{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T20:39:07Z","timestamp":1786653547817,"version":"build-2736575974"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>\n                    Chronic methamphetamine (Meth) exposure has been recognized as a critical risk factor for male reproductive dysfunction, yet its mechanistic underpinnings remain elusive. This study elucidates the molecular pathways through which Meth compromises spermatogenesis in a murine model. Male mice subjected to 15 days of chronic Meth administration presented severe testicular atrophy, characterized by seminiferous epithelial disorganization and diminished sperm reserves in both the testes and epididymides. Quantitative assessments revealed marked reductions in sperm motility and increased tail abnormalities. Transcriptomic profiling revealed significant down-regulation of methyltransferase-like 21C (\n                    <jats:italic toggle=\"yes\">Mettl21c<\/jats:italic>\n                    ), an undifferentiated spermatogonial-enriched methyltransferase, within pathways governing germ cell differentiation. Immunofluorescence analysis revealed predominant Mettl21c colocalization with undifferentiated spermatogonial marker ubiquitin carboxyl-terminal hydrolase L1 (Uchl1), with minimal overlap in tyrosine-protein kinase Kit (Kit) positive differentiated populations.\n                    <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                    suppression of Mettl21c in C18-4 lines triggered proliferation arrest and increased apoptosis. These findings establish Mettl21c as a pivotal mediator of Meth-induced spermatogenic failure through spermatogonial maintenance pathways. Our work provides novel insights into the epigenetic regulation of drug-associated male infertility and identifies Mettl21c as a potential therapeutic target for preserving fertility in substance abuse cases.\n                  <\/jats:p>","DOI":"10.4103\/aja202558","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T12:00:17Z","timestamp":1768305617000},"page":"267-275","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Methamphetamine-induced inhibition of Mettl21c in undifferentiated spermatogonia impairs male fertility in mice"],"prefix":"10.4103","volume":"28","author":[{"given":"Xue-Heng","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, China"},{"name":"Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, China"},{"name":"Hunan Provincial Key Laboratory of Regional Hereditary Birth Defect Prevention and Control, Changsha Hospital for Maternal and Child Health Care Affiliated to Hunan Normal University, Changsha 410000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Tao","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, China"},{"name":"The Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Qing","family":"Fan","sequence":"additional","affiliation":[{"name":"Institute of Reproduction and Stem Cell Engineering, School of Basic Medicine Science, Central South University, Changsha 410000, China"},{"name":"Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"R1-20260430","doi-asserted-by":"crossref","DOI":"10.1056\/EVIDra2300160","article-title":"Methamphetamine toxicities and clinical management","volume":"2","author":"Coffin","year":"2023","journal-title":"NEJM Evid"},{"key":"R2-20260430","doi-asserted-by":"crossref","first-page":"105380","DOI":"10.1016\/j.neubiorev.2023.105380","article-title":"A systematic review and meta-analysis of health, functional, and cognitive outcomes in young people who use methamphetamine","volume":"153","author":"Guerin","year":"2023","journal-title":"Neurosci Biobehav Rev"},{"key":"R3-20260430","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.drugalcdep.2006.01.002","article-title":"Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths","volume":"84","author":"Wu","year":"2006","journal-title":"Drug Alcohol Depend"},{"key":"R4-20260430","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.3109\/10826084.2013.808217","article-title":"Methamphetamine use in club subcultures","volume":"48","author":"Kelly","year":"2013","journal-title":"Subst Use Misuse"},{"key":"R5-20260430","doi-asserted-by":"crossref","first-page":"e14441","DOI":"10.1111\/and.14441","article-title":"Methamphetamine can induce alteration of histopathology and sex determination gene expression through the oxidative stress pathway in the testes of human post-mortem","volume":"54","author":"Aryan","year":"2022","journal-title":"Andrologia"},{"key":"R6-20260430","article-title":"Toxic effects of methamphetamine on reproductive systems, embryo development, and newborns:an evidence-based review","author":"Chen","year":"2024","journal-title":"Curr Med Chem"},{"key":"R7-20260430","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4077\/CJP.2014.BAB155","article-title":"Induction of testicular damage by daily methamphetamine administration in rats","volume":"57","author":"Lin","year":"2014","journal-title":"Chin J Physiol"},{"key":"R8-20260430","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1439-0272.2010.01071.x","article-title":"Methamphetamine induces abnormal sperm morphology, low sperm concentration and apoptosis in the testis of male rats","volume":"43","author":"Nudmamud-Thanoi","year":"2011","journal-title":"Andrologia"},{"key":"R9-20260430","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/taap.2001.9330","article-title":"Methamphetamine induces apoptosis in seminiferous tubules in male mice testis","volume":"178","author":"Yamamoto","year":"2002","journal-title":"Toxicol Appl Pharmacol"},{"key":"R10-20260430","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.toxlet.2009.08.002","article-title":"Chronic exposure to MDMA (ecstasy) increases DNA damage in sperm and alters testes histopathology in male rats","volume":"191","author":"Barenys","year":"2009","journal-title":"Toxicol Lett"},{"key":"R11-20260430","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12958-023-01098-2","article-title":"Psychoactive drugs and male fertility:impacts and mechanisms","volume":"21","author":"Hamed","year":"2023","journal-title":"Reprod Biol