{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:36:47Z","timestamp":1790163407370,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Manipal Academy of Higher Education, Manipal"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cyclophosphamide (CY) exposure is known to affect the ovary and impair fertility. Clinically, treatment is generally given over multiple doses, but research models have generally used single doses. The relative effects of administering multiple small doses of CY in the prepubertal period are not elucidated. Two-week-old early-prepubertal Swiss albino female mice were administered with either large single (200\u00a0mg\/Kg x 1; CY200X1) or small multiple (75\u00a0mg\/Kg x 4; CY75X4) CY doses, thus a 50% higher total dose. Surviving females were assessed for estrous cyclicity, ovarian follicle reserve, oocyte functional competence, and postnatal assessment of first-generation (F1) pups. Exposure to CY75X4 reduced the loss of ovarian follicles (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), and body weight (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), and resulted in a larger population of cycling females (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) with higher oocyte yield (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) compared to CY200X1. Although CY200X1 exposed cycling females had comparable oocyte quality, and fertility index, the postnatal mortality was higher in F1 pups (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) in comparison to the CY75X4 group. Although both strategies affect oocyte quality and functional competence similarly, CY75X4, despite the higher overall dose, results in reduced follicle loss, produces higher oocyte\/blastocyst yield, and exhibits lower postnatal mortality rates, suggesting a potential advantage over CY200X1 for later fertility and offspring health. The differences in effects of the two treatment models show the need for designing animal model studies that more closely mimic the clinical administration of gonadotoxic therapies such as cyclophosphamide.\n                  <\/jats:p>","DOI":"10.1038\/s41598-024-82264-3","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T22:38:38Z","timestamp":1735339118000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comparison of large single and small multiple doses of cyclophosphamide exposure in mice during early prepubertal age on fertility outcome"],"prefix":"10.1038","volume":"14","author":[{"given":"Sujith Raj","family":"Salian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshatha","family":"Daddangadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhakshanya","family":"Predheepan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya Deeleep","family":"Bhagat Amonkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riddhi Kirit","family":"Pandya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sindhura Lakshmi Koulmane","family":"Laxminarayana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubhashree","family":"Uppangala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guruprasad","family":"Kalthur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish Kumar","family":"Adiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"key":"82264_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s40272-016-0170-8","volume":"18","author":"C Thorbinson","year":"2016","unstructured":"Thorbinson, C., Oni, L., Smith, E., Midgley, A. & Beresford, M. W. Pharmacological management of childhood-onset systemic lupus erythematosus. Paediatr. Drugs. 18, 181\u2013195 (2016).","journal-title":"Paediatr. Drugs"},{"key":"82264_CR2","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nrclinonc.2009.146","volume":"6","author":"A Emadi","year":"2009","unstructured":"Emadi, A., Jones, R. J. & Brodsky, R. A. Cyclophosphamide and cancer: golden anniversary. Nat. Rev. Clin. Oncol. 6, 638\u2013647 (2009).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"82264_CR3","doi-asserted-by":"publisher","first-page":"185ra62","DOI":"10.1126\/scitranslmed.3005402","volume":"5","author":"L Kalich-Philosoph","year":"2013","unstructured":"Kalich-Philosoph, L. et al. Cyclophosphamide triggers follicle activation and burnout; AS101 prevents follicle loss and preserves fertility. Sci. Transl Med. 5, 185ra62 (2013).","journal-title":"Sci. Transl Med."