{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:58:39Z","timestamp":1792591119497,"version":"4.5.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA188305"],"award-info":[{"award-number":["R01CA188305"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R21CA185021"],"award-info":[{"award-number":["R21CA185021"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Male infertility might be caused by genetic and\/or environmental factors that impair spermatogenesis and epididymal sperm maturation. Here we report that heterozygous deletion of the nuclear receptor coactivator-5 (<jats:italic>Ncoa5<\/jats:italic>) gene resulted in decreased motility and progression of spermatozoa in the cauda epididymis, leading to infertility in male mice. Light microscopic and ultrastructural analysis revealed morphological defects in the spermatozoa collected from the cauda epididymis of <jats:italic>Ncoa5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice. Immunohistochemistry showed that interleukin-6 (IL-6) expression in epithelial cells of <jats:italic>Ncoa5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> epididymis was higher than wild type counterparts. Furthermore, heterozygous deletion of <jats:italic>Il-6<\/jats:italic> gene in <jats:italic>Ncoa5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> male mice partially improved spermatozoa motility and moderately rescued infertility phenotype. Our results uncover a previously unknown physiological role of NCOA5 in the regulation of epididymal sperm maturation and suggest that NCOA5 deficiency could cause male infertility through increased IL-6 expression in epididymis.<\/jats:p>","DOI":"10.1038\/s41598-019-52105-9","type":"journal-article","created":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T20:29:48Z","timestamp":1572467388000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["NCOA5 Haplo-insufficiency Results in Male Mouse Infertility through Increased IL-6 Expression in the Epididymis"],"prefix":"10.1038","volume":"9","author":[{"given":"Shenglan","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengfeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria I.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"52105_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-015-0032-1","volume":"13","author":"A Agarwal","year":"2015","unstructured":"Agarwal, A., Mulgund, A., Hamada, A. & Chyatte, M. R. A unique view on male infertility around the globe. Reprod Biol Endocrinol 13, 37 (2015).","journal-title":"Reprod Biol Endocrinol"},{"key":"52105_CR2","doi-asserted-by":"publisher","first-page":"14737","DOI":"10.1073\/pnas.250473597","volume":"97","author":"S Ogawa","year":"2000","unstructured":"Ogawa, S. et al. Abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO). Proceedings of the National Academy of Sciences of the United States of America 97, 14737\u201314741 (2000).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"52105_CR3","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.5754\/hge10799","volume":"58","author":"XH Pang","year":"2011","unstructured":"Pang, X. H. et al. Preoperative levels of serum interleukin-6 in patients with hepatocellular carcinoma. Hepatogastroenterology 58, 1687\u20131693 (2011).","journal-title":"Hepatogastroenterology"},{"key":"52105_CR4","doi-asserted-by":"publisher","first-page":"18643","DOI":"10.1073\/pnas.1413186112","volume":"111","author":"B Xu","year":"2014","unstructured":"Xu, B., Washington, A. M. & Hinton, B. T. PTEN signaling through RAF1 proto-oncogene serine\/threonine kinase (RAF1)\/ERK in the epididymis is essential for male fertility. Proc Natl Acad Sci USA 111, 18643\u201318648 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"52105_CR5","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1093\/humupd\/dmp032","volume":"16","author":"CL Borg","year":"2010","unstructured":"Borg, C. L., Wolski, K. M., Gibbs, G. M. & O\u2019Bryan, M. K. Phenotyping male infertility in the mouse: how to get the most out of a \u2018non-performer\u2019. Hum Reprod Update 16, 205\u2013224 (2010).","journal-title":"Hum Reprod Update"},{"key":"52105_CR6","doi-asserted-by":"publisher","first-page":"R27","DOI":"10.1530\/REP-13-0420","volume":"147","author":"JL Dacheux","year":"2014","unstructured":"Dacheux, J. L. & Dacheux, F. New insights into epididymal function in relation to sperm maturation. Reproduction 147, R27\u201342 (2014).","journal-title":"Reproduction"},{"key":"52105_CR7","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.fertnstert.2018.08.015","volume":"110","author":"JT Choy","year":"2018","unstructured":"Choy, J. T. & Eisenberg, M. L. Male infertility as a window to health. Fertil Steril 110, 