{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:00:38Z","timestamp":1791644438795,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Research Projects Coordination Unit of Recep Tayyip Erdo\u011fan University, Rize, Turkey","award":["TSA-2025-2202"],"award-info":[{"award-number":["TSA-2025-2202"]}]},{"award":["TSA-2025-2202"],"award-info":[{"award-number":["TSA-2025-2202"]}],"id":[{"id":"https:\/\/ror.org\/0468j1635","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005322","name":"Recep Tayyip Erdogan University Development Foundation","doi-asserted-by":"publisher","award":["02026006019418"],"award-info":[{"award-number":["02026006019418"]}],"id":[{"id":"10.13039\/501100005322","id-type":"DOI","asserted-by":"publisher"}]},{"award":["02026006019418"],"award-info":[{"award-number":["02026006019418"]}],"id":[{"id":"https:\/\/ror.org\/0468j1635","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Cisplatin-induced testicular toxicity is commonly associated with oxidative stress; however, the early biological events preceding overt tissue injury remain incompletely characterized. Identifying interventions capable of preserving redox homeostasis during this subacute phase may improve our understanding of the initial mechanisms underlying testicular dysfunction. This study investigated whether methylsulfonylmethane (MSM), a naturally occurring organosulfur compound with antioxidant properties, modulates early oxidative responses in a subacute rat model of cisplatin-induced testicular toxicity. Methods: Thirty-two adult male Sprague\u2013Dawley rats were randomly assigned to Control, Cisplatin (CIS), MSM, and CIS + MSM groups (n = 8\/group). MSM (500 mg\/kg\/day, intraperitoneally) was administered for 10 consecutive days, while a single dose of cisplatin (7 mg\/kg, intraperitoneally) was given on day 7. Oxidative stress biomarkers, antioxidant enzyme activities, intratesticular testosterone concentrations, inflammatory cytokines, GPX4 and HO-1 protein expression, histopathological alterations, and correlation analyses were evaluated. Results: Cisplatin exposure induced a marked oxidative imbalance, evidenced by increased malondialdehyde levels and reduced superoxide dismutase, catalase, glutathione peroxidase, and intratesticular testosterone concentrations (p &lt; 0.05). MSM administration attenuated lipid peroxidation, restored antioxidant enzyme activities, and preserved intratesticular testosterone levels. Western blot analysis demonstrated a significant increase in GPX4 protein expression following cisplatin exposure, whereas MSM normalized GPX4 expression toward control values. In contrast, HO-1 expression and intratesticular IL-6 and TNF-\u03b1 levels did not differ among the experimental groups. Histopathological evaluation revealed only mild structural alterations without corresponding differences in Johnsen score, indicating that biochemical and molecular disturbances preceded overt tissue degeneration. Correlation analysis further demonstrated close associations between antioxidant defense and preservation of endocrine function. Conclusions: Subacute cisplatin exposure primarily disrupted testicular redox homeostasis before prominent histopathological injury became evident. MSM was associated with attenuation of these early oxidative alterations accompanied by improved endogenous antioxidant enzyme activity, higher intratesticular testosterone concentrations, and normalization of GPX4 expression. These findings suggest that MSM may contribute to the maintenance of testicular redox homeostasis during the early phase of cisplatin-induced toxicity under the present experimental conditions.<\/jats:p>","DOI":"10.3390\/nu18142392","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T09:20:39Z","timestamp":1784712039000},"page":"2392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Methylsulfonylmethane (MSM) Mitigates Cisplatin-Induced Early Oxidative Testicular Dysfunction Through Modulation of Antioxidant Defense and GPX4 Response"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-496X","authenticated-orcid":false,"given":"Pelin","family":"\u0130smailo\u011flu","sequence":"first","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehra Topal","family":"Suzan","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esra","family":"Deniz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4842-1173","authenticated-orcid":false,"given":"Adnan","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-5087","authenticated-orcid":false,"given":"Sibel","family":"Matarac\u0131 Karaka\u015f","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1953-7572","authenticated-orcid":false,"given":"Nevnihal","family":"Akbayt\u00fcrk","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Giresun University, Giresun 28100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-2005","authenticated-orcid":false,"given":"Hatice","family":"Sevim Nalk\u0131ran","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-2592","authenticated-orcid":false,"given":"\u0130hsan","family":"Nalk\u0131ran","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00dcnzile","family":"Yaman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Izmir Katip Celebi University, Izmir 35620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u015eenay","family":"\u00c7ak\u0131ro\u011flu","sequence":"additional","affiliation":[{"name":"Experimental Animals Application and Research Center, Recep Tayyip Erdo\u011fan University, Rize 53020, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levent","family":"T\u00fcmkaya","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine, Ondokuz May\u0131s University, Samsun 55200, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mariconda, A., Ceramella, J., Catalano, A., Saturnino, C., Sinicropi, M.S., and Longo, P. (2025). Cisplatin, the Timeless Molecule. Inorganics, 13.","DOI":"10.3390\/inorganics13070246"},{"key":"ref_2","first-page":"511445","article-title":"Testicular Cancer: Diagnosis, Treatment, and Biomarker Advances","volume":"18","author":"Kraft","year":"2026","journal-title":"Res. Rep. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127489","DOI":"10.1016\/j.jtemb.2024.127489","article-title":"Testicular toxicity in cisplatin-treated Wistar rats is mitigated by Daflon and associated with modulation of Nrf2\/HO-1 and TLR4\/NF-kB signaling","volume":"85","author":"Akhigbe","year":"2024","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Badr, A.M., Aloyouni, S., Mahran, Y., Henidi, H., Elmongy, E.I., Alsharif, H.M., Almomen, A., and Soliman, S. (2025). Thymol Preserves Spermatogenesis and Androgen Production in Cisplatin-Induced Testicular Toxicity by Modulating Ferritinophagy, Oxidative Stress, and the Keap1\/Nrf2\/HO-1 Pathway. Biomolecules, 15.","DOI":"10.3390\/biom15091277"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nizami, Z.N., Aburawi, H.E., Semlali, A., Muhammad, K., and Iratni, R. (2023). Oxidative stress inducers in cancer therapy: Preclinical and clinical evidence. Antioxidants, 12.","DOI":"10.3390\/antiox12061159"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mirzaei, S., Hushmandi, K., Zabolian, A., Saleki, H., Torabi, S.M.R., Ranjbar, A., SeyedSaleh, S., Sharifzadeh, S.O., Khan, H., and Ashrafizadeh, M. (2021). Elucidating role of reactive oxygen species (ROS) in cisplatin chemotherapy: A focus on molecular pathways and possible therapeutic strategies. Molecules, 26.","DOI":"10.3390\/molecules26082382"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2460\/ajvr.24.10.0288","article-title":"Glycyrrhizin alleviated cisplatin-induced testicular injury by inhibiting the oxidative, apoptotic, hormonal, and histological alterations","volume":"86","author":"Alharbi","year":"2025","journal-title":"Am. J. Vet. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1016\/j.ymthe.2024.02.029","article-title":"Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL\/6 mice","volume":"32","author":"Liu","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.21873\/anticanres.18048","article-title":"Roles of GPX4 and FSP1 in Esophageal Squamous Cell Carcinoma Treated With Neoadjuvant Chemotherapy","volume":"46","author":"Takahashi","year":"2026","journal-title":"Anticancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/S1357-2725(02)00097-3","article-title":"Protective effect of HO-1 against oxidative stress in human hepatoma cell line (HepG2) is independent of telomerase enzyme activity","volume":"34","author":"Ghattas","year":"2002","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1186\/s13046-024-03249-8","article-title":"OTULIN confers cisplatin resistance in osteosarcoma by mediating GPX4 protein homeostasis to evade the mitochondrial apoptotic pathway","volume":"43","author":"Zheng","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Butawan, M., Benjamin, R.L., and Bloomer, R.J. (2017). Methylsulfonylmethane: Applications and safety of a novel dietary supplement. Nutrients, 9.","DOI":"10.3390\/nu9030290"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1248\/bpb.32.651","article-title":"The anti-inflammatory effects of methylsulfonylmethane on lipopolysaccharide-induced inflammatory responses in murine macrophages","volume":"32","author":"Kim","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Beder, M., Yemenoglu, H., Bostan, S.A., Kose, O., Karakas, S.M., Mercantepe, T., Y\u0131lmaz, A., and Tumkaya, L. (2025). Investigation of the preventive effect of methylsulfonylmethane on alveolar bone loss and oxidative stress in a rat model of periodontitis. BMC Oral Health, 25.","DOI":"10.1186\/s12903-025-05447-y"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"88","DOI":"10.18678\/dtfd.1597470","article-title":"Evaluation of the Effects of Acute Cisplatin Administration on Testicular and Ovarian Tissue in Rats","volume":"27","author":"Kalkan","year":"2025","journal-title":"Duzce Med. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, D., Wang, L., Tang, L., Zhang, Y., Zhang, H., and Zou, L. (2025). Protective Effect of Methyl Sulfonyl Methane on the Progression of Age-Induced Bone Loss by Regulating Oxidative Stress-Mediated Bone Resorption. Antioxidants, 14.","DOI":"10.3390\/antiox14020216"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1038\/s41598-018-22640-y","article-title":"Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism","volume":"8","author":"Yu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mohammed, S.A.A., Saad, H.M., Esmail, K.A., Eliwa, D., Rohiem, A.H., Awad, A.A., El-Adawy, S.A., Amer, S.S., and Abdelhiee, E.Y. (2026). Protection by Vitis vinifera L. Against Cisplatin-Induced Testicular Injury: Oxidative Stress, Inflammation, and Ferroptosis. Pharmaceuticals, 19.","DOI":"10.3390\/ph19010178"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s00580-026-03783-1","article-title":"Syringic acid assuages cisplatin-induced testicular apoptosis via p53 and caspase-3 inhibition and oxidative stress via the regulation of superoxide dismutase in male Wistar rats: In vivo and computational evidence","volume":"35","author":"Somade","year":"2026","journal-title":"Comp. Clin. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e70201","DOI":"10.1002\/jbt.70201","article-title":"Cross-Talk Signaling Between Non-Small Cell Lung Cancer Cell Lines and Fibroblasts Attenuates the Cytotoxic Effect of Cisplatin","volume":"39","author":"Ebid","year":"2025","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100228","DOI":"10.1016\/j.crtox.2025.100228","article-title":"A long-term mouse testis organ culture system to identify germ cell damage induced by chemotherapy","volume":"8","author":"Yokota","year":"2025","journal-title":"Curr. Res. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1080\/10408444.2026.2649599","article-title":"The effect of antioxidants on antineoplastic-induced male reproductive system damage: A systematic review of experimental studies","volume":"56","author":"Bayram","year":"2026","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"127792","DOI":"10.1016\/j.jtemb.2025.127792","article-title":"Azelastine attenuates Cisplatin-induced renal and testicular injury: Involvement of Nrf2\/SLC7A11-GPX4 and NCOA4-mediated ferroptosis","volume":"92","author":"Zaghloul","year":"2025","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"McFarlin, B.K., Curtis, J.H., du Preez, H.N., and McFarlin, M.A. (2025). Using the Rise and Fall of Oxidative Stress and Inflammation Post-Exercise to Evaluate the Effect of Methylsulfonylmethane Supplementation on Immune Response mRNA. Nutrients, 17.","DOI":"10.3390\/nu17111761"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1080\/02772248.2025.2486828","article-title":"Evaluation of the use of a herbal combination together with the chemotherapeutic drug cisplatin in a spermatogenic cycle of male mice","volume":"107","author":"Esmaeli","year":"2025","journal-title":"Toxicol. Environ. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Parastesh, M., Ghahfarrokhi, M.M., Bayatiani, M.R., Abbasi, Y., Pooladi, M., Khalounejad, H., and Nobari, H. (2025). Effects of high and moderate intensity exercise training on sex hormones and testicular damage induced by cisplatin in rats. BMC Sports Sci. Med. Rehabil., 17.","DOI":"10.1186\/s13102-025-01379-w"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"22720","DOI":"10.1038\/s41598-025-08235-4","article-title":"Morin hydrate protects against cisplatin-induced testicular toxicity by modulating ferroptosis and steroidogenesis genes\u2019 expression and upregulating Nrf2\/Heme oxygenase-1","volume":"15","author":"Mahran","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"865","DOI":"10.5534\/wjmh.230268","article-title":"Ferroptosis is crucial for cisplatin induced sertoli cell injury via N6-methyladenosine dependent manner","volume":"42","author":"Fan","year":"2024","journal-title":"World J. Men\u2019s Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102382","DOI":"10.1016\/j.redox.2022.102382","article-title":"Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes","volume":"54","author":"Kim","year":"2022","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yang, Q., and Wang, W. (2022). The nuclear translocation of heme oxygenase-1 in human diseases. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.890186"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1165\/ajrcmb.15.1.8679227","article-title":"Heme oxygenase-1: Function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury","volume":"15","author":"Choi","year":"1996","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1089\/ars.2010.3226","article-title":"Nrf2-Mediated heme oxygenase-1 upregulation as adaptive survival response to glucose deprivation-induced apoptosis in HepG2 cells","volume":"13","author":"Lee","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_33","first-page":"891","article-title":"Possible protective effect of melatonin on cisplatin-induced testicular toxicity in adult albino rats. A histological and immunohistochemical study","volume":"43","author":"Filobbos","year":"2020","journal-title":"Egypt. J. Histol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tozak Y\u0131ld\u0131z, H.T., Kalkan, K.T., Baydilli, N., G\u00f6nen, Z.B., Mat, \u00d6.C., K\u00f6seo\u011flu, E., \u00d6nder, G.\u00d6., and Yay, A. (2025). Extracellular vesicles therapy alleviates cisplatin-\u0131nduced testicular tissue toxicity in a rat model. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0314093"},{"key":"ref_35","unstructured":"U.S. Food and Drug Administration (FDA) (2026, July 14). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, Available online: https:\/\/www.fda.gov\/media\/72309\/download."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/14\/2392\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T09:30:09Z","timestamp":1784712609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/14\/2392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":36,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nu18142392"],"URL":"https:\/\/doi.org\/10.3390\/nu18142392","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}