},{"key":"82264_CR4","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1530\/JOE-18-0370","volume":"240","author":"Y Luan","year":"2019","unstructured":"Luan, Y., Edmonds, M. E., Woodruff, T. K. & Kim, S. Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. J. Endocrinol. 240, 243\u2013256 (2019).","journal-title":"J. Endocrinol."},{"key":"82264_CR5","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1093\/molehr\/gaz020","volume":"25","author":"QN Nguyen","year":"2019","unstructured":"Nguyen, Q. N. et al. Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes. Mol. Hum. Reprod. 25, 433\u2013444 (2019).","journal-title":"Mol. Hum. Reprod."},{"key":"82264_CR6","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/s41419-019-1961-y","volume":"10","author":"G Bellusci","year":"2019","unstructured":"Bellusci, G. et al. Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility. Cell. Death Dis. 10, 726 (2019).","journal-title":"Cell. Death Dis."},{"key":"82264_CR7","doi-asserted-by":"publisher","first-page":"e0235140","DOI":"10.1371\/journal.pone.0235140","volume":"15","author":"SR Salian","year":"2020","unstructured":"Salian, S. R. et al. Early prepubertal cyclophosphamide exposure in mice results in long-term loss of ovarian reserve, and impaired embryonic development and blastocyst quality. PloS One. 15, e0235140 (2020).","journal-title":"PloS One"},{"key":"82264_CR8","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1093\/humrep\/16.4.632","volume":"16","author":"D Meirow","year":"2001","unstructured":"Meirow, D., Epstein, M., Lewis, H., Nugent, D. & Gosden, R. G. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum. Reprod. 16, 632\u2013637 (2001).","journal-title":"Hum. Reprod."},{"key":"82264_CR9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s40360-020-00468-5","volume":"22","author":"J Kim","year":"2021","unstructured":"Kim, J. & You, S. Extended adverse effects of cyclophosphamide on mouse ovarian function. BMC Pharmacol. Toxicol. 22, 3 (2021).","journal-title":"BMC Pharmacol. Toxicol."},{"key":"82264_CR10","doi-asserted-by":"publisher","first-page":"3387","DOI":"10.1016\/j.ejca.2013.06.038","volume":"49","author":"K Lien","year":"2013","unstructured":"Lien, K., Georgsdottir, S., Sivanathan, L., Chan, K. & Emmenegger, U. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur. J. cancer. 49, 3387\u20133395 (2013).","journal-title":"Eur. J. cancer"},{"key":"82264_CR11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/bdr2.1603","volume":"112","author":"VR Athira","year":"2020","unstructured":"Athira, V. R., Saranya, M. K., Shivanandappa, T. & Yajurvedi, H. N. Multiple dose treatment reduces cyclophosphamide-induced ovarian follicular loss in mice. Birth Defects Res. 112, 71\u201380 (2020).","journal-title":"Birth Defects Res."},{"key":"82264_CR12","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/0531-5565(94)90006-X","volume":"29","author":"RG Gosden","year":"1994","unstructured":"Gosden, R. G. & Faddy, M. J. Ovarian aging, follicular depletion, and steroidogenesis. Exp. Gerontol. 29, 265\u2013274 (1994).","journal-title":"Exp. Gerontol."},{"key":"82264_CR13","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1093\/humupd\/dmt057","volume":"20","author":"MC Richardson","year":"2014","unstructured":"Richardson, M. C., Guo, M., Fauser, B. C. & Macklon, N. S. Environmental and developmental origins of ovarian reserve. Hum. Reprod. Update. 20, 353\u2013369 (2014).","journal-title":"Hum. Reprod. Update"},{"key":"82264_CR14","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1093\/humupd\/dmz027","volume":"25","author":"N Spears","year":"2019","unstructured":"Spears, N. et al. Ovarian damage from chemotherapy and current approaches to its protection. Hum. Reprod. Update. 25, 673\u2013693 (2019).","journal-title":"Hum. Reprod. Update"},{"key":"82264_CR15","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1095\/biolreprod64.4.1056","volume":"64","author":"CR Anzalone","year":"2001","unstructured":"Anzalone, C. R., Hong, L. S., Lu, J. K. & LaPolt, P. S. Influences of age and ovarian follicular reserve on estrous cycle patterns, ovulation, and hormone secretion in the Long-Evans rat. Biol. Reprod. 64, 1056\u20131062 (2001).","journal-title":"Biol. Reprod."