{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:17:05Z","timestamp":1790223425496,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre of Poland","doi-asserted-by":"crossref","award":["MINIATURA 5, No. DEC-2021\/05\/X\/NZ7\/00721"],"award-info":[{"award-number":["MINIATURA 5, No. DEC-2021\/05\/X\/NZ7\/00721"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The effects of three-drug immunosuppressive regimens on the testis are still not fully known. The aim of this study was to evaluate the long-term effects of immunosuppressive protocols based on calcineurin inhibitors (CNIs) and their conversion to monotherapy with sirolimus on morphology, proliferation, and nuclear DNA fragmentation in the male gonad using an experimental model. For 6\u00a0months, male Wistar rats were treated with cyclosporin A (CsA), tacrolimus (FK-506), sirolimus (SRL), mycophenolate mofetil (MMF), and prednisone (Pred). The following protocols were used: CMP (CsA, MMF, and Pred), CMP\/S (CsA, MMF, and Pred with conversion to SRL), TMP (FK-506, MMF, and Pred), and TMP\/S (FK-506, MMF, and Pred with conversion to SRL). Morphological analyses, including morphometric analysis, immunohistochemical evaluation for proliferation (Ki67), and nuclear DNA fragmentation using the terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) method in the testis, were conducted. In the testes of all the experimental groups, disorders in the organization of the seminiferous epithelium, a lower diameter and area of seminiferous tubules, and a lower percentage of Ki67-positive germinal cells than those in the control group were observed. A lower height of the seminiferous epithelium in the CMP, CMP\/S and TMP\/S groups than in the control group was noted. A higher percentage of TUNEL-positive germinal cells was detected in the CMP and TMP groups. In the groups with conversion to SRL, a lower diameter and area of seminiferous tubules and height of the seminiferous epithelium (TMP\/S vs. TMP) and a lower percentage of Ki67- and TUNEL-positive cells (TMP\/S vs. TMP; CMP\/S vs. CMP) were revealed. The long-term administration of CNIs in multiple regimens can influence the course of spermatogenesis in the testes of rats, which manifests as morphological alterations in the seminiferous epithelium, vascular accumulation of collagen fibres in interstitial tissue, decreased proliferation of germinal cells and increased nuclear DNA fragmentation related to the apoptotic process. The conversion of treatment with CNIs to SRL also had adverse effects on the seminiferous epithelium; however, it had positive antiapoptotic effects. The obtained results may allow for a better understanding of changes in men undergoing immunosuppressive therapy and a preliminary assessment of which drug combination would be most beneficial in specific clinical cases.<\/jats:p>","DOI":"10.1038\/s41598-025-26892-3","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:14:38Z","timestamp":1764324878000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The treatment based on calcineurin inhibitors and their conversion to sirolimus alter the morphology in the rat testis"],"prefix":"10.1038","volume":"15","author":[{"given":"Marta","family":"Grabowska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Micha\u0142ek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"K\u0119dzierska-Kapuza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamil","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Piasecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"26892_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-818731-9.00068-9","author":"Y Hussain","year":"2022","unstructured":"Hussain, Y. & Khan, H. Immunosuppressive drugs. Encycloped. Infect. Immun. https:\/\/doi.org\/10.1016\/B978-0-12-818731-9.00068-9 (2022).","journal-title":"Encycloped. Infect. Immun."},{"key":"26892_CR2","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.2147\/TCRM.S164323","volume":"14","author":"YF Tsai","year":"2018","unstructured":"Tsai, Y. F., Liu, F. C., Kuo, C. F., Chung, T. T. & Yu, H. P. Graft outcomes following immunosuppressive therapy with different combinations in kidney transplant recipients: A nationwide cohort study. Ther. Clin. Risk Manag. 