Download fulltext
HTML
Delkhosh, A., Shabani, F., & Delashoub, M. (2024). Experimental accelerating testicular tissue recovery post-methotrexate treatment in rats: A promising role of Sertoli cell-conditioned medium: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 22(4), 295–304. https://doi.org/10.18502/ijrm.v22i4.16390
https://doi.org/10.18502/ijrm.v22i4.16390
statistics
- 44 Abstract Views
- 27 PDF Views
- 0 HTML Views
authors
-
Aref Delkhosh
Aref Delkhosh
Department of Pathobiology, Faculty of Veterinary Medicine, Division of Pathology, Urmia University, Urmia, Iran.
-
Fatemeh Shabani
Fatemeh Shabani
Midwifery Department, Faculty of Nursing and Midwifery, Tabriz University of Medical Sciences, Tabriz, Iran.
-
Masoud Delashoub
Masoud Delashoub
Department of Basic Sciences, Faculty of Veterinary Medicine, Tabriz Medical Sciences, Islamic Azad University, Tabriz, Iran.
Published Date
- Jun 8, 2024
Experimental accelerating testicular tissue recovery post-methotrexate treatment in rats: A promising role of Sertoli cell-conditioned medium: An experimental study
Abstract
Background: Methotrexate (MET) is one of the most important chemotherapy agents used against various tumors and cancer diseases. One of the critical side effects of MET is inducing male infertility.
Objective: The current study aimed to investigate Sertoli cell culture-conditioned medium (SCM) recovery effects on MET-induced conditions in rats.
Materials and Methods: 30 mature male Wistar rats were randomly divided into 3 groups (n = 10). In the first group, rats received normal saline intraperitoneally. In the second group, animals received MET (10 mg/kg; intraperitoneally) once a week for 2 wk. The rats in the third group (MET+SCM) received MET and a single injection of SCM for 56 days post-MET administration. 56 days later, serum, epididymis, and testicular tissue samples were collected, and the animals were euthanized. Sperm parameters, serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone were examined. The testicular tissues were stained using hematoxylin and eosin solution, and histopathological changes were analyzed.
Results: The MET-induced condition resulted in significant pathological changes in the testis, decreased hormone levels, and downregulated sperm parameters. However, SCM injection improved hormonal levels, testicular changes, and sperm parameters.
Conclusion: It can be concluded that a single intra-testicular SCM injection accelerates male reproductive system recovery post-MET treatment.
Key words: Sertoli cell, Conditioned culture media, Methotrexate, Testis, Histopathology, Rats.
References
[1] Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertil Steril 2018; 109: 20–26.
[2] Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 2020; 16: 145–154.
[3] Gutierrez JC, Hwang K. The toxicity of methotrexate in male fertility and paternal teratogenicity. Exp Opin Drug Metab Toxicol 2017; 13: 51–58.
[4] Daggulli M, Dede O, Utangac MM, Bodakci MN, Hatipoglu NK, Penbegul N, et al. Protective effects of carvacrol against methotrexate-induced testicular toxicity in rats. Int J Clin Exp Med 2014; 7: 5511.
[5] Sayed AM, Hassanein EH, Ali FE, Omar ZM, Rashwan EK, Mohammedsaleh ZM, et al. Regulation of Keap-1/Nrf2/AKT and iNOS/NF-?B/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis. Life Sci 2021; 284: 119911.
[6] Ahmed AA, Selim MA, El-Sayed NM. ??-Lipoic acid ameliorates oral mucositis and oxidative stress induced by methotrexate in rats: Histological and immunohistochemical study. Life Sci 2017; 171: 51–59.
[7] Aflatoonian B, Ruban L, Jones M, Aflatoonian R, Fazeli A, Moore HD. In vitro post-meiotic germ cell development from human embryonic stem cells. Hum Reprod 2009; 24: 3150–3159.
[8] Parekh PA, Garcia TX, Hofmann M-C. Regulation of GDNF expression in Sertoli cells. Reproduction 2019; 157: R95- R107.