},{"key":"82264_CR16","doi-asserted-by":"publisher","first-page":"682060","DOI":"10.3389\/fcell.2021.682060","volume":"9","author":"W Yang","year":"2021","unstructured":"Yang, W. et al. Cyclophosphamide exposure causes long-term detrimental effect of oocytes developmental competence through affecting the epigenetic modification and maternal factors\u2019 transcription during oocyte growth. Front. Cell. Dev. Biol. 9, 682060 (2021).","journal-title":"Front. Cell. Dev. Biol."},{"key":"82264_CR17","doi-asserted-by":"publisher","first-page":"6141","DOI":"10.1038\/sj.onc.1210444","volume":"26","author":"SK Adiga","year":"2007","unstructured":"Adiga, S. K. et al. p21 provides stage specific DNA damage control to preimplantation embryos. Oncogene 26, 6141\u20136149 (2007).","journal-title":"Oncogene"},{"key":"82264_CR18","doi-asserted-by":"publisher","first-page":"2486","DOI":"10.1016\/j.fertnstert.2009.06.015","volume":"93","author":"SK Adiga","year":"2010","unstructured":"Adiga, S. K., Upadhya, D., Kalthur, G., Bola Sadashiva, S. R. & Kumar, P. Transgenerational changes in somatic and germ line genetic integrity of first-generation offspring derived from the DNA damaged sperm. Fertil. Steril. 93, 2486\u20132490 (2010).","journal-title":"Fertil. Steril."},{"key":"82264_CR19","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1080\/15592294.2019.1631111","volume":"14","author":"G Di Emidio","year":"2019","unstructured":"Di Emidio, G. et al. Pre-conceptional maternal exposure to cyclophosphamide results in modifications of DNA methylation in F1 and F2 mouse oocytes: evidence for transgenerational effects. Epigenetics 14, 1057\u20131064 (2019).","journal-title":"Epigenetics"},{"key":"82264_CR20","unstructured":"Cyclophosphamide for Injection, U. S. P., Cyclophosphamide Tablets, U. S. P. & Reference, I. D. 3110030. FDA. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2012\/012142s109lbl.pdf. Last accessed on 18th Oct 2024."},{"key":"82264_CR21","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1111\/j.1365-2125.1979.tb01004.x","volume":"8","author":"FD Juma","year":"1979","unstructured":"Juma, F. D., Rogers, H. J. & Trounce, J. R. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration. Br. J. Clin. Pharmacol. 8, 209\u2013217 (1979).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"82264_CR22","doi-asserted-by":"publisher","first-page":"e35538","DOI":"10.1371\/journal.pone.0035538","volume":"7","author":"SL Byers","year":"2012","unstructured":"Byers, S. L., Wiles, M. V., Dunn, S. L. & Taft, R. A. Mouse estrous cycle identification tool and images. PloS One. 7, e35538 (2012).","journal-title":"PloS One"},{"key":"82264_CR23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cryobiol.2020.02.012","volume":"93","author":"A Daddangadi","year":"2020","unstructured":"Daddangadi, A., Uppangala, S., Kalthur, G., Talevi, R. & Adiga, S. K. Germinal stage vitrification is superior to MII stage vitrification in prepubertal mouse oocytes. Cryobiology 93, 49\u201355 (2020).","journal-title":"Cryobiology"},{"key":"82264_CR24","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1530\/JOE-20-0382","volume":"248","author":"S Uppangala","year":"2021","unstructured":"Uppangala, S. et al. Stage-specific response in early mouse embryos exposed to prednisolone in vitro. J. Endocrinol. 248, 237\u2013247 (2021).","journal-title":"J. Endocrinol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-82264-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-82264-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-82264-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T12:06:09Z","timestamp":1735387569000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-82264-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,28]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["82264"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-82264-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,28]]},"assertion":[{"value":"9 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 December 2024","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"}},{"value":"The study was approved by the Institutional Animal Ethics Committee (Kasturba Medical College, Manipal & Kasturba Hospital Institutional Ethics Committee) approval# IAEC\/KMC\/73\/2020 & IAEC\/KMC\/39\/2021).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Approval for animal experiments"}}],"article-number":"31042"}}