Therapeutic Effects of Biogenic Silver Nanoparticles against Diethyl Nitrosamine-Induced Gonadal Toxicity in Male Rats
DOI:
https://doi.org/10.70749/ijbr.v4i3.2976Keywords:
Diethylnitrosamine (DEN), Gonadal Toxicity, Apoptosis, Silver Nanoparticles (AgNPs)Abstract
Background: The testicular cancer is one of the most common types of malignancies in young adult men, and cause infertility and hormonal disproportions which remains a major concern in the male reproductive health. Aim: The current research aimed to assess the carcinogenic effect of DEN (Diethylnitrosamine) and to determine the protective effect of biogenic silver nanoparticles (AgNPs) against DEN-induced damage in gonadal tissues of male rats. Materials & Methods: Twenty male albino rats were divided randomly into four experimental groups, including Control, DEN, DEN+AgNPs, and AgNPs. Animals were sacrificed after five weeks of treatment and the alterations in the body weight, hormonal profile, histopathology, genomic DNA and apoptosis related molecules were observed. Results: A significant reduction in the body weight and a marked increase in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were observed in DEN-treated rats. Furthermore, degeneration of germinal epithelium, necrosis and fibrotic seminiferous tubules were found in the DEN group. AgNPs co-treatment showed recovery in body weight, attenuation of the histopathological damage and improved the gonadal architecture. A significant decline in the expression level of p53, DR5 and caspase-9 was noted while AgNPs co-administration reversed the pro-apoptotic gene levels. Conclusion: Altogether, AgNPs have a protective effects against DEN-induced toxicity in the gonadal tissues in male rats. Furthermore, these results showed that AgNPs can be considered as a therapeutic agent against testicular carcinogenesis.
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References
1. Houda, A., Nyaz, S., Sobhy, B. M., Bosilah, A. H., Romeo, M., Michael, J. P., & Eid, H. M. (2021). Seminiferous tubules and spermatogenesis. In Male reproductive anatomy. IntechOpen.
https://www.intechopen.com/chapters/79014
2. Martins, A. L., Dias, F. C., Rodrigues, G. A., Oliveira, E. L., Araújo, A. R., De Avelar, G. F., & Da Matta, S. L. (2025). Testicular Histomorphometric Parameters and Spermatogenic Dynamics of Monodelphis americana (Müller, 1776) (Didelphimorphia: Didelphidae). Anatomia, Histologia, Embryologia, 54(4).
https://doi.org/10.1111/ahe.70047
3. Zhou, R., Wu, J., Liu, B., Jiang, Y., Chen, W., Li, J., He, Q., & He, Z. (2019). The roles and mechanisms of Leydig cells and myoid cells in regulating spermatogenesis. Cellular and Molecular Life Sciences, 76(14), 2681-2695.
https://doi.org/10.1007/s00018-019-03101-9
4. Piprek, R. P., Kloc, M., Porebska, K., Mizia, P. C., Rams-Pociecha, I., & Kubiak, J. Z. (2024). Origin and role of testicular macrophages in testis development, Steroidogenesis, and spermatogenesis. Results and Problems in Cell Differentiation, 137-157.
https://doi.org/10.1007/978-3-031-65944-7_5
5. Xiao, Y., Zhang, J., Guan, Y., Wang, M., Liu, D., Xiong, S., Li, J., & Yu, X. (2025). Research progress on Sertoli cell secretion during spermatogenesis. Frontiers in Endocrinology, 15.
https://doi.org/10.3389/fendo.2024.1456410
6. Di Costanzo, F., Rescigno, P., Seidel, C., Morrall, T., Oliveira, P., Hentrich, M., & Oing, C. (2025). Management of advanced germ cell tumours. Oncology Research and Treatment, 49(1-2), 35-47.
https://doi.org/10.1159/000546798
7. Pandey, A., Choudhary, S., Verma, C. P., & Mani, N. (2022). Seminoma of testis with isolated BONY metastasis at presentation. Journal of Cancer Research and Therapeutics, 19(2), 484-486.
https://doi.org/10.4103/jcrt.jcrt_1957_21
8. Li, K., Sun, F., & Fan, C. (2024). Characteristics and prognosis of testicular mixed teratoma and seminoma. Journal of Cancer Research and Therapeutics, 20(7), 2074-2081.
https://doi.org/10.4103/jcrt.jcrt_1109_23
9. Singla, N., Bagrodia, A., Baraban, E., Fankhauser, C. D., & Ged, Y. M. (2025). Testicular germ cell tumors. JAMA, 333(9), 793.
https://doi.org/10.1001/jama.2024.27122
10. Yin, X., Gu, H., Ning, D., Li, Y., & Tang, H. (2024). Testosterone exacerbates the formation of liver cancer induced by environmental N-nitrosamines exposure: Potential mechanisms and implications for human health. OncoTargets and Therapy, 17, 395-409.