14, 1099\u20131110. https:\/\/doi.org\/10.2147\/TCRM.S164323 (2018).","journal-title":"Ther. Clin. Risk Manag."},{"key":"26892_CR3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.29245\/2578-3009\/2019\/4.1178","volume":"3","author":"E Claeys","year":"2019","unstructured":"Claeys, E. & Vermeire, K. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: Mode of action and side effects. J. Immunol. Sci. 3, 14\u201321. https:\/\/doi.org\/10.29245\/2578-3009\/2019\/4.1178 (2019).","journal-title":"J. Immunol. Sci."},{"key":"26892_CR4","doi-asserted-by":"publisher","first-page":"690382","DOI":"10.1155\/2013\/690382","volume":"2013","author":"Y Chen","year":"2013","unstructured":"Chen, Y. et al. Long-term impact of immunosuppressants at therapeutic doses on male reproductive system in unilateral nephrectomized rats: a comparative study. Biomed. Res. Int. 2013, 690382. https:\/\/doi.org\/10.1155\/2013\/690382 (2013).","journal-title":"Biomed. Res. Int."},{"key":"26892_CR5","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.trre.2016.10.006","volume":"31","author":"MA Lim","year":"2017","unstructured":"Lim, M. A., Kohli, J. & Bloom, R. D. Immunosuppression for kidney transplantation: Where are we now and where are we going?. Transpl. Rev. (Orlando) 31, 10\u201317. https:\/\/doi.org\/10.1016\/j.trre.2016.10.006 (2017).","journal-title":"Transpl. Rev. (Orlando)"},{"key":"26892_CR6","doi-asserted-by":"publisher","first-page":"F336","DOI":"10.1152\/ajprenal.00262.2020","volume":"320","author":"AC Ume","year":"2021","unstructured":"Ume, A. C., Wenegieme, T. Y. & Williams, C. R. Calcineurin inhibitors: A double-edged sword. Am. J. Physiol. Renal Physiol. 320, F336\u2013F341. https:\/\/doi.org\/10.1152\/ajprenal.00262.2020 (2021).","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"26892_CR7","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1016\/j.athoracsur.2009.09.081","volume":"89","author":"T Oto","year":"2010","unstructured":"Oto, T. et al. Calcineurin inhibitor-related cholestasis complicating lung transplantation. Ann. Thorac. Surg. 89, 1664\u20131665. https:\/\/doi.org\/10.1016\/j.athoracsur.2009.09.081 (2010).","journal-title":"Ann. Thorac. Surg."},{"key":"26892_CR8","doi-asserted-by":"publisher","first-page":"166","DOI":"10.2174\/157488408785747674","volume":"3","author":"A Magnasco","year":"2008","unstructured":"Magnasco, A. et al. Cyclosporin and organ specific toxicity: Clinical aspects, pharmacogenetics and perspectives. Curr. Clin. Pharmacol. 3, 166\u2013173. https:\/\/doi.org\/10.2174\/157488408785747674 (2008).","journal-title":"Curr. Clin. Pharmacol."},{"key":"26892_CR9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.29333\/ejgm\/81898","volume":"13","author":"AE El-Agroudy","year":"2016","unstructured":"El-Agroudy, A. E. et al. Sirolimus-based, calcineurin inhibitor-free regimen in kidney transplant patients: An open-label, randomized, controlled trial. Eur. J. Gen. Med. 13, 16\u201322. https:\/\/doi.org\/10.29333\/ejgm\/81898 (2016).","journal-title":"Eur. J. Gen. Med."},{"key":"26892_CR10","doi-asserted-by":"publisher","first-page":"3056","DOI":"10.1016\/j.transproceed.2021.09.019","volume":"53","author":"AR de Souza","year":"2021","unstructured":"de Souza, A. R. et al. Mammalian target of rapamycin inhibitors vs calcineurin inhibitors in chronic graft rejection after lung transplantation: A systematic review and meta-analysis. Transplant. Proc. 53, 3056\u20133064. https:\/\/doi.org\/10.1016\/j.transproceed.2021.09.019 (2021).","journal-title":"Transplant. Proc."