Endocrinol"},{"key":"R12-20260430","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3109\/01480545.2016.1141421","article-title":"Changes of sperm quality and hormone receptors in the rat testis after exposure to methamphetamine","volume":"39","author":"Nudmamud-Thanoi","year":"2016","journal-title":"Drug Chem Toxicol"},{"key":"R13-20260430","doi-asserted-by":"crossref","first-page":"e0273888","DOI":"10.1371\/journal.pone.0273888","article-title":"Differential protein expression of GABA A receptor alpha 1 subunit and calbindin in rat spermatozoa associated with proteomic analysis in testis following methamphetamine administration","volume":"18","author":"Kaewman","year":"2023","journal-title":"PLoS One"},{"key":"R14-20260430","doi-asserted-by":"crossref","first-page":"e14534","DOI":"10.1111\/and.14534","article-title":"Molecular mechanism behind methamphetamine-induced damages in testicular tissue:evidences for oxidative stress, autophagy, and apoptosis","volume":"54","author":"Peirouvi","year":"2022","journal-title":"Andrologia"},{"key":"R15-20260430","doi-asserted-by":"crossref","first-page":"173257","DOI":"10.1016\/j.pbb.2021.173257","article-title":"Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice","volume":"209","author":"Kitanaka","year":"2021","journal-title":"Pharmacol Biochem Behav"},{"key":"R16-20260430","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.neulet.2006.12.052","article-title":"Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain","volume":"414","author":"Numachi","year":"2007","journal-title":"Neurosci Lett"},{"key":"R17-20260430","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4137\/DTI.S38342","article-title":"Brain histamine N-methyltransferase as a possible target of treatment for methamphetamine overdose","volume":"10","author":"Kitanaka","year":"2016","journal-title":"Drug Target Insights"},{"key":"R18-20260430","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s13059-024-03332-5","article-title":"N6-methyladenosine writer METTL16-mediated alternative splicing and translation control are essential for murine spermatogenesis","volume":"25","author":"Ma","year":"2024","journal-title":"Genome Biol"},{"key":"R19-20260430","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/cr.2017.100","article-title":"Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation","volume":"27","author":"Xu","year":"2017","journal-title":"Cell Res"},{"key":"R20-20260430","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1752-0509-4-87","article-title":"The spermatozoa caught in the net:the biological networks to study the male gametes post-ejaculatory life","volume":"4","author":"Bernab\u00f2","year":"2010","journal-title":"BMC Syst Biol"},{"key":"R21-20260430","doi-asserted-by":"crossref","first-page":"24345","DOI":"10.1038\/srep24345","article-title":"Increased N 6-methyladenosine in human sperm RNA as a risk factor for asthenozoospermia","volume":"6","author":"Yang","year":"2016","journal-title":"Sci Rep"},{"key":"R22-20260430","first-page":"0647","article-title":"Essential regulation of spermatogonial stem cell fate decisions and male fertility by APBB1 via interaction with KAT5 and GDF15 in humans and mice","volume":"8","author":"Zhou","year":"2025","journal-title":"Research (Wash D C)"},{"key":"R23-20260430","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/cr.2017.117","article-title":"Mettl3-\/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis","volume":"27","author":"Lin","year":"2017","journal-title":"Cell Res"},{"key":"R24-20260430","first-page":"161","article-title":"Administration of high dose of methamphetamine has detrimental effects on sperm parameters and DNA integrity in mice","volume":"15","author":"Sabour","year":"2017","journal-title":"Int J Reprod Biomed"},{"key":"R25-20260430","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s00213-023-06516-2","article-title":"METH exposure alters sperm DNA methylation in F0 mice and mPFC transcriptome in male F1 mice","volume":"241","author":"Li","year":"2024","journal-title":"Psychopharmacology (Berl)"},{"key":"R26-20260430","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/jbmr.2200","article-title":"METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-\u03baB signaling pathway","volume":"29","author":"Huang","year":"2014","journal-title":"J Bone Miner Res"},{"key":"R27-20260430","doi-asserted-by":"crossref","first-page":"109555","DOI":"10.1016\/j.jnutbio.2023.109555","article-title":"Betaine attenuates age-related suppression in autophagy via Mettl21c\/p97\/VCP axis to delay muscle loss","volume":"125","author":"Chen","year":"2024","journal-title":"J Nutr Biochem"},{"key":"R28-20260430","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.celrep.2018.03.136","article-title":"Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulates autophagy-associated protein breakdown","volume":"23","author":"Wiederstein","year":"2018","journal-title":"Cell Rep"},{"key":"R29-20260430","doi-asserted-by":"crossref","first-page":"13718","DOI":"10.1074\/jbc.RA119.008430","article-title":"Methyltransferase-like 21c methylates and stabilizes the heat shock protein Hspa8 in type I myofibers in mice","volume":"294","author":"Wang","year":"2019","journal-title":"J Biol Chem"},{"key":"R30-20260430","doi-asserted-by":"crossref","first-page":"11822","DOI":"10.1074\/jbc.RA120.014505","article-title":"Methyltransferase-like 21C (METTL21C) methylates alanine tRNA synthetase at Lys-943 in muscle tissue","volume":"295","author":"Zoabi","year":"2020","journal-title":"J Biol Chem"}],"container-title":["Asian Journal of Andrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/aja202558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T19:39:13Z","timestamp":1786649953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/aja202558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/aja202558","relation":{},"ISSN":["1745-7262","1008-682X"],"issn-type":[{"value":"1745-7262","type":"print"},{"value":"1008-682X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,13]]},"assertion":[{"value":"2024-10-17","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-25","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}