[9] Bernardino RL, Dias TR, Moreira BP, Cunha M, Barros A, Oliveira E, et al. Carbonic anhydrases are involved in mitochondrial biogenesis and control the production of lactate by human Sertoli cells. FEBS J 2019; 286: 1393– 1406.
[10] Ghaem Maghami R, Mirzapour T, Bayrami A. Differentiation of mesenchymal stem cells to germlike cells under induction of Sertoli cell-conditioned medium and retinoic acid. Andrologia 2018; 50: e12887.
[11] Panahi S, Karamian A, Sajadi E, Aliaghaei A, Nazarian H, Abdi S, et al. Sertoli cell-conditioned medium restores spermatogenesis in azoospermic mouse testis. Cell Tissue Res 2020; 379: 577–587.
[12] Nouri HS, Azarmi Y, Movahedin M. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats. Andrologia 2009; 41: 105–110.
[13] Minas A, Talebi H, Ray MT, Eisalou MY, Alves MG, Razi M. Insulin treatment to type 1 male diabetic rats protects fertility by avoiding testicular apoptosis and cell cycle arrest. Gene 2021; 799: 145847.
[14] Mobarak H, Rahbarghazi R, Nouri M, Heidarpour M, Mahdipour M. Intratesticular versus intraperitoneal injection of busulfan for the induction of azoospermia in a rat model. BMC Pharmacol Toxicol 2022; 23: 50.
[15] Rastogi D, Narayan R, Saxena D, Chowdhuri DK. Endosulfan induced cell death in Sertoli-germ cells of male Wistar rat follows intrinsic mode of cell death. Chemosphere 2014; 94: 104–115.
[16] Zaker H, Razi M, Mahmoudian A, Soltanalinejad F. Boosting effect of testosterone on GDNF expression in Sertoli cell line (TM4); comparison between TM3 cellsproduced and exogenous testosterone. Gene 2022; 812: 146112.
[17] Akyash F, Aflatoonian R, Yazd EF, Golzadeh J, Tahajjodi SS, Moore H. Testicular sperm extraction derived cells conditioned medium as an in vitro niche supports germ cells development from human embryonic stem cells. Proceedings of the 35th Annual Meeting of the Europian Society for Human Reprodactive and Embryology. Viena, Austria 2019 Jun.
[18] Maadi MA, Minas A, Sepehri Vafa R, Tabatabaei-Naeini A, Bertolla RP. Apoptotic balance during testicular detorsion after one hour induced torsion in rats. Andrologia 2022; 54: e14349.
[19] Minas A, Najafi G, Jalali AS, Razi M. Fennel induces cytotoxic effects against testicular germ cells in mice; evidences for suppressed pre-implantation embryo development. Environ Toxicol 2018; 33: 841–850.
[20] Badri S, Vanithakumari G, Malini T. Studies on methotrexate effects on testicular steroidogenesis in rats. Endocr Res 2000; 26: 247–262.
[21] Minas A, Fernandes ACC, Maciel Júnior VL, Adami L, Intasqui P, Bertolla RP. Influence of physical activity on male fertility. Andrologia 2022; 54: e14433.
[22] Mansour DF, Saleh DO, Ahmed-Farid OA, Rady M, Bakeer RM, Hashad IM. Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: Targeting oxidative stress, energy deficit and spermatogenesis. Biomed Pharmacother 2021; 143: 112201.
[23] Shoorei H, Khaki A, Shokoohi M, Khaki A, Alihemmati A, Moghimian M, et al. Evaluation of carvacrol on pituitary and sexual hormones and their receptors in the testicle of male diabetic rats. Hum Exp Toxicol 2020; 39: 1019–1030.
[24] Rebourcet D, Wu J, Cruickshanks L, Smith SE, Milne L, Fernando A, et al. Sertoli cells modulate testicular vascular network development, structure, and function to influence circulating testosterone concentrations in adult male mice. Endocrinology 2016; 157: 2479–2488.
