Farelere Uygulanan Paklitaksel’in Testis Dokusu Üzerine Etkileri
Yıl 2025,
Cilt: 9 Sayı: 3, 301 - 309, 22.12.2025
Sadık Küçükgünay
,
Oya Korkmaz
,
Ali Erdem Öztürk
,
Ayşe Sari
,
Halime Tozak Yıldız
,
Halil İbrahim Kuz
,
Mustafa Numan Bucak
Öz
Amaç: Kemoterapötik ilaçlar, sperm kalitesini ve erkek fertilitesini etkileyerek üreme bozukluklarına neden olabilir. Birçok kanser türünün tedavisinde aktif olarak kullanılan paklitaksel (PTS), dokularda oksidatif stresin artmasına neden olarak toksik etki gösterir. Mevcut çalışmada, farelere PTS uygulaması yapılarak PTS'nin erkek üreme sistemi üzerindeki hasar verici etkilerinin ortaya konulması amaçlandı.
Araçlar ve Yöntem: Çalışmada 8-10 haftalık erkek Balb/c cinsi fareler kullanıldı. Her bir grupta n:5 olacak şekilde hayvanlar rastgele seçildi. 1, 3 ve 5. günlerde intraperitoneal olarak kontrol grubu farelerine serum fizyolojik, PTS grubu farelerine ise 2 mg/kg PTS uygulandı. Hayvanlar, deneyin sonunda (7. gün) sakrifiye edildi, testis dokuları toplandı ve histopatolojik incelemeler (Hematoksilen-eozin, Masson trikrom, Periyodik asit schiff) yapıldı. Ayrıca farelerden sperm örnekleri toplandı, yayma preparatlar hazırlandı ve DNA kromatin bütünlüğü Toluidin mavisi boyama ile değerlendirildi.
Bulgular: PTS grubunda testis histolojik yapısında bozulmalar gözlendi. Seminifer tübüllerde bozulma, germinal epiteldeki spermatojenik seri hücrelerinde azalma, seminifer tübüllerin bazal membranında bozulma, interstisyel bağ dokuda azalma, ödem ve hemoraji gözlendi. Ayrıca, PTS grubunda zayıf bir peritübüler interstisyel doku reaksiyonu ve leydig hücrelerinde azalma mevcuttu. Gruplar DNA kromatin bütünlüğü bakımından karşılaştırıldığında, PTS grubunda DNA bütünlüğünde bozulmanın yüksek düzeyde olduğu ve gruplar arasında istatistiksel olarak anlamlı bir farklılık belirlendi (p=0.009).
Sonuç: Elde ettiğimiz bulgular, PTS'nin fare testis dokusunda toksisiteye neden olabileceğini ve sperm DNA integritesini olumsuz olarak etkileyerek erkek infertilitesine neden olabileceğini göstermektedir.
Etik Beyan
Etik Kurul Onayı Kırşehir Ahi Evran Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu'ndan alındı (Tarih: 27/06/2024; Karar no: 12/6).
Kaynakça
-
1. World Health Organization. Cancer prevention and control in the context of an integrated approach. World Health Assembly Resolution WHA70. Geneva, Switzerland: World Health Organization; 2017.
-
2. Vurgun H, Sezer G, Yay A. The role of autophagy in paclitaxel and cremophor induced damage to rat testis. Biotech Histochem. 2022;97(6):433-440.
-
3. Gur C, Kandemir FM, Caglayan C, Satıcı E. Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways. Chem Biol Interact. 2022;365:110073.
-
4. Aboelwafa HR, Ramadan RA, El-Kott AF, Abdelhamid FM. The protective effect of melatonin supplementation against taxol-induced testicular cytotoxicity in adult rats. Braz J Med Biol Res. 2022;55:11614.
-
5. Okkay U, Ferah Okkay I, Cicek B, ve ark. Achillea millefolium alleviates testicular damage in paclitaxel-intoxicated rats via attenuation of testicular oxido-inflammatory stress and apoptotic responses. Andrologia. 2021;53(5):14028.
-
6. Semet M, Paci M, Saïas-Magnan J, ve ark. The impact of drugs on male fertility: a review. Andrology. 2017;5(4):640-663.
-
7. Kumaresan A, Johannisson A, Al-Essawe EM, Morrell JM. Sperm viability, reactive oxygen species, and DNA fragmentation index combined can discriminate between above- and below-average fertility bulls. J Dairy Sci. 2017;100(7):5824-5836.
