{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T16:48:24Z","timestamp":1771606104095,"version":"3.50.1"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Male infertility is a complex and polygenic reproductive disease. 10\u201315% of the males are affected by idiopathic infertility conditions. Acetylcholine (ACh), a major neurotransmitter has been reported to play a non-neuronal role as well. Acetylcholinesterase (AChE) is the primary ACh hydrolyzing enzyme whose over or lower expression influence the availability of ACh for physiological roles. The purpose of the study was to find the possible impact and association of acetylcholinesterase,<jats:italic>ACHE<\/jats:italic>gene variant rs 17228602, and pro-inflammatory cytokines in clinically diagnosed infertile males. The study includes clinically diagnosed fifty non-infertile (control) and forty-five infertile males. Whole blood AChE enzymatic activity was measured. Genotyping of rs17228602 was carried out from peripheral blood by standard molecular methods. Pro-inflammatory cytokines were determined by the ELISA method. AChE enzyme was found to be significantly elevated in infertile than non-infertile males.<jats:italic>ACHE<\/jats:italic>SNP rs17228602 had shown significant association in dominant model (odd ratio = 0.378, 95% CI = 0.157\u20130.911, p-value 0.046). Pro-inflammatory cytokine IL-1\u03b2 was notably increased with statistical significance (p \u22640.05) in male infertile patients. The study concludes and speculates that AChE plays role in the pathogenesis of male infertility through the modulation of inflammatory pathways. Further studies in this direction may resolve the idiopathic cases of male infertility. Other variants of<jats:italic>ACHE<\/jats:italic>and the association of miRNA for the regulation of AChE in male infertility are suggested for further insight.<\/jats:p>","DOI":"10.1371\/journal.pone.0282579","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T17:29:57Z","timestamp":1680888597000},"page":"e0282579","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Acetylcholinesterase, pro-inflammatory cytokines, and association of ACHE SNP rs 17228602 with male infertility"],"prefix":"10.1371","volume":"18","author":[{"given":"Khulah","family":"Sadia","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mbah Ntepe","family":"Leonel Javeres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faheem","family":"Tahir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-9374","authenticated-orcid":true,"given":"Syed Tahir Abbas","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabia","family":"Habib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahid","family":"Muneer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabir","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-1511","authenticated-orcid":true,"given":"Syed Muhammad","family":"Nurulain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"pone.0282579.ref001","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4103\/0974-1208.170370","article-title":"Trends of male factor infertility, an important cause of infertility: A review of literature","volume":"8","author":"N Kumar","year":"2015","journal-title":"J Hum Reprod Sci"},{"key":"pone.0282579.ref002","article-title":"Sperm Disorders and Aetiologies of Male Infertility in Pakistan: Meta-Analyses and Review","volume":"2","author":"M Irfan","year":"2015","journal-title":"Austin J Reprod Med Infertil"},{"key":"pone.0282579.ref003","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1007\/s10815-018-1301-7","article-title":"Genetic evaluation of patients with non-syndromic male infertility","volume":"35","author":"O Okutman","year":"2018","journal-title":"J Assist Reprod Genet"},{"key":"pone.0282579.ref004","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/s41585-018-0003-3","article-title":"Genetics of male infertility","volume":"15","author":"C Krausz","year":"2018","journal-title":"Nat Rev Urol"},{"key":"pone.0282579.ref005","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bpobgyn.2017.05.002","article-title":"Genetic diagnostics of male infertility in clinical practice","volume":"44","author":"R Flannigan","year":"2017","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"pone.0282579.ref006","first-page":"1","volume":"8","author":"DH Volle","year":"2017","journal-title":"Cytokines in Male Fertility and Reproductive Pathologies: immunoregulation and Beyond The Contributions of Cytokines to Testicular"},{"key":"pone.0282579.ref007","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.aju.2017.11.001","article-title":"Role of reactive oxygen species in male infertility: An updated review of literature","volume":"16","author":"H Wagner","year":"2018","journal-title":"Arab J Urol"},{"key":"pone.0282579.ref008","doi-asserted-by":"crossref","DOI":"10.3390\/antiox9030219","article-title":"Efficacy of Antioxidant Supplementation on Conventional and Advanced Sperm Function Tests in Patients with Idiopathic Male Infertility","volume":"9","author":"M Arafa","year":"2020","journal-title":"Antioxidants"},{"key":"pone.0282579.ref009","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00018-019-03253-8","article-title":"Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management","volume":"77","author":"E Barati","year":"2020","journal-title":"Cell Mol Life Sci CMLS"},{"key":"pone.0282579.ref010","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.33549\/physiolres.933671","article-title":"Vagal-immune interactions involved in cholinergic anti-inflammatory pathway","volume":"66","author":"I Zila","year":"2017","journal-title":"Physiol Res"},{"key":"pone.0282579.ref011","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s40520-019-01359-4","article-title":"Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders","volume":"33","author":"R Benfante","year":"2021","journal-title":"Aging Clin Exp