[25] Takashima S, Kanatsu-Shinohara M, Tanaka T, Morimoto H, Inoue K, Ogonuki N, et al. Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal. Stem Cell Reports 2015; 4: 489–502.
[26] Belhan S, Çomakli S, Küçükler S, Gülyüz F, Yildirim S, Yener Z. Effect of chrysin on methotrexate-induced testicular damage in rats. Andrologia 2019; 51: e13145.
[27] Zarei L, Shahrooz R. Protective effects of cornus mas fruit extract on methotrexate-induced alterations in mice testicular tissue: Evidences for histochemical and histomorphometrical changes in an animal model study. Vet Res Forum 2019; 10: 307–313.
[28] Nayernia K, Lee JH, Drusenheimer N, Nolte J, Wulf G, Dressel R, et al. Derivation of male germ cells from bone marrow stem cells. Lab Invest 2006; 86: 654–663.
[29] Morikawa M, Derynck R, Miyazono K. TGF-?? and the TGF-?? family: Context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 2016; 8: a021873.
[30] Monfared MH, Minaee B, Rastegar T, Khrazinejad E, Barbarestani M. Sertoli cell condition medium can induce germ like cells from bone marrow derived mesenchymal stem cells. Iran J Basic Med Sci 2016; 19: 1186–1192.
[2] Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 2020; 16: 145–154.
[3] Gutierrez JC, Hwang K. The toxicity of methotrexate in male fertility and paternal teratogenicity. Exp Opin Drug Metab Toxicol 2017; 13: 51–58.
[4] Daggulli M, Dede O, Utangac MM, Bodakci MN, Hatipoglu NK, Penbegul N, et al. Protective effects of carvacrol against methotrexate-induced testicular toxicity in rats. Int J Clin Exp Med 2014; 7: 5511.
[5] Sayed AM, Hassanein EH, Ali FE, Omar ZM, Rashwan EK, Mohammedsaleh ZM, et al. Regulation of Keap-1/Nrf2/AKT and iNOS/NF-?B/TLR4 signals by apocynin abrogated methotrexate-induced testicular toxicity: Mechanistic insights and computational pharmacological analysis. Life Sci 2021; 284: 119911.
[6] Ahmed AA, Selim MA, El-Sayed NM. ??-Lipoic acid ameliorates oral mucositis and oxidative stress induced by methotrexate in rats: Histological and immunohistochemical study. Life Sci 2017; 171: 51–59.
[7] Aflatoonian B, Ruban L, Jones M, Aflatoonian R, Fazeli A, Moore HD. In vitro post-meiotic germ cell development from human embryonic stem cells. Hum Reprod 2009; 24: 3150–3159.
[8] Parekh PA, Garcia TX, Hofmann M-C. Regulation of GDNF expression in Sertoli cells. Reproduction 2019; 157: R95- R107.
[9] Bernardino RL, Dias TR, Moreira BP, Cunha M, Barros A, Oliveira E, et al. Carbonic anhydrases are involved in mitochondrial biogenesis and control the production of lactate by human Sertoli cells. FEBS J 2019; 286: 1393– 1406.
[10] Ghaem Maghami R, Mirzapour T, Bayrami A. Differentiation of mesenchymal stem cells to germlike cells under induction of Sertoli cell-conditioned medium and retinoic acid. Andrologia 2018; 50: e12887.
[11] Panahi S, Karamian A, Sajadi E, Aliaghaei A, Nazarian H, Abdi S, et al. Sertoli cell-conditioned medium restores spermatogenesis in azoospermic mouse testis. Cell Tissue Res 2020; 379: 577–587.
[12] Nouri HS, Azarmi Y, Movahedin M. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats. Andrologia 2009; 41: 105–110.
[13] Minas A, Talebi H, Ray MT, Eisalou MY, Alves MG, Razi M. Insulin treatment to type 1 male diabetic rats protects fertility by avoiding testicular apoptosis and cell cycle arrest. Gene 2021; 799: 145847.