-
8. Neuhauser S, Bollwein H, Siuda M, Handler J. Effects of Different Freezing Protocols on Motility, Viability, Mitochondrial Membrane Potential, Intracellular Calcium Level, and DNA Integrity of Cryopreserved Equine Epididymal Sperm. J Equine Vet Sci. 2019;82:102801.
-
9. Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod. 2010;16(1):3-13.
-
10. Didion BA, Kasperson KM, Wixon RL, Evenson DP. Boar fertility and sperm chromatin structure status: a retrospective report. J Androl. 2009;30(6):655-660.
-
11. Peris-Frau P, Álvarez-Rodríguez M, Martín-Maestro A, ve ark. Comparative evaluation of DNA integrity using sperm chromatin structure assay and Sperm-Ovis-Halomax during in vitro capacitation of cryopreserved ram spermatozoa. Reprod Domest Anim. 2019;54 (4):46-49.
-
12. Chi HJ, Kim SG, Kim YY, ve ark. ICSI significantly improved the pregnancy rate of patients with a high sperm DNA fragmentation index. Clin Exp Reprod Med. 2017;44(3):132-140.
-
13. Aktaş İ, Gur FM, Bilgiç S. Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats. Prostaglandins Other Lipid Mediat. 2024;171:106813.
-
14. Gür FM, Bilgiç S. Silymarin, an antioxidant flavonoid, protects the liver from the toxicity of the anticancer drug paclitaxel. Tissue Cell. 2023;83:102158.
-
15. Gür FM, Aktaş İ. Silymarin Protects Kidneys from Paclitaxel-Induced Nephrotoxicity. Turkish JAF Sci. Tech. 2022;10:452-458.
-
16. Ito Y, Unagami M, Yamabe F, ve ark. A method for utilizing automated machine learning for histopathological classification of testis based on Johnsen scores. Sci Rep. 2021;11(1):9962.
-
17. Talebi AR, Vahidi S, Aflatoonian A, ve ark. Cytochemical evaluation of sperm chromatin and DNA integrity in couples with unexplained recurrent spontaneous abortions. Andrologia. 2012;44(1):462-470.
-
18. Kankılıç NA, Küçükler S, Gür C, ve ark. Naringin protects against paclitaxel-induced toxicity in rat testicular tissues by regulating genes in pro-inflammatory cytokines, oxidative stress, apoptosis, and JNK/MAPK signaling pathways. J Biochem Mol Toxicol. 2024;38(7):23751.
-
19. Drechsel KCE, Broer SL, van Breda HMK, ve ark. Semen analysis and reproductive hormones in boys with classical Hodgkin lymphoma treated according to the EuroNet-PHL-C2 protocol. Hum Reprod. 2024;39(11):2411-2422.
-
20. Aktaş İ, Yahyazadeh A. Protective potential of misoprostol against kidney alteration via alleviating oxidative stress in rat following exposure to paclitaxel. Tissue Cell. 2022;79:101966.
-
21. Çomaklı S, Özdemir S, Güloğlu M. Chrysin attenuates paclitaxel-induced hepatorenal toxicity in rats by suppressing oxidative damage, inflammation, and apoptosis. Life Sci. 2023;332:122096.
-
22. Shokoohi M, Khaki A, Shoorei H, ve ark. Hesperidin attenuated apoptotic-related genes in testicle of a male rat model of varicocoele. Andrology. 2020;8(1):249-258.
-
23. Cicek B, Hacimuftuoglu A, Kuzucu M, ve ark. Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries. Pharmaceuticals (Basel). 2023;16(2):221.
-
24. Borovskaya TG, Goldberg VE, Rumpel OA, ve ark. The rat spermatogenesis after injection of paclitaxel (antitumor agent). Bull Exp Biol Med. 2009;147(6):715-718.
-
25. Borovskaya TG, Shchemerova YA, Poluektova ME, ve ark. Mechanisms of reparative regeneration of rat testis after injection of paclitaxel. Bull Exp Biol Med. 2014;156(4):483-485.
-
26. Ghafouri-Fard S, Shoorei H, Abak A, ve ark. Effects of chemotherapeutic agents on male germ cells and possible ameliorating impact of antioxidants. Biomed Pharmacother. 2021;142:112040.
-
27. Wang Z, Teng Z, Wang Z, ve ark. Melatonin ameliorates paclitaxel-induced mice spermatogenesis and fertility defects. J Cell Mol Med. 2022;26(4): 1219-1228.