https://doi.org/10.2147/ott.s456746
11. Janmeda, P., Jain, D., Chaudhary, P., Meena, M., & Singh, D. (2024). A systematic review on multipotent carcinogenic agent, n‐nitrosodiethylamine (NDEA), its major risk assessment, and precautions. Journal of Applied Toxicology, 44(8), 1108-1128.
https://doi.org/10.1002/jat.4574
12. Schulien, I., Hockenjos, B., Van Marck, V., Ayata, C. K., Follo, M., Thimme, R., & Hasselblatt, P. (2020). Extracellular ATP and Purinergic P2Y2 receptor signaling promote liver Tumorigenesis in mice by exacerbating DNA damage. Cancer Research, 80(4), 699-708.
https://doi.org/10.1158/0008-5472.can-19-1909
13. Yadav J, V., et al., Pathological effects of diethyl nitrosamine (DEN) on testes of wistar albino rats. 2023: p. 1347-1348.
14. Nagata, S. (2018). Apoptosis and clearance of Apoptotic cells. Annual Review of Immunology, 36(1), 489-517.
https://doi.org/10.1146/annurev-immunol-042617-053010
15. Elmore, S. (2007). Apoptosis: A review of programmed cell death. Toxicologic Pathology, 35(4), 495-516.
https://doi.org/10.1080/01926230701320337
16. Kale, J., Osterlund, E. J., & Andrews, D. W. (2017). BCL-2 family proteins: Changing partners in the dance towards death. Cell Death & Differentiation, 25(1), 65-80.
https://doi.org/10.1038/cdd.2017.186
17. Slee, E. A., Adrain, C., & Martin, S. J. (2001). Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of Apoptosis. Journal of Biological Chemistry, 276(10), 7320-7326.
https://doi.org/10.1074/jbc.m008363200
18. Shah, S. Z. A., Ullah, W., Hasan, M. A., Sajjad, S., Khan, B., Rehman, S., ... & Khan, G. N. (2025). Biogenic Silver Nanoparticles Protect Against Diethylnitrosamine-Induced Toxicity in Rats. Indus Journal of Bioscience Research, 3(12), 253-266.
https://www.ijbr.com.pk/IJBR/article/view/2600
19. Deeh, P. B., Natesh, N. S., Alagarsamy, K., Arumugam, M. K., Dasnamoorthy, R., Sivaji, T., & Vishwakarma, V. (2024). Biosynthesis of silver nanoparticles using Pterorhachis zenkeri: Characterization and evaluation of antioxidant, anti-apoptotic, and androgenic properties in TM3 Leydig cells exposed to cyclophosphamide.
https://doi.org/10.21203/rs.3.rs-4299408/v1
20. Rudi, L., Zinicovscaia, I., Cepoi, L., Chiriac, T., Grozdov, D., & Kravtsova, A. (2024). The impact of silver nanoparticles Functionalized with spirulina protein extract on rats. Pharmaceuticals, 17(9), 1247.
https://doi.org/10.3390/ph17091247
21. Pervez, A., Khan, B., Khan, G. N., Khattak, S., Ali, M., Mujeeb, K., Nasib, B., Kim, H. G., Qureshi, I. Z., & Arshad, M. (2025). Evaluation of hepatic cancer stem cells (CD73+, CD44+, and CD90+) induced by diethylnitrosamine in male rats and treatment with biologically synthesized silver nanoparticles. Molecular Biology Reports, 52(1).
https://doi.org/10.1007/s11033-025-10495-2
22. Zhang, H., Liu, Y., Yu, B., & Lu, R. (2023). An optimized trizol-based method for isolating RNA from adipose tissue. BioTechniques, 74(5), 203-209.
https://doi.org/10.2144/btn-2022-0120
23. Dara, M., Nazari, F., Dianatpour, M., Karimi, F., Alaee, S., Shirazi, R., & Khodabandeh, Z. (2024). “Effect of sunset yellow on testis: Molecular evaluation, and protective role of coenzyme Q10 in male Sprague-Dawley rats”. Cell Biochemistry and Biophysics, 82(3), 2827-2835.
https://doi.org/10.1007/s12013-024-01398-3
24. Gomes, H. I., Martins, C. S., & Prior, J. A. (2021). Silver nanoparticles as carriers of Anticancer drugs for efficient target treatment of cancer cells. Nanomaterials, 11(4), 964.
https://doi.org/10.3390/nano11040964
25. Mou, J., Ma, Z., Zhang, M., Yuan, Q., Wang, Z., Liu, Q., Li, F., Liu, Z., & Wang, L. (2024). Structural abnormality of hepatic glycogen in rat liver with diethylnitrosamine-induced carcinogenic injury. International Journal of Biological Macromolecules, 260, 129432.
https://doi.org/10.1016/j.ijbiomac.2024.129432
26. Liao, D. J., Blanck, A., Eneroth, P., Gustafsson, J. A., & Hällström, I. P. (2001). Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat. Environmental Health Perspectives, 109(9), 943-947.
