{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:06:47Z","timestamp":1792033607780,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T00:00:00Z","timestamp":1751760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Tramadol, a central analgesic drug, is used to treat moderate to severe pain but can cause reproductive disorders. The pathogenesis of tramadol-induced reproductive damage may involve increased oxidative stress, pro-inflammatory cytokines, ATP depletion, and reduced antioxidant levels. In this study, subjects were divided into four groups: healthy control (HC), tramadol only (TM), ATP only (ATP), and ATP + tramadol (ATM). ATP was administered intraperitoneally at 4 mg\/kg, and tramadol was administered orally at 50 mg\/kg. Distilled water was given to the HC group. This regimen was repeated for three weeks. At the end of the treatment, testicular tissues from six rats in each group were analyzed biochemically and histopathologically after euthanasia. The remaining rats\u2019 reproductive functions were evaluated. Long-term tramadol exposure resulted in oxidative stress, inflammation in testicular tissue, and reduced male reproductive capacity. Thinning of seminiferous tubule walls and thickening of basement membrane, irregularity in germ cells, increase in interstitial connective tissue, congestion in vessels, increase in Leyding cells and hyperplasia were found in the TM group. ATP treatment significantly reduced tramadol-induced increases in oxidants and pro-inflammatory cytokines, reversed the decline in antioxidants, and mitigated infertility in testicular tissue. Furthermore, ATP preserved the morphology of the testicular tissue. These findings suggest that ATP may offer therapeutic potential for tramadol-induced infertility.<\/jats:p>","DOI":"10.3390\/life15071078","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T02:53:07Z","timestamp":1751856787000},"page":"1078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Relationship Between Tramadol-Induced Oxidative Testis Injury and Reproductive Function Disorder and Adenosine Triphosphate"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0506-0777","authenticated-orcid":false,"given":"Fevzi","family":"Bedir","sequence":"first","affiliation":[{"name":"Department of Urology, Health Sciences University, Erzurum Regional Training and Research Hospital, Erzurum 25070, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7254-7692","authenticated-orcid":false,"given":"H\u00fcseyin","family":"Kocat\u00fcrk","sequence":"additional","affiliation":[{"name":"Department of Urology, Health Sciences University, Erzurum Regional Training and Research Hospital, Erzurum 25070, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-0666","authenticated-orcid":false,"given":"Mehmet Sefa","family":"Altay","sequence":"additional","affiliation":[{"name":"Department of Urology, Health Sciences University, Erzurum Regional Training and Research Hospital, Erzurum 25070, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5785-1960","authenticated-orcid":false,"given":"Renad","family":"Mammadov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5795-3177","authenticated-orcid":false,"given":"Bahad\u0131r","family":"S\u00fcleyman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1711-5499","authenticated-orcid":false,"given":"Taha Abdulkadir","family":"Coban","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6989-997X","authenticated-orcid":false,"given":"G\u00fclce Naz","family":"Yazici","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, School of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4992-1241","authenticated-orcid":false,"given":"Seval","family":"Bulut","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9239-4099","authenticated-orcid":false,"given":"Halis","family":"S\u00fcleyman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan 24100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111316","DOI":"10.1016\/j.jclinane.2023.111316","article-title":"Tramadol antimicrobial activity in peripheral nerve blocks. Is it a real possibility?","volume":"92","author":"Pilia","year":"2024","journal-title":"J. Clin. Anesth."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"879","DOI":"10.2165\/00003088-200443130-00004","article-title":"Clinical Pharmacology of Tramadol","volume":"43","author":"Grond","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.eururo.2011.09.013","article-title":"Tramadol for the treatment of premature ejaculation","volume":"61","author":"Giuliano","year":"2012","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.tox.2017.05.003","article-title":"Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats","volume":"385","author":"Faria","year":"2017","journal-title":"Toxicology"},{"key":"ref_5","first-page":"118","article-title":"Ameliorative Effect of Melatonin Against Reproductive Toxicity of Tramadol in Rats via the Regulation of Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis-related Gene Expression Signaling Pathway","volume":"12","author":"Koohsari","year":"2020","journal-title":"Addict. Health"},{"key":"ref_6","first-page":"56","article-title":"Effects of tramadol on the reproductive function of Wistar albino rats","volume":"5","year":"2015","journal-title":"Eur. J. Exp. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101697","DOI":"10.1016\/j.tice.2021.101697","article-title":"Vitamin B12 ameliorates tramadol-induced oxidative stress, endocrine imbalance, apoptosis and NO\/iNOS\/NF-\u03baB expression in Sprague Dawley rats through regulatory mechanism in the pituitary-gonadal axis","volume":"74","author":"Adelakun","year":"2022","journal-title":"Tissue Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"100049","DOI":"10.1016\/j.crphar.2021.100049","article-title":"Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury","volume":"2","author":"Mousavi","year":"2021","journal-title":"Curr. Res. Pharmacol. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tox.2016.06.010","article-title":"Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells","volume":"359\u2013360","author":"Faria","year":"2016","journal-title":"Toxicology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Elmorsy, E.M., Al Doghaither, H.A., and Al-Ghafari, A.B. (2024). Bioenergetics disruption, oxidative stress, and inflammation as underlying mechanisms of tramadol-induced nephrotoxicity. J. Biochem. Mol. Toxicol., 38.","DOI":"10.1002\/jbt.23777"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.4103\/ijpvm.ijpvm_10_24","article-title":"Minocycline Acts as a Neuroprotective Agent Against Tramadol-Induced Neurodegeneration: Behavioral and Molecular Evidence","volume":"15","author":"Gholami","year":"2024","journal-title":"Int. J. Prev. Med."},{"key":"ref_12","unstructured":"Dunn, J., and Grider, M.H. (2022). Physiology, Adenosine Triphosphate. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s11302-012-9305-8","article-title":"ATP synthesis and storage","volume":"8","author":"Bonora","year":"2012","journal-title":"Purinergic Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/14620316.2000.11511231","article-title":"Changes in ATP, ADP and pyridine nucleotide levels related to the incidence of physiological disorders in \u2018Conference\u2019 pears and \u2018Jonagold\u2019 apples during controlled atmosphere storage","volume":"75","author":"Saquet","year":"2000","journal-title":"J. Hortic. Sci. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.foodchem.2009.04.074","article-title":"ATP-regulation of antioxidant properties and phenolics in litchi fruit during browning and pathogen infection process","volume":"118","author":"Yi","year":"2010","journal-title":"Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.freeradbiomed.2019.06.018","article-title":"Negative effects of ROS generated during linear sperm motility on gene expression and ATP generation in boar sperm mitochondria","volume":"141","author":"Zhu","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.31557\/APJCP.2023.24.3.1007","article-title":"Protective Effect of Adenosine Triphosphate Against 5-Fluorouracil-Induced Oxidative Ovarian Damage In Vivo","volume":"24","author":"Ozer","year":"2023","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1007\/s12031-020-01592-x","article-title":"Neurotoxic, hepatotoxic and nephrotoxic effects of tramadol administration in rats","volume":"70","author":"Ali","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0009-8981(91)90067-M","article-title":"A simple method for determination of serum catalase activity and revision of reference range","volume":"196","author":"Goth","year":"1991","journal-title":"Clin. Chim. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1016\/S0022-5347(17)49278-0","article-title":"Histological changes occurring in the contralateral testes of prepubertal rats subjected to various durations of unilateral spermatic cord torsion","volume":"133","author":"Cosentino","year":"1985","journal-title":"J. Urol."},{"key":"ref_21","first-page":"S17","article-title":"Effect of sunitinib on testicular oxidative and proinflammatory damage induced by ischemia\u2013reperfusion in rats","volume":"20","author":"Keskin","year":"2022","journal-title":"Rev. Int. De Androlog\u00eda"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yeter, B., Suleyman, Z., Bulut, S., Cicek, B., Coban, T.A., Demir, O., and Suleyman, H. (2025). Effect of adenosine triphosphate on methylphenidate-induced oxidative and inflammatory kidney damage in rats. Drug Chem. Toxicol., 1\u20139.","DOI":"10.1080\/01480545.2025.2457386"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47","DOI":"10.5152\/eajm.2013.08","article-title":"Tissue damage and oxidant\/antioxidant balance","volume":"45","author":"Kisaoglu","year":"2013","journal-title":"Eurasian J. Med."