-
28. Toraman E, Budak B, Bayram C, ve ark. Role of parthenolide in paclitaxel-induced oxidative stress injury and impaired reproductive function in rat testicular tissue. Chem Biol Interact. 2024;387: 110793.
-
29. Dygai AM, Chaikovskii AV, Zhdanov VV, ve ark. Responses of Spermatogenous Tissue and Mechanisms of Their Development Upon Cytostatic Exposure. Bull Exp Biol Med. 2015;159(6):743-746.
-
30. Aksu EH, Kandemir FM, Küçükler S, Mahamadu A. Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. J Biochem Mol Toxicol. 2018;32(11):22201.
-
31. Moradi Maryamneghari S, Shokri-Asl V, Abdolmaleki A, Jalili C. Genetic, biochemical and histopathological evaluations of thymoquinone on male reproduction system damaged by paclitaxel in Wistar rats. Andrologia. 2021;53(10):14192.
-
32. Sarıözkan S, Türk G, Eken A, ve ark. Gilaburu (Viburnum opulus L.) fruit extract alleviates testis and sperm damages induced by taxane-based chemotherapeutics. Biomed Pharmacother. 2017;95: 1284-1294.
-
33. Zhang Y, Liu Y, Teng Z, ve ark. Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility. Biol Res. 2023;56(1):47.
-
34. Ili P, Sari F, Bucak MN, ve ark. DNA damaging effect of paclitaxel in the epididymal sperms as a chemotherapeutic agent and possible remedies to prevent this effect: A study on reproductive potential of male cancer patients of reproductive age. Theriogenology. 2019;132:201-211.
-
35. Balcıoğlu E, Göktepe Ö, Tan FC, Bilgici P, Yakan B, Özdamar S. The role of curcumin against paclitaxel-induced oxidative stress and DNA damage in testes of adult male rats. Turk J Med Sci. 2023;53(1):40-50.
-
36. Abd-Elrazek AM, El-Dash HA, Said NI. The role of propolis against paclitaxel-induced oligospermia, sperm abnormality, oxidative stress and DNA damage in testes of male rats. Andrologia. 2020;52(1):13394.
-
37. Sariözkan S, Türk G, Güvenç M, ve ark. Effects of Cinnamon (C. zeylanicum) Bark Oil Against Taxanes-Induced Damages in Sperm Quality, Testicular and Epididymal Oxidant/Antioxidant Balance, Testicular Apoptosis, and Sperm DNA Integrity. Nutr Cancer. 2016;68(3):481-494.
Effects of Paclitaxel Administered to Mice on Testicular Tissue
Yıl 2025,
Cilt: 9 Sayı: 3, 301 - 309, 22.12.2025
Sadık Küçükgünay
,
Oya Korkmaz
,
Ali Erdem Öztürk
,
Ayşe Sari
,
Halime Tozak Yıldız
,
Halil İbrahim Kuz
,
Mustafa Numan Bucak
Öz
Purpose: Chemotherapy drugs can cause reproductive disorders by affecting sperm quality and male fertility. Paclitaxel (PTS), which is actively used in the treatment of many types of cancer, exhibits toxic effects by causing an increase in oxidative stress in tissues. In the present study, PTS was administered to mice to investigate its damaging effects on the male reproductive system.
Materials and Methods: Male Balb/c mice aged 8-10 weeks were used in the study. Animals were randomly selected as n:5 in each group. On days 1, 3 and 5, saline was administered intraperitoneally to control group mice and 2 mg/kg Paclitaxel to PTS group mice. Animals were sacrificed at the end of the experiment (day 7), testicular tissues were collected and histopathological examinations (Haematoxylin-eosin, Masson trichrome, Periodic acid schiff) were performed. In addition, sperm samples were collected from mice, smear preparations were prepared and DNA chromatin integrity was evaluated by Toluidine blue staining.
Results: Testicular histology was abnormal in the PTS group. The seminiferous tubules had abnormalities, a decrease in germinal epithelial spermatogenic series cells, damage to the basal membrane, a decrease in interstitial connective tissue, oedema, and haemorrhage. PTS group also had a limited peritubular interstitial tissue reactivity and fewer leydig cells. High DNA chromatin integrity damage was reported in the PTS group, with a significant difference between the groups (p=0.009).
Conclusion: Our findings indicate that PTS may cause toxicity in mouse testicular tissue and may cause male infertility by adversely affecting sperm DNA integrity.