https://doi.org/10.1289/ehp.01109943
27. Roychoudhury, S., Chakraborty, S., Choudhury, A. P., Das, A., Jha, N. K., Slama, P., Nath, M., Massanyi, P., Ruokolainen, J., & Kesari, K. K. (2021). Environmental factors-induced oxidative stress: Hormonal and molecular pathway disruptions in Hypogonadism and erectile dysfunction. Antioxidants, 10(6), 837.
https://doi.org/10.3390/antiox10060837
28. Sangeeta, K., & Yenugu, S. (2022). Ablation of the sperm-associated antigen 11a (SPAG11A) protein by active immunization promotes epididymal oncogenesis in the rat. Cell and Tissue Research, 389(1), 115-128.
https://doi.org/10.1007/s00441-022-03623-y
29. Ding, Y., Wu, Z., Wei, Y., Shu, L., & Peng, Y. (2017). Hepatic inflammation-fibrosis-cancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine. Journal of Cancer Research and Clinical Oncology, 143(5), 821-834.
https://doi.org/10.1007/s00432-017-2364-z
30. Hopkins, J. L., Lan, L., & Zou, L. (2022). DNA repair defects in cancer and therapeutic opportunities. Genes & Development, 36(5-6), 278-293.
https://doi.org/10.1101/gad.349431.122
31. Newton, K., Strasser, A., Kayagaki, N., & Dixit, V. M. (2024). Cell death. Cell, 187(2), 235-256.
https://doi.org/10.1016/j.cell.2023.11.044
32. Vousden, K. H., & Prives, C. (2009). Blinded by the light: The growing complexity of p53. Cell, 137(3), 413-431.
https://doi.org/10.1016/j.cell.2009.04.037
33. Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019). The multiple mechanisms that regulate p53 activity and cell fate. Nature Reviews Molecular Cell Biology, 20(4), 199-210.
https://doi.org/10.1038/s41580-019-0110-x
34. Avrutsky, M. I., & Troy, C. M. (2021). Caspase-9: A multimodal therapeutic target with diverse cellular expression in human disease. Frontiers in Pharmacology, 12.
https://doi.org/10.3389/fphar.2021.701301
35. Guo, Y., Wang, H., Liu, S., Zhang, X., Zhu, X., Huang, L., Zhong, W., Guan, L., Chen, Y., Xiao, M., Ou, L., Yang, J., Chen, X., Huang, A. C., Mitchell, T., Amaravadi, R., Karakousis, G., Miura, J., Schuchter, L., … Xu, X. (2025). Engineered extracellular vesicles with DR5 agonistic scFvs simultaneously target tumor and immunosuppressive stromal cells. Science Advances, 11(3).
https://doi.org/10.1126/sciadv.adp9009
36. Chen, X., Velu, P., Vijayalakshmi, A., & Zhang, H. (2025). Voacangine targeting of PI3K/Akt/ERK via the knockdown of inflammation in DEN-induced liver cancer: In vivo and in silico approach. Journal of Molecular Histology, 56(5).
https://doi.org/10.1007/s10735-025-10577-2
37. Zaky, M. Y., Morsy, H. M., Abdel-Moneim, A., Zoheir, K. M., Bragoli, A., Abdel-Maksoud, M. A., Alamri, A., & Ahmed, O. M. (2025). Anticancer potential of eugenol in hepatocellular carcinoma through modulation of oxidative stress, inflammation, apoptosis, and proliferation mechanisms. Discover Oncology, 16(1).
https://doi.org/10.1007/s12672-025-02243-6
38. Asadi, M., Taghizadeh, S., Kaviani, E., Vakili, O., Taheri‐Anganeh, M., Tahamtan, M., & Savardashtaki, A. (2021). Caspase‐3: Structure, function, and biotechnological aspects. Biotechnology and Applied Biochemistry, 69(4), 1633-1645.
https://doi.org/10.1002/bab.2233
39. Wang, Z., Jiang, X., Zhang, L., & Chen, H. (2023). Protective effects of Althaea officinalis L. extract against N-diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats through antioxidative, anti-inflammatory, mitochondrial apoptosis and PI3K/Akt/mTOR signaling pathways. Food Science & Nutrition, 11(8), 4756-4772.
https://doi.org/10.1002/fsn3.3455
40. Huan, J., Grivas, P., Birch, J., & Hansel, D. E. (2022). Emerging roles for mammalian target of Rapamycin (mTOR) complexes in bladder cancer progression and therapy. Cancers, 14(6), 1555.
https://doi.org/10.3390/cancers14061555
41. Abdel‐Bakky, M. S., Mohammed, H. A., Mahmoud, N. I., Amin, E., Alsharidah, M., Al Rugaie, O., & Ewees, M. G. (2024). Targeting the PI3K/pAKT/mTOR/NF-κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk. Environmental Toxicology, 39(6), 3666-3678.
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