[14] Mobarak H, Rahbarghazi R, Nouri M, Heidarpour M, Mahdipour M. Intratesticular versus intraperitoneal injection of busulfan for the induction of azoospermia in a rat model. BMC Pharmacol Toxicol 2022; 23: 50.
[15] Rastogi D, Narayan R, Saxena D, Chowdhuri DK. Endosulfan induced cell death in Sertoli-germ cells of male Wistar rat follows intrinsic mode of cell death. Chemosphere 2014; 94: 104–115.
[16] Zaker H, Razi M, Mahmoudian A, Soltanalinejad F. Boosting effect of testosterone on GDNF expression in Sertoli cell line (TM4); comparison between TM3 cellsproduced and exogenous testosterone. Gene 2022; 812: 146112.
[17] Akyash F, Aflatoonian R, Yazd EF, Golzadeh J, Tahajjodi SS, Moore H. Testicular sperm extraction derived cells conditioned medium as an in vitro niche supports germ cells development from human embryonic stem cells. Proceedings of the 35th Annual Meeting of the Europian Society for Human Reprodactive and Embryology. Viena, Austria 2019 Jun.
[18] Maadi MA, Minas A, Sepehri Vafa R, Tabatabaei-Naeini A, Bertolla RP. Apoptotic balance during testicular detorsion after one hour induced torsion in rats. Andrologia 2022; 54: e14349.
[19] Minas A, Najafi G, Jalali AS, Razi M. Fennel induces cytotoxic effects against testicular germ cells in mice; evidences for suppressed pre-implantation embryo development. Environ Toxicol 2018; 33: 841–850.
[20] Badri S, Vanithakumari G, Malini T. Studies on methotrexate effects on testicular steroidogenesis in rats. Endocr Res 2000; 26: 247–262.
[21] Minas A, Fernandes ACC, Maciel Júnior VL, Adami L, Intasqui P, Bertolla RP. Influence of physical activity on male fertility. Andrologia 2022; 54: e14433.
[22] Mansour DF, Saleh DO, Ahmed-Farid OA, Rady M, Bakeer RM, Hashad IM. Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: Targeting oxidative stress, energy deficit and spermatogenesis. Biomed Pharmacother 2021; 143: 112201.
[23] Shoorei H, Khaki A, Shokoohi M, Khaki A, Alihemmati A, Moghimian M, et al. Evaluation of carvacrol on pituitary and sexual hormones and their receptors in the testicle of male diabetic rats. Hum Exp Toxicol 2020; 39: 1019–1030.
[24] Rebourcet D, Wu J, Cruickshanks L, Smith SE, Milne L, Fernando A, et al. Sertoli cells modulate testicular vascular network development, structure, and function to influence circulating testosterone concentrations in adult male mice. Endocrinology 2016; 157: 2479–2488.
[25] Takashima S, Kanatsu-Shinohara M, Tanaka T, Morimoto H, Inoue K, Ogonuki N, et al. Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal. Stem Cell Reports 2015; 4: 489–502.
[26] Belhan S, Çomakli S, Küçükler S, Gülyüz F, Yildirim S, Yener Z. Effect of chrysin on methotrexate-induced testicular damage in rats. Andrologia 2019; 51: e13145.
[27] Zarei L, Shahrooz R. Protective effects of cornus mas fruit extract on methotrexate-induced alterations in mice testicular tissue: Evidences for histochemical and histomorphometrical changes in an animal model study. Vet Res Forum 2019; 10: 307–313.
[28] Nayernia K, Lee JH, Drusenheimer N, Nolte J, Wulf G, Dressel R, et al. Derivation of male germ cells from bone marrow stem cells. Lab Invest 2006; 86: 654–663.
[29] Morikawa M, Derynck R, Miyazono K. TGF-?? and the TGF-?? family: Context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol 2016; 8: a021873.
[30] Monfared MH, Minaee B, Rastegar T, Khrazinejad E, Barbarestani M. Sertoli cell condition medium can induce germ like cells from bone marrow derived mesenchymal stem cells. Iran J Basic Med Sci 2016; 19: 1186–1192.