Etik Beyan
This study was approved by the Kırşehir Ahi Evran University Animal Experiments Local Ethics Committee (dated 27/06/2024 and numbered 12/6).
Kaynakça
-
1. World Health Organization. Cancer prevention and control in the context of an integrated approach. World Health Assembly Resolution WHA70. Geneva, Switzerland: World Health Organization; 2017.
-
2. Vurgun H, Sezer G, Yay A. The role of autophagy in paclitaxel and cremophor induced damage to rat testis. Biotech Histochem. 2022;97(6):433-440.
-
3. Gur C, Kandemir FM, Caglayan C, Satıcı E. Chemopreventive effects of hesperidin against paclitaxel-induced hepatotoxicity and nephrotoxicity via amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways. Chem Biol Interact. 2022;365:110073.
-
4. Aboelwafa HR, Ramadan RA, El-Kott AF, Abdelhamid FM. The protective effect of melatonin supplementation against taxol-induced testicular cytotoxicity in adult rats. Braz J Med Biol Res. 2022;55:11614.
-
5. Okkay U, Ferah Okkay I, Cicek B, ve ark. Achillea millefolium alleviates testicular damage in paclitaxel-intoxicated rats via attenuation of testicular oxido-inflammatory stress and apoptotic responses. Andrologia. 2021;53(5):14028.
-
6. Semet M, Paci M, Saïas-Magnan J, ve ark. The impact of drugs on male fertility: a review. Andrology. 2017;5(4):640-663.
-
7. Kumaresan A, Johannisson A, Al-Essawe EM, Morrell JM. Sperm viability, reactive oxygen species, and DNA fragmentation index combined can discriminate between above- and below-average fertility bulls. J Dairy Sci. 2017;100(7):5824-5836.
-
8. Neuhauser S, Bollwein H, Siuda M, Handler J. Effects of Different Freezing Protocols on Motility, Viability, Mitochondrial Membrane Potential, Intracellular Calcium Level, and DNA Integrity of Cryopreserved Equine Epididymal Sperm. J Equine Vet Sci. 2019;82:102801.
-
9. Aitken RJ, De Iuliis GN. On the possible origins of DNA damage in human spermatozoa. Mol Hum Reprod. 2010;16(1):3-13.
-
10. Didion BA, Kasperson KM, Wixon RL, Evenson DP. Boar fertility and sperm chromatin structure status: a retrospective report. J Androl. 2009;30(6):655-660.
-
11. Peris-Frau P, Álvarez-Rodríguez M, Martín-Maestro A, ve ark. Comparative evaluation of DNA integrity using sperm chromatin structure assay and Sperm-Ovis-Halomax during in vitro capacitation of cryopreserved ram spermatozoa. Reprod Domest Anim. 2019;54 (4):46-49.
-
12. Chi HJ, Kim SG, Kim YY, ve ark. ICSI significantly improved the pregnancy rate of patients with a high sperm DNA fragmentation index. Clin Exp Reprod Med. 2017;44(3):132-140.
-
13. Aktaş İ, Gur FM, Bilgiç S. Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats. Prostaglandins Other Lipid Mediat. 2024;171:106813.
-
14. Gür FM, Bilgiç S. Silymarin, an antioxidant flavonoid, protects the liver from the toxicity of the anticancer drug paclitaxel. Tissue Cell. 2023;83:102158.
-
15. Gür FM, Aktaş İ. Silymarin Protects Kidneys from Paclitaxel-Induced Nephrotoxicity. Turkish JAF Sci. Tech. 2022;10:452-458.
-
16. Ito Y, Unagami M, Yamabe F, ve ark. A method for utilizing automated machine learning for histopathological classification of testis based on Johnsen scores. Sci Rep. 2021;11(1):9962.
-
17. Talebi AR, Vahidi S, Aflatoonian A, ve ark. Cytochemical evaluation of sperm chromatin and DNA integrity in couples with unexplained recurrent spontaneous abortions. Andrologia. 2012;44(1):462-470.
-
18. Kankılıç NA, Küçükler S, Gür C, ve ark. Naringin protects against paclitaxel-induced toxicity in rat testicular tissues by regulating genes in pro-inflammatory cytokines, oxidative stress, apoptosis, and JNK/MAPK signaling pathways. J Biochem Mol Toxicol. 2024;38(7):23751.
-
19. Drechsel KCE, Broer SL, van Breda HMK, ve ark. Semen analysis and reproductive hormones in boys with classical Hodgkin lymphoma treated according to the EuroNet-PHL-C2 protocol. Hum Reprod. 2024;39(11):2411-2422.