810\u2013814 (2018).","journal-title":"Fertil Steril"},{"key":"52105_CR8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.2164\/jandrol.107.003731","volume":"29","author":"SS Kasturi","year":"2008","unstructured":"Kasturi, S. S., Tannir, J. & Brannigan, R. E. The metabolic syndrome and male infertility. J Androl 29, 251\u2013259 (2008).","journal-title":"J Androl"},{"key":"52105_CR9","doi-asserted-by":"publisher","first-page":"1883","DOI":"10.1016\/j.bpj.2009.07.033","volume":"97","author":"K Franze","year":"2009","unstructured":"Franze, K. et al. Neurite branch retraction is caused by a threshold-dependent mechanical impact. Biophys J 97, 1883\u20131890 (2009).","journal-title":"Biophys J"},{"key":"52105_CR10","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/j.1439-0272.2007.00819.x","volume":"40","author":"G Haidl","year":"2008","unstructured":"Haidl, G., Allam, J. P. & Schuppe, H. C. Chronic epididymitis: impact on semen parameters and therapeutic options. Andrologia 40, 92\u201396 (2008).","journal-title":"Andrologia"},{"key":"52105_CR11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cyto.2014.05.024","volume":"70","author":"J Wolf","year":"2014","unstructured":"Wolf, J., Rose-John, S. & Garbers, C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine 70, 11\u201320 (2014).","journal-title":"Cytokine"},{"key":"52105_CR12","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/0092-8674(90)90411-7","volume":"63","author":"M Hibi","year":"1990","unstructured":"Hibi, M. et al. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149\u20131157 (1990).","journal-title":"Cell"},{"key":"52105_CR13","first-page":"161","volume":"16","author":"H Potashnik","year":"2005","unstructured":"Potashnik, H. et al. Interleukin-6 expression during normal maturation of the mouse testis. Eur Cytokine Netw 16, 161\u2013165 (2005).","journal-title":"Eur Cytokine Netw"},{"key":"52105_CR14","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/S1472-6483(10)60309-4","volume":"17","author":"F Lampiao","year":"2008","unstructured":"Lampiao, F. & du Plessis, S. S. TNF-alpha and IL-6 affect human sperm function by elevating nitric oxide production. Reprod Biomed Online 17, 628\u2013631 (2008).","journal-title":"Reprod Biomed Online"},{"key":"52105_CR15","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0303-7207(95)03475-M","volume":"108","author":"H Hakovirta","year":"1995","unstructured":"Hakovirta, H., Syed, V., Jegou, B. & Parvinen, M. Function of interleukin-6 as an inhibitor of meiotic DNA synthesis in the rat seminiferous epithelium. Molecular and cellular endocrinology 108, 193\u2013198 (1995).","journal-title":"Molecular and cellular endocrinology"},{"key":"52105_CR16","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1016\/j.urology.2004.05.045","volume":"64","author":"KP Nallella","year":"2004","unstructured":"Nallella, K. P. et al. Relationship of interleukin-6 with semen characteristics and oxidative stress in patients with varicocele. Urology 64, 1010\u20131013 (2004).","journal-title":"Urology"},{"key":"52105_CR17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3109\/01485019808988545","volume":"41","author":"I Matalliotakis","year":"1998","unstructured":"Matalliotakis, I. et al. Interleukin-6 in seminal plasma of fertile and infertile men. Arch Androl 41, 43\u201350 (1998).","journal-title":"Arch Androl"},{"key":"52105_CR18","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1128\/MCB.21.1.343-353.2001","volume":"21","author":"F Sauve","year":"2001","unstructured":"Sauve, F. et al. CIA, a novel estrogen receptor coactivator with a bifunctional nuclear receptor interacting determinant. Mol Cell Biol 21, 343\u2013353 (2001).","journal-title":"Mol Cell Biol"},{"key":"52105_CR19","doi-asserted-by":"publisher","first-page":"27781","DOI":"10.1074\/jbc.M401809200","volume":"279","author":"C Jiang","year":"2004","unstructured":"Jiang, C. et al. TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription. J Biol Chem 279, 27781\u201327789 (2004).","journal-title":"J Biol Chem"},{"key":"52105_CR20","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.15252\/embj.201489819","volume":"34","author":"MA Gillespie","year":"2015","unstructured":"Gillespie, M. A. et al. An LXR-NCOA5 gene regulatory complex directs inflammatory crosstalk-dependent repression of macrophage cholesterol efflux. EMBO J 34, 1244\u20131258 (2015).","journal-title":"EMBO J"},{"key":"52105_CR21","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.ccr.2013.11.005","volume":"24","author":"S Gao","year":"2013","unstructured":"Gao, S. et al. NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma. Cancer Cell 24, 725\u2013737 (2013).","journal-title":"Cancer