{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:52:07Z","timestamp":1789696327030,"version":"4.0.1"},"posted":{"date-parts":[[2025,1,15]]},"group-title":"Pathology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T00:00:00Z","timestamp":1736899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Autoimmune regulator (AIRE), a transcription factor expressed by medullary thymic epithelial cells, is required for shaping the self-antigen tolerant T cell receptor repertoire. Humans with mutations in\n                  <jats:italic>AIRE<\/jats:italic>\n                  suffer from Autoimmune Polyglandular Syndrome Type 1 (APS-1). Among many symptoms, men with APS-1 commonly experience testicular insufficiency and infertility, but the mechanisms causing infertility are unknown. Using an\n                  <jats:italic>Aire<\/jats:italic>\n                  -deficient mouse model, we demonstrate that male subfertility is caused by sterile epididymitis characterized by immune cell infiltration and extensive fibrosis. In addition, we reveal that the presence of autoreactive immune cells and inflammation in epididymides of\n                  <jats:italic>Aire-<\/jats:italic>\n                  deficient mice are required for iron (Fe) deposition in the interstitium, which is brought on by macrophages. We further demonstrate that male subfertility is associated with a decrease in metals zinc (Zn), copper (Cu), and selenium (Se) which serve as cofactors in several antioxidant enzymes. We also show increase in DNA damage of epididymal sperm of\n                  <jats:italic>\n                    Aire\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                  <\/jats:italic>\n                  animals as a key contributing factor to subfertility. The absence of\n                  <jats:italic>Aire<\/jats:italic>\n                  results in autoimmune attack of the epididymis leading to fibrosis, Fe deposition, and Cu, Zn and Se imbalance, ultimately resulting in sperm DNA damage and subfertility. These results highlight the requirement of\n                  <jats:italic>Aire<\/jats:italic>\n                  to promote immune tolerance throughout the epididymis, disruption of which causes an imbalance of inorganic elements with resulting consequence on male fertility.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:p>Breakdown of epididymal self-tolerance promotes disruption of inorganic elements. Autoimmunity causes interstitial fibrosis resulting in sperm DNA damage and subfertility. Elevated interstitial iron and macrophages contribute to fibrosis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.11.632558","type":"posted-content","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T06:40:11Z","timestamp":1736923211000},"source":"Crossref","is-referenced-by-count":4,"title":["Autoimmune regulator deficiency causes sterile epididymitis and impacts male fertility through disruption of inorganic physiology"],"prefix":"10.64898","author":[{"given":"Soo Hyun","family":"Ahn","sequence":"first","affiliation":[{"name":"Department of Pathobiology Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina","family":"Halgren","sequence":"additional","affiliation":[{"name":"Lyman Briggs College, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Grzesiak","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith W.","family":"MacRenaris","sequence":"additional","affiliation":[{"name":"Elemental Health Institute and Department of Microbiology Genetics and Immunology, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Sue","sequence":"additional","affiliation":[{"name":"Elemental Health Institute and Department of Microbiology Genetics and Immunology, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huirong","family":"Xie","sequence":"additional","affiliation":[{"name":"Transgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Research Technology Support Facility, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Demireva","sequence":"additional","affiliation":[{"name":"Transgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Research Technology Support Facility, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas V.","family":"O\u2019Halloran","sequence":"additional","affiliation":[{"name":"Elemental Health Institute and Department of Microbiology Genetics and Immunology, Michigan State University, East Lansing, MI, USA"},{"name":"Department of Chemistry, Michigan State University, East Lansing, MI, USA"},{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret G.","family":"Petroff","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA"},{"name":"Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA"},{"name":"Department of Microbiology, Genomics, and Immunology, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041021322194000_2025.01.11.632558v2.1","unstructured":"Infertility Prevalence Estimates, 1990\u20132021. Geneva: World Health Organization.; 2023."