},{"key":"26892_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4557-0268-8.00097-X","author":"R Ruiz","year":"2015","unstructured":"Ruiz, R. & Kirk, A. D. Long-term toxicity of immunosuppressive therapy. Transplant. Liver https:\/\/doi.org\/10.1016\/B978-1-4557-0268-8.00097-X (2015).","journal-title":"Transplant. Liver"},{"key":"26892_CR12","doi-asserted-by":"publisher","first-page":"6935","DOI":"10.3390\/jcm12216935","volume":"12","author":"B Opa\u0142ka","year":"2023","unstructured":"Opa\u0142ka, B., \u017bo\u0142nierczuk, M. & Grabowska, M. Immunosuppressive agents\u2014Effects on the cardiovascular system and selected metabolic aspects: A review. J. Clin. Med. 12, 6935. https:\/\/doi.org\/10.3390\/jcm12216935 (2023).","journal-title":"J. Clin. Med."},{"key":"26892_CR13","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1007\/s43440-023-00521-0","volume":"75","author":"M Grabowska","year":"2023","unstructured":"Grabowska, M. et al. The long-term effects of multidrug immunosuppressive protocols based on calcineurin inhibitors and conversion to rapamycin on the morphology, apoptosis, and proliferation of rat salivary glands. Pharmacol. Rep. 75, 1240\u20131253. https:\/\/doi.org\/10.1007\/s43440-023-00521-0 (2023).","journal-title":"Pharmacol. Rep."},{"key":"26892_CR14","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1477-7827-7-19.PMCID:PMC2660339","volume":"7","author":"BH Caneguim","year":"2009","unstructured":"Caneguim, B. H., Cerri, P. S., Spolid\u00f3rio, L. C., Miraglia, S. M. & Sasso-Cerri, E. Structural alterations in the seminiferous tubules of rats treated with immunosuppressor tacrolimus. Reprod. Biol. Endocrinol. 7, 19. https:\/\/doi.org\/10.1186\/1477-7827-7-19.PMCID:PMC2660339 (2009).","journal-title":"Reprod. Biol. Endocrinol."},{"key":"26892_CR15","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1097\/TP.0b013e31824bf1f0","volume":"93","author":"J Rovira","year":"2012","unstructured":"Rovira, J. et al. Sirolimus-associated testicular toxicity: Detrimental but reversible. Transplantation 93, 874\u2013879. https:\/\/doi.org\/10.1097\/TP.0b013e31824bf1f0 (2012).","journal-title":"Transplantation"},{"key":"26892_CR16","doi-asserted-by":"publisher","first-page":"4029","DOI":"10.3892\/mmr.2017.7120.PMCID:PMC5646984","volume":"16","author":"S Liu","year":"2017","unstructured":"Liu, S. et al. Rapamycin inhibits spermatogenesis by changing the autophagy status through suppressing mechanistic target of rapamycin-p70S6 kinase in male rats. Mol. Med. Rep. 16, 4029\u20134037. https:\/\/doi.org\/10.3892\/mmr.2017.7120.PMCID:PMC5646984 (2017).","journal-title":"Mol. Med. Rep."},{"key":"26892_CR17","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1097\/01.TP.0000079830.03841.9E","volume":"76","author":"L Bererhi","year":"2003","unstructured":"Bererhi, L. et al. Rapamycin-induced oligospermia. Transplantation 76, 885\u2013886. https:\/\/doi.org\/10.1097\/01.TP.0000079830.03841.9E (2003).","journal-title":"Transplantation"},{"key":"26892_CR18","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1046\/j.1600-6135.2003.00279.x","volume":"4","author":"L Fritsche","year":"2004","unstructured":"Fritsche, L. et al. Testosterone concentrations and sirolimus in male renal transplant patients. Am. J. Transplant. 4, 130\u2013131. https:\/\/doi.org\/10.1046\/j.1600-6135.2003.00279.x (2004).","journal-title":"Am. J. Transplant."},{"key":"26892_CR19","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1111\/j.1600-6143.2008.02267.x","volume":"8","author":"J Zuber","year":"2008","unstructured":"Zuber, J. et al. Sirolimus may reduce fertility in male renal transplant recipients. Am. J. Transplant. 8, 1471\u20131479. https:\/\/doi.org\/10.1111\/j.1600-6143.2008.02267.x (2008).","journal-title":"Am. J. Transplant."},{"key":"26892_CR20","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/bdrb.20338","volume":"92","author":"JC Sasaki","year":"2011","unstructured":"Sasaki, J. C. et al. Incidence and nature of testicular toxicity findings in pharmaceutical development. Birth Defects Res. B Dev. Reprod. Toxicol. 92, 511\u2013525 (2011).","journal-title":"Birth Defects Res. B Dev. Reprod. Toxicol."