},{"key":"ref_24","first-page":"17","article-title":"The effect of taxifolin on experimental testicular ischemia reperfusion injury in rats. A biochemical and histopathological analysis","volume":"20","author":"Bedir","year":"2022","journal-title":"Rev. Int. Androl."},{"key":"ref_25","first-page":"25","article-title":"Molecular Mechanism of Ischemia Reperfusion Injury","volume":"2","year":"2020","journal-title":"Arch. Basic Clin. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.4196\/kjpp.2017.21.5.457","article-title":"Effect of etoricoxib on experimental oxidative testicular ischemia-reperfusion damage in rats induced with torsion-detorsion","volume":"21","author":"Yapanoglu","year":"2017","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1080\/14786419.2022.2090937","article-title":"Protective and restorative potency of diosmin natural flavonoid compound against tramadol-induced testicular damage and infertility in male rats","volume":"37","author":"Anwar","year":"2023","journal-title":"Nat. Prod. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Irato, P., and Santovito, G. (2021). Enzymatic and Non-Enzymatic Molecules with Antioxidant Function. Antioxidants, 10.","DOI":"10.3390\/antiox10040579"},{"key":"ref_29","first-page":"464","article-title":"The protective effect of ozone on the mice testicular damage induced by methotrexate","volume":"28","author":"Khorsandi","year":"2024","journal-title":"JBRA Assist. Reprod."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dutta, S., Sengupta, P., Slama, P., and Roychoudhury, S. (2021). Oxidative Stress, Testicular Inflammatory Pathways, and Male Reproduction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810043"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5358","DOI":"10.1007\/s12011-023-03580-9","article-title":"Alternations of Fertility Parameters by Graded Dose of Inorganic Arsenic in Adult Male White Pekin Ducks","volume":"201","author":"Kumar","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhuang, X., Li, L., Liu, T., Zhang, R., Yang, P., Wang, X., and Dai, L. (2022). Mechanisms of isoniazid and rifampicin-induced liver injury and the effects of natural medicinal ingredients: A review. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1037814"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Walenta, L., Fleck, D., Fr\u00f6hlich, T., von Eysmondt, H., Arnold, G.J., Spehr, J., Schwarzer, J.U., K\u00f6hn, F.M., Spehr, M., and Mayerhofer, A. (2018). ATP-mediated Events in Peritubular Cells Contribute to Sterile Testicular Inflammation. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19624-3"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.repbio.2019.10.003","article-title":"Oxidative stress, inflammatory reactions and apoptosis mediated the negative effect of chronic stress induced by maternal separation on the reproductive system in male mice","volume":"19","author":"Khodamoradi","year":"2019","journal-title":"Reprod. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/toxres\/tfaa009","article-title":"Moringa oleifera leaves extract modulates toxicity, sperms alterations, oxidative stress, and testicular damage induced by tramadol in male rats","volume":"9","author":"Abd","year":"2020","journal-title":"Toxicol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Minisy, F.M., Shawki, H.H., El Omri, A., Massoud, A.A., Omara, E.A., Metwally, F.G., Badawy, M.A., Hassan, N.A., Hassan, N.S., and Oishi, H. (2020). Pomegranate Seeds Extract Possesses a Protective Effect against Tramadol-Induced Testicular Toxicity in Experimental Rats. Biomed. Res. Int., 2020.","DOI":"10.1155\/2020\/2732958"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s12291-023-01141-4","article-title":"Biochemical and Pharmacological Assessments of Tramadol Abuse on Human Male Fertility: Relation to Seminal Plasma 8-Hydroxyguanosine and Zinc","volume":"39","author":"Hassan","year":"2024","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marinaro, C., Lettieri, G., Chianese, T., Bianchi, A.R., Zarrelli, A., Palatucci, D., Scudiero, R., Rosati, L., De Maio, A., and Piscopo, M. (2024). Exploring the Molecular and Toxicological Mechanism Associated with Interactions Between Heavy Metals and the Reproductive System of Mytilus galloprovincialis. Comp. Biochem. Physiol. Part C Toxicol. Pharmacol., 275.","DOI":"10.1016\/j.cbpc.2023.109778"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/7\/1078\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:05:30Z","timestamp":1760033130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/7\/1078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,6]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["life15071078"],"URL":"https:\/\/doi.org\/10.3390\/life15071078","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,6]]}}}