},{"issue":"3","key":"2026041021322194000_2025.01.11.632558v2.2","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1016\/j.fertnstert.2014.12.103","article-title":"Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion","volume":"103","year":"2015","journal-title":"Fertil Steril"},{"key":"2026041021322194000_2025.01.11.632558v2.3","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa781"},{"key":"2026041021322194000_2025.01.11.632558v2.4","doi-asserted-by":"publisher","DOI":"10.1097\/01.XHA.0000397686.82729.09"},{"key":"2026041021322194000_2025.01.11.632558v2.5","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13389"},{"key":"2026041021322194000_2025.01.11.632558v2.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958"},{"key":"2026041021322194000_2025.01.11.632558v2.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199006283222601"},{"key":"2026041021322194000_2025.01.11.632558v2.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra030158"},{"key":"2026041021322194000_2025.01.11.632558v2.9","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.40"},{"key":"2026041021322194000_2025.01.11.632558v2.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2021.05.021"},{"key":"2026041021322194000_2025.01.11.632558v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(08)60337-3"},{"key":"2026041021322194000_2025.01.11.632558v2.12","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12630"},{"key":"2026041021322194000_2025.01.11.632558v2.13","doi-asserted-by":"publisher","DOI":"10.1111\/andr.12320"},{"issue":"7","key":"2026041021322194000_2025.01.11.632558v2.14","first-page":"515","article-title":"The first cleavage of tubal sheep eggs after fertilization with epididymal or ejaculated spermatozoa","volume":"292","year":"1981","journal-title":"C R Seances Acad Sci III"},{"key":"2026041021322194000_2025.01.11.632558v2.15","doi-asserted-by":"crossref","unstructured":"Rinaldi VD , Donnard E , Gellatly K , et al. An atlas of cell types in the mouse epididymis and vas deferens. Elife. 2020;9.","DOI":"10.7554\/eLife.55474"},{"key":"2026041021322194000_2025.01.11.632558v2.16","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.10312"},{"key":"2026041021322194000_2025.01.11.632558v2.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1745-7262.2007.00299.x"},{"key":"2026041021322194000_2025.01.11.632558v2.18","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod33.3.588"},{"key":"2026041021322194000_2025.01.11.632558v2.19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.656363"},{"key":"2026041021322194000_2025.01.11.632558v2.20","doi-asserted-by":"crossref","unstructured":"Chabory E , Damon C , Lenoir A , et al. Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice. J Clin Invest. Published online June 22, 2009.","DOI":"10.1172\/JCI38940"},{"key":"2026041021322194000_2025.01.11.632558v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102183"},{"key":"2026041021322194000_2025.01.11.632558v2.22","doi-asserted-by":"publisher","DOI":"10.1139\/y93-108"},{"key":"2026041021322194000_2025.01.11.632558v2.23","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-89340-8_15"},{"key":"2026041021322194000_2025.01.11.632558v2.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2022.102152"},{"key":"2026041021322194000_2025.01.11.632558v2.25","doi-asserted-by":"publisher","DOI":"10.1258\/la.2012.150312"},{"key":"2026041021322194000_2025.01.11.632558v2.26","doi-asserted-by":"crossref","unstructured":"Ding D , Liu J , Dong K , et al. PNLDC1 is essential for piRNA 3\u2032 end trimming and transposon silencing during spermatogenesis in mice. Nat Commun. 2017;8(1).","DOI":"10.1038\/s41467-017-00854-4"},{"key":"2026041021322194000_2025.01.11.632558v2.27","unstructured":"Croy A , Yamada AT , Demayo FJ , Adamson SL . The Guide to Investigation of Mouse Pregnancy. Elsevier Gezondheidszorg; 2018."},{"key":"2026041021322194000_2025.01.11.632558v2.28","doi-asserted-by":"publisher","DOI":"10.1039\/c1ja10172b"},{"key":"2026041021322194000_2025.01.11.632558v2.29","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.111.097501"},{"key":"2026041021322194000_2025.01.11.632558v2.30","doi-asserted-by":"publisher","DOI":"10.3390\/biom11081095"},{"key":"2026041021322194000_2025.01.11.632558v2.31","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i5.521"},{"issue":"11","key":"2026041021322194000_2025.01.11.632558v2.32","first-page":"695","article-title":"Iron overload in patients with chronic liver disease","volume":"12","year":"2016","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"2026041021322194000_2025.01.11.632558v2.33","doi-asserted-by":"publisher","DOI":"10.1002\/path.5401"},{"key":"2026041021322194000_2025.01.11.632558v2.