},{"key":"26892_CR21","doi-asserted-by":"publisher","first-page":"100757","DOI":"10.1016\/j.repbio.2023.100757","volume":"23","author":"M Freus","year":"2023","unstructured":"Freus, M., Kabat-Koperska, J., Frulenko, I., Wiszniewska, B. & Kolasa, A. Morphology of the male rat gonad after in utero exposure to immunosuppressants. Reprod. Biol. 23, 100757. https:\/\/doi.org\/10.1016\/j.repbio.2023.100757 (2023).","journal-title":"Reprod. Biol."},{"key":"26892_CR22","doi-asserted-by":"publisher","first-page":"4614","DOI":"10.3390\/ijerph17124614","volume":"17","author":"M Grabowska","year":"2020","unstructured":"Grabowska, M. et al. The effects of long-term immunosuppressive therapies on the structure of the rat prostate. Int. J. Environ. Res. Public Health 17, 4614. https:\/\/doi.org\/10.3390\/ijerph17124614 (2020).","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"26892_CR23","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s00795-003-0213-4","volume":"36","author":"H Masuda","year":"2003","unstructured":"Masuda, H. et al. Ultrastructural study on cytotoxic effects of cyclosporine A in spermiogenesis in rats. Med. Electron Microsc. 36, 183\u2013191. https:\/\/doi.org\/10.1007\/s00795-003-0213-4 (2003).","journal-title":"Med. Electron Microsc."},{"key":"26892_CR24","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/s0022-5347(17)43479-3","volume":"138","author":"L Seethalakshmi","year":"1987","unstructured":"Seethalakshmi, L., Menon, M., Malhotra, R. K. & Diamond, D. A. Effect of cyclosporine A on male reproduction in rats. J. Urol. 138, 991\u2013995. https:\/\/doi.org\/10.1016\/s0022-5347(17)43479-3 (1987).","journal-title":"J. Urol."},{"key":"26892_CR25","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/BF02890074","volume":"58","author":"L Cavallini","year":"1990","unstructured":"Cavallini, L., Malendowicz, L. K., Mazzocchi, G., Belloni, A. S. & Nussdorfer, G. G. Effects of prolonged cyclosporine-A treatment on the Leydig cells of the rat testis. Virchows Arch. B Cell. Pathol. Incl. Mol. Pathol. 58, 215\u2013220. https:\/\/doi.org\/10.1007\/BF02890074 (1990).","journal-title":"Virchows Arch. B Cell. Pathol. Incl. Mol. Pathol."},{"key":"26892_CR26","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1007\/s003830050346","volume":"13","author":"M Srinivas","year":"1998","unstructured":"Srinivas, M. et al. Effect of cyclosporine on fertility in male rats. Pediatr. Surg. Int. 13, 388\u2013391. https:\/\/doi.org\/10.1007\/s003830050346 (1998).","journal-title":"Pediatr. Surg. Int."},{"key":"26892_CR27","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1093\/humrep\/deh192","volume":"19","author":"L Tauchmanov\u00e0","year":"2004","unstructured":"Tauchmanov\u00e0, L. et al. Hypothalamic-pituitary-gonadal axis function after successful kidney transplantation in men and women. Hum. Reprod. 19, 867\u2013873. https:\/\/doi.org\/10.1093\/humrep\/deh192 (2004).","journal-title":"Hum. Reprod."},{"key":"26892_CR28","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.theriogenology.2006.10.013","volume":"67","author":"G T\u00fcrk","year":"2007","unstructured":"T\u00fcrk, G., Ate\u015f\u015fahin, A., S\u00f6nmez, M., Y\u00fcce, A. & Ceriba\u015fi, A. O. Lycopene protects against cyclosporine A-induced testicular toxicity in rats. Theriogenology 67, 778\u2013785. https:\/\/doi.org\/10.1016\/j.theriogenology.2006.10.013 (2007).","journal-title":"Theriogenology"},{"key":"26892_CR29","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1016\/j.transproceed.2012.03.067","volume":"45","author":"Z He","year":"2013","unstructured":"He, Z. et al. Long-term effects of conversion from cyclosporine to rapamycin on testicular function and morphology in a rat transplantation model. Transplant. Proc. 45, 763\u2013769. https:\/\/doi.org\/10.1016\/j.transproceed.2012.03.067 (2013).","journal-title":"Transplant. Proc."},{"key":"26892_CR30","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1111\/j.1432-2277.2006.00423.x","volume":"20","author":"E Huyghe","year":"2007","unstructured":"Huyghe, E. et al. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl. Int. 20, 305\u2013311. https:\/\/doi.org\/10.1111\/j.1432-2277.2006.00423.x (2007).","journal-title":"Transpl. Int."