-
20. Aktaş İ, Yahyazadeh A. Protective potential of misoprostol against kidney alteration via alleviating oxidative stress in rat following exposure to paclitaxel. Tissue Cell. 2022;79:101966.
-
21. Çomaklı S, Özdemir S, Güloğlu M. Chrysin attenuates paclitaxel-induced hepatorenal toxicity in rats by suppressing oxidative damage, inflammation, and apoptosis. Life Sci. 2023;332:122096.
-
22. Shokoohi M, Khaki A, Shoorei H, ve ark. Hesperidin attenuated apoptotic-related genes in testicle of a male rat model of varicocoele. Andrology. 2020;8(1):249-258.
-
23. Cicek B, Hacimuftuoglu A, Kuzucu M, ve ark. Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries. Pharmaceuticals (Basel). 2023;16(2):221.
-
24. Borovskaya TG, Goldberg VE, Rumpel OA, ve ark. The rat spermatogenesis after injection of paclitaxel (antitumor agent). Bull Exp Biol Med. 2009;147(6):715-718.
-
25. Borovskaya TG, Shchemerova YA, Poluektova ME, ve ark. Mechanisms of reparative regeneration of rat testis after injection of paclitaxel. Bull Exp Biol Med. 2014;156(4):483-485.
-
26. Ghafouri-Fard S, Shoorei H, Abak A, ve ark. Effects of chemotherapeutic agents on male germ cells and possible ameliorating impact of antioxidants. Biomed Pharmacother. 2021;142:112040.
-
27. Wang Z, Teng Z, Wang Z, ve ark. Melatonin ameliorates paclitaxel-induced mice spermatogenesis and fertility defects. J Cell Mol Med. 2022;26(4): 1219-1228.
-
28. Toraman E, Budak B, Bayram C, ve ark. Role of parthenolide in paclitaxel-induced oxidative stress injury and impaired reproductive function in rat testicular tissue. Chem Biol Interact. 2024;387: 110793.
-
29. Dygai AM, Chaikovskii AV, Zhdanov VV, ve ark. Responses of Spermatogenous Tissue and Mechanisms of Their Development Upon Cytostatic Exposure. Bull Exp Biol Med. 2015;159(6):743-746.
-
30. Aksu EH, Kandemir FM, Küçükler S, Mahamadu A. Improvement in colistin-induced reproductive damage, apoptosis, and autophagy in testes via reducing oxidative stress by chrysin. J Biochem Mol Toxicol. 2018;32(11):22201.
-
31. Moradi Maryamneghari S, Shokri-Asl V, Abdolmaleki A, Jalili C. Genetic, biochemical and histopathological evaluations of thymoquinone on male reproduction system damaged by paclitaxel in Wistar rats. Andrologia. 2021;53(10):14192.
-
32. Sarıözkan S, Türk G, Eken A, ve ark. Gilaburu (Viburnum opulus L.) fruit extract alleviates testis and sperm damages induced by taxane-based chemotherapeutics. Biomed Pharmacother. 2017;95: 1284-1294.
-
33. Zhang Y, Liu Y, Teng Z, ve ark. Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility. Biol Res. 2023;56(1):47.
-
34. Ili P, Sari F, Bucak MN, ve ark. DNA damaging effect of paclitaxel in the epididymal sperms as a chemotherapeutic agent and possible remedies to prevent this effect: A study on reproductive potential of male cancer patients of reproductive age. Theriogenology. 2019;132:201-211.
-
35. Balcıoğlu E, Göktepe Ö, Tan FC, Bilgici P, Yakan B, Özdamar S. The role of curcumin against paclitaxel-induced oxidative stress and DNA damage in testes of adult male rats. Turk J Med Sci. 2023;53(1):40-50.
-
36. Abd-Elrazek AM, El-Dash HA, Said NI. The role of propolis against paclitaxel-induced oligospermia, sperm abnormality, oxidative stress and DNA damage in testes of male rats. Andrologia. 2020;52(1):13394.
-
37. Sariözkan S, Türk G, Güvenç M, ve ark. Effects of Cinnamon (C. zeylanicum) Bark Oil Against Taxanes-Induced Damages in Sperm Quality, Testicular and Epididymal Oxidant/Antioxidant Balance, Testicular Apoptosis, and Sperm DNA Integrity. Nutr Cancer. 2016;68(3):481-494.