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.11.033"},{"key":"2026041021322194000_2025.01.11.632558v2.35","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1978.58.2.317"},{"key":"2026041021322194000_2025.01.11.632558v2.36","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.50.5.471"},{"key":"2026041021322194000_2025.01.11.632558v2.37","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1206713"},{"key":"2026041021322194000_2025.01.11.632558v2.38","doi-asserted-by":"publisher","DOI":"10.1017\/S1751731107000961"},{"key":"2026041021322194000_2025.01.11.632558v2.39","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gal119"},{"key":"2026041021322194000_2025.01.11.632558v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2004.06.021"},{"key":"2026041021322194000_2025.01.11.632558v2.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cotox.2017.11.001"},{"key":"2026041021322194000_2025.01.11.632558v2.42","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deg202"},{"issue":"7","key":"2026041021322194000_2025.01.11.632558v2.43","first-page":"2074","article-title":"Epididymis seleno-independent glutathione peroxidase 5 maintains sperm DNA integrity in mice","volume":"119","year":"2009","journal-title":"J Clin Invest"},{"key":"2026041021322194000_2025.01.11.632558v2.44","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-020-03215-8"},{"key":"2026041021322194000_2025.01.11.632558v2.45","doi-asserted-by":"crossref","unstructured":"Pleuger C , Ai D , Hoppe ML , et al. The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis. Elife. 2022;11.","DOI":"10.7554\/eLife.82193"},{"key":"2026041021322194000_2025.01.11.632558v2.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102509"},{"key":"2026041021322194000_2025.01.11.632558v2.47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162152"},{"key":"2026041021322194000_2025.01.11.632558v2.48","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00928-2"},{"key":"2026041021322194000_2025.01.11.632558v2.49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055984"},{"key":"2026041021322194000_2025.01.11.632558v2.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.100841"},{"key":"2026041021322194000_2025.01.11.632558v2.51","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(16)48261-0"},{"issue":"4","key":"2026041021322194000_2025.01.11.632558v2.52","first-page":"343","article-title":"Role of trace elements for oxidative status and quality of human sperm","volume":"34","year":"2017","journal-title":"Balkan Med J"},{"key":"2026041021322194000_2025.01.11.632558v2.53","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod28.5.1129"},{"key":"2026041021322194000_2025.01.11.632558v2.54","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2795(199812)51:4<362::AID-MRD2>3.0.CO;2-L"},{"key":"2026041021322194000_2025.01.11.632558v2.55","doi-asserted-by":"publisher","DOI":"10.2164\/jandrol.110.012823"},{"key":"2026041021322194000_2025.01.11.632558v2.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2005.12.027"},{"key":"2026041021322194000_2025.01.11.632558v2.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102077"},{"key":"2026041021322194000_2025.01.11.632558v2.58","doi-asserted-by":"crossref","unstructured":"Barrachina F , Ottino K , Elizagaray ML , et al. Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility. Proc Natl Acad Sci U S A. 2023;120(37).","DOI":"10.1073\/pnas.2306797120"},{"key":"2026041021322194000_2025.01.11.632558v2.59","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(97)00536-0"},{"key":"2026041021322194000_2025.01.11.632558v2.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2003.12.039"},{"key":"2026041021322194000_2025.01.11.632558v2.61","doi-asserted-by":"crossref","unstructured":"Lawler T , Parlato L , Warren Andersen S . Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control. Published online September 9, 2023.","DOI":"10.1007\/s10552-023-01783-y"},{"key":"2026041021322194000_2025.01.11.632558v2.62","doi-asserted-by":"crossref","unstructured":"Chung S , Overstreet JM , Li Y , et al. TGF-\u03b2 promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration. JCI Insight. 2018;3(21).","DOI":"10.1172\/jci.insight.123563"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.11.632558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T04:32:32Z","timestamp":1775881952000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.11.632558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,15]]},"references-count":62,"URL":"https:\/\/doi.org\/10.1101\/2025.01.11.632558","relation":{},"subject":[],"published":{"date-parts":[[2025,1,15]]},"subtype":"preprint"}}