},{"key":"26892_CR31","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/j.1365-2613.2009.00692.x","volume":"91","author":"F de Souza Predes","year":"2010","unstructured":"de Souza Predes, F., Diamante, M. A. & Dolder, H. Testis response to low doses of cadmium in Wistar rats. Int. J. Exp. Pathol. 91, 125\u2013131. https:\/\/doi.org\/10.1111\/j.1365-2613.2009.00692.x (2010).","journal-title":"Int. J. Exp. Pathol."},{"key":"26892_CR32","doi-asserted-by":"publisher","first-page":"e20200029","DOI":"10.1590\/1984-3143-ar2020-0029","volume":"18","author":"MAM Arroyo","year":"2021","unstructured":"Arroyo, M. A. M., Santos, P. R. D. S. & De Oliveira, M. F. Prolonged use of letrozole causes morphological changes on gonads in Galea spixii. Anim. Reprod. 18, e20200029. https:\/\/doi.org\/10.1590\/1984-3143-ar2020-0029 (2021).","journal-title":"Anim. Reprod."},{"key":"26892_CR33","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/s0890-6238(02)00075-8","volume":"17","author":"SK Singh","year":"2003","unstructured":"Singh, S. K. & Chakravarty, S. Antispermatogenic and antifertility effects of 20,25-diazacholesterol dihydrochloride in mice. Reprod. Toxicol. 17, 37\u201344. https:\/\/doi.org\/10.1016\/s0890-6238(02)00075-8 (2003).","journal-title":"Reprod. Toxicol."},{"key":"26892_CR34","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.3390\/ani15121696","volume":"15","author":"V Seco-Rovira","year":"2025","unstructured":"Seco-Rovira, V. et al. Gradual thickening of the peritubular lamina propria in healthy boar seminiferous tubules due to cryptorchidism: Increased immunoexpression of diverse proteins in Sertoli and myoid cells. Animals 15, 1696. https:\/\/doi.org\/10.3390\/ani15121696 (2025).","journal-title":"Animals"},{"key":"26892_CR35","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.14670\/HH-11-606","volume":"30","author":"M Grabowska","year":"2015","unstructured":"Grabowska, M. et al. The influence of immunosuppressants on the morphology, proliferating cell nuclear antigen (PCNA) and apoptosis in the rat ventral prostate. Histol. Histopathol. 30, 1089\u20131100. https:\/\/doi.org\/10.14670\/HH-11-606 (2015).","journal-title":"Histol. Histopathol."},{"key":"26892_CR36","doi-asserted-by":"publisher","first-page":"2899","DOI":"10.2147\/DDDT.S111695","volume":"10","author":"M Grabowska","year":"2016","unstructured":"Grabowska, M. et al. Effects of an immunosuppressive treatment on the rat prostate. Drug Des. Devel. Ther. 10, 2899\u20132915. https:\/\/doi.org\/10.2147\/DDDT.S111695 (2016).","journal-title":"Drug Des. Devel. Ther."},{"key":"26892_CR37","doi-asserted-by":"publisher","first-page":"2374","DOI":"10.1093\/ndt\/gfn008","volume":"23","author":"F Kleinclauss","year":"2008","unstructured":"Kleinclauss, F. et al. Prostate cancer in renal transplant recipients. Nephrol. Dial. Transplant. 23, 2374\u20132380 (2008).","journal-title":"Nephrol. Dial. Transplant."},{"key":"26892_CR38","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1210\/er.2014-1101","volume":"36","author":"DD Mruk","year":"2015","unstructured":"Mruk, D. D. & Cheng, C. Y. The mammalian blood-testis barrier: Its biology and regulation [retracted in: Endocr. Rev. 2016 Feb;2016(1):43]. Endocr. Rev. 36, 564\u2013591. https:\/\/doi.org\/10.1210\/er.2014-1101 (2015).","journal-title":"Endocr. Rev."},{"key":"26892_CR39","unstructured":"European Medicines Agency. EMA recommends additional measures to prevent use of mycophenolate in pregnancy. Published October 23, 2015. Accessed August 1, 2025."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26892-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26892-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26892-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T10:14:39Z","timestamp":1764324879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-26892-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["26892"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-26892-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"3 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"42612"}}