Cell"},{"key":"52105_CR22","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.cmet.2013.12.010","volume":"19","author":"D Dhar","year":"2014","unstructured":"Dhar, D., Seki, E. & Karin, M. NCOA5, IL-6, type 2 diabetes, and HCC: The deadly quartet. Cell Metab 19, 6\u20137, https:\/\/doi.org\/10.1016\/j.cmet.2013.12.010 (2014).","journal-title":"Cell Metab"},{"key":"52105_CR23","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.reprotox.2006.04.016","volume":"22","author":"A Ferlin","year":"2006","unstructured":"Ferlin, A., Arredi, B. & Foresta, C. Genetic causes of male infertility. Reprod Toxicol 22, 133\u2013141 (2006).","journal-title":"Reprod Toxicol"},{"key":"52105_CR24","doi-asserted-by":"publisher","first-page":"16023","DOI":"10.1038\/npjgenmed.2016.23","volume":"1","author":"N Kothandaraman","year":"2016","unstructured":"Kothandaraman, N., Agarwal, A., Abu-Elmagd, M. & Al-Qahtani, M. H. Pathogenic landscape of idiopathic male infertility: new insight towards its regulatory networks. NPJ Genom Med 1, 16023, https:\/\/doi.org\/10.1038\/npjgenmed.2016.23 (2016).","journal-title":"NPJ Genom Med"},{"key":"52105_CR25","doi-asserted-by":"crossref","unstructured":"Fainberg, J. & Kashanian, J. A. Recent advances in understanding and managing male infertility. F1000Res 8, doi:F1000 Faculty Rev-670 (2019).","DOI":"10.12688\/f1000research.17076.1"},{"key":"52105_CR26","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1080\/014850101316901280","volume":"47","author":"MI Camejo","year":"2001","unstructured":"Camejo, M. I., Segnini, A. & Proverbio, F. Interleukin-6 (IL-6) in seminal plasma of infertile men, and lipid peroxidation of their sperm. Arch Androl 47, 97\u2013101 (2001).","journal-title":"Arch Androl"},{"key":"52105_CR27","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.fertnstert.2013.09.006","volume":"101","author":"YG Duan","year":"2014","unstructured":"Duan, Y. G. et al. Dendritic cells in semen of infertile men: association with sperm quality and inflammatory status of the epididymis. Fertil Steril 101, 70\u201377 (2014).","journal-title":"Fertil Steril"},{"key":"52105_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/srep28012","volume":"6","author":"G Huang","year":"2016","unstructured":"Huang, G. et al. IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3\/STAT3 pathway. Sci Rep 6, 28012 (2016).","journal-title":"Sci Rep"},{"key":"52105_CR29","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1095\/biolreprod.109.079889","volume":"82","author":"A Joseph","year":"2010","unstructured":"Joseph, A. et al. Absence of estrogen receptor alpha leads to physiological alterations in the mouse epididymis and consequent defects in sperm function. Biol Reprod 82, 948\u2013957 (2010).","journal-title":"Biol Reprod"},{"key":"52105_CR30","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1095\/biolreprod.109.080366","volume":"82","author":"A Joseph","year":"2010","unstructured":"Joseph, A., Shur, B. D., Ko, C., Chambon, P. & Hess, R. A. Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse. Biol Reprod 82, 958\u2013967 (2010).","journal-title":"Biol Reprod"},{"key":"52105_CR31","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1095\/biolreprod.110.087353","volume":"84","author":"A Joseph","year":"2011","unstructured":"Joseph, A., Shur, B. D. & Hess, R. A. Estrogen, efferent ductules, and the epididymis. Biol Reprod 84, 207\u2013217 (2011).","journal-title":"Biol Reprod"},{"key":"52105_CR32","doi-asserted-by":"publisher","first-page":"6852","DOI":"10.1073\/pnas.0701669104","volume":"104","author":"H Zheng","year":"2007","unstructured":"Zheng, H. et al. Lack of Spem1 causes aberrant cytoplasm removal, sperm deformation, and male infertility. Proc Natl Acad Sci USA 104, 6852\u20136857 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"52105_CR33","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1038\/onc.2012.253","volume":"32","author":"A Li","year":"2013","unstructured":"Li, A. et al. TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. Oncogene 32, 2273\u20132281 (2013).","journal-title":"Oncogene"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52105-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52105-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52105-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T15:09:20Z","timestamp":1671289760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-52105-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["52105"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-52105-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]},"assertion":[{"value":"15 January 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15525"}}