genta MS (2000) The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Archives of internal medicine 160(5): 610-619.
  56. Gore-Langton RE (1988) Cyclosporine differentially affects estrogen and progestin synthesis by rat granulosa cells in vitro.  Molecular and cellular endocrinology 57(3): 187-198.
  57. Sikka SC, Bhasin S, Coy DC, Koyle MA, Swerdloff RS, Rajfer J (1988) Effects of cyclosporine on the hypothalamic- pituitary-gonadal axis in the male rat: mechanism of action. Endocrinology 123(2): 1069-1074.
  58. Esquifino AI, Moreno ML, Arce A, Agrasal C, Pérez-Díaz J, et al. (1995) Effects of cyclosporine at the hypothalamic- pituitary axis in pituitary-grafted young female rats. Journal of endocrinology 144(1): 159-164.
  59. Ramirez G, Narvarte J, Bittle PA, Ayers-Chastain C, Dean SE (1991) Cyclosporine-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients. Nephron 58(1): 27-32.
  60. Watkins PB (1990) The role of cytochromes P-450 in cyclosporine metabolism. Journal of the American Academy of Dermatology 23(6): 1301-1311.
  61. Abdul-Hamid M, Abdella EM, Galaly SR, Ahmed RH (2016) Protective effect of ellagic acid against cyclosporine A-induced histopathological, ultrastructural changes, oxidative stress, and cytogenotoxicity in albino rats. Ultrastructural Pathology 40(4): 205-221.
  62. Ghazipour AM, Shirpoor A, Ghiasi R, Pourheydar B, Khalaji N, et al. (2020) Cyclosporine A induces testicular injury via mitochondrial apoptotic pathway by regulation of mir-34a and sirt-1 in male rats: The rescue effect of curcumin. Chemico-Biological Interactions 327: 109180.
  63. Wan M, Huang L, Liu J, Liu F, Chen G, et al. (2021) Cyclosporine A induces cardiac developmental toxicity in zebrafish by up-regulation of wnt signaling and oxidative stress. Frontiers in Pharmacology 12: 747991.
  64. May-Panloup P, Boguenet M, El Hachem H, Bouet PE, Reynier P (2021) Embryo and its mitochondria. Antioxidants 10(2): 139.
  65. Tesi EP, Ben‐Azu B, Mega OO, Mordi J, Knowledge OO, et al. (2022) Kolaviron, a flavonoid‐rich extract ameliorates busulfan‐induced chemo‐brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways. Journal of food biochemistry 46(4): e14071.
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@article{oyovwi2024,
  title   = {A Mini Review on Reproductive Toxicity of Cyclosporine in Male 
Animals},
  author  = {Oyovwi Mega O},
  journal = {Advances in Clinical Toxicology},
  year    = {2024},
  volume  = {9},
  number  = {2},
  doi     = {10.23880/act-16000307}
}
Oyovwi Mega O (2024). A Mini Review on Reproductive Toxicity of Cyclosporine in Male 
Animals. Advances in Clinical Toxicology, 9(2). https://doi.org/10.23880/act-16000307
TY  - JOUR
TI  - A Mini Review on Reproductive Toxicity of Cyclosporine in Male 
Animals
AU  - Oyovwi Mega O
JO  - Advances in Clinical Toxicology
PY  - 2024
VL  - 9
IS  - 2
DO  - 10.23880/act-16000307
ER  -