Res"},{"key":"pone.0282579.ref012","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.clinbiochem.2020.12.007","article-title":"Increased oxidative stress and inflammatory markers contrasting with the activation of the cholinergic anti-inflammatory pathway in patients with metabolic syndrome","volume":"89","author":"CC Martins","year":"2021","journal-title":"Clin Biochem"},{"key":"pone.0282579.ref013","doi-asserted-by":"crossref","first-page":"E6432","DOI":"10.3390\/ijms21176432","article-title":"Oxidative Stress and Analysis of Selected SNPs of ACHE (rs 2571598), BCHE (rs 3495), CAT (rs 7943316), SIRT1 (rs 10823108), GSTP1 (rs 1695), and Gene GSTM1, GSTT1 in Chronic Organophosphates Exposed Groups from Cameroon and Pakistan","volume":"21","author":"LJ Mbah Ntepe","year":"2020","journal-title":"Int J Mol Sci"},{"key":"pone.0282579.ref014","doi-asserted-by":"crossref","first-page":"e13978","DOI":"10.1111\/and.13978","article-title":"Iprodione and chlorpyrifos induce testicular damage, oxidative stress, apoptosis and suppression of steroidogenic- and spermatogenic-related genes in immature male albino rats","volume":"53","author":"MA Hassan","year":"2021","journal-title":"Andrologia"},{"key":"pone.0282579.ref015","article-title":"Antioxidant enzymes and association of CAT SNP-21 A\/T (rs7943316) with male infertility","author":"K Sadia","year":"2021","journal-title":"Mol Reprod Dev"},{"key":"pone.0282579.ref016","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/nm.2371","article-title":"Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans","volume":"17","author":"R Rodriguez-Diaz","year":"2011","journal-title":"Nat Med"},{"key":"pone.0282579.ref017","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1254\/jjp.85.24","article-title":"The non-neuronal cholinergic system in the endothelium: evidence and possible pathobiological significance","volume":"85","author":"CJ Kirkpatrick","year":"2001","journal-title":"Jpn J Pharmacol"},{"key":"pone.0282579.ref018","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/sj.bjp.0704335","article-title":"Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters","volume":"134","author":"I Wessler","year":"2001","journal-title":"Br J Pharmacol"},{"key":"pone.0282579.ref019","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1478-811X-4-4","article-title":"The placental cholinergic system: localization to the cytotrophoblast and modulation of nitric oxide","volume":"4","author":"MB Bhuiyan","year":"2006","journal-title":"Cell Commun Signal CCS"},{"key":"pone.0282579.ref020","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1016\/j.lfs.2007.02.010","article-title":"Non-neuronal acetylcholine and urinary bladder urothelium","volume":"80","author":"AT Hanna-Mitchell","year":"2007","journal-title":"Life Sci"},{"key":"pone.0282579.ref021","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0163-7258(99)00071-6","article-title":"Extraneuronal cholinergic system in lymphocytes","volume":"86","author":"K Kawashima","year":"2000","journal-title":"Pharmacol Ther"},{"key":"pone.0282579.ref022","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1023\/A:1022840416292","article-title":"Upregulation of mRNA encoding the M5 muscarinic acetylcholine receptor in human T- and B-lymphocytes during immunological responses","volume":"28","author":"T Fujii","year":"2003","journal-title":"Neurochem Res"},{"key":"pone.0282579.ref023","doi-asserted-by":"crossref","first-page":"106359","DOI":"10.1016\/j.intimp.2020.106359","article-title":"Cholinergic leukocytes in sepsis and at the neuroimmune junction in the spleen","volume":"81","author":"DB Hoover","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"pone.0282579.ref024","first-page":"H468","article-title":"Cholinergic neurotransmission in human corpus cavernosum. II. Acetylcholine synthesis","volume":"254","author":"R Blanco","year":"1988","journal-title":"Am J Physiol"},{"key":"pone.0282579.ref025","first-page":"H459","article-title":"Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue","volume":"254","author":"I Saenz de Tejada","year":"1988","journal-title":"Am J Physiol"},{"key":"pone.0282579.ref026","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1007\/s10815-019-01579-7","article-title":"Novel association between apoptotic sperm biomarkers with seminal biochemical parameters and acetylcholinesterase activity in patients with teratozoospermia","volume":"36","author":"O Ammar","year":"2019","journal-title":"J Assist Reprod Genet"},{"key":"pone.0282579.ref027","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/B978-0-12-382032-7.10066-9","volume-title":"Reproductive and Developmental Toxicology","author":"I Mor","year":"2011"},{"key":"pone.0282579.ref028","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.cbi.2019.05.036","article-title":"Association of status of acetylcholinesterase and ACHE gene 3\u2019 UTR variants (rs17228602, rs17228616) with drug addiction vulnerability in pakistani population","volume":"308","author":"T Javed","year":"2019","journal-title":"Chem Biol Interact"},{"key":"pone.0282579.ref029","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fnmol.2011.00028","article-title":"Cholinesterase-Targeting microRNAs Identified in silico Affect Specific Biological Processes","volume":"4","author":"G Hanin","year":"2011","journal-title":"Front Mol Neurosci"},{"key":"pone.0282579.ref030","first-page":"2039","article-title":"Modified testicular expression of stress-associated \u201creadthrough\u201d acetylcholinesterase predicts male infertility","volume":"15","author":"I Mor","year":"2001","journal-title":"FASEB J Off Publ Fed Am Soc Exp Biol"},{"key":"pone.0282579.ref031","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1007\/s11926-010-0124-z","article-title":"Regulation of peripheral inflammation by the central nervous system","volume":"12","author":"J-M Waldburger","year":"2010","journal-title":"Curr Rheumatol Rep"},{"key":"pone.0282579.ref032","doi-asserted-by":"crossref","first-page":"5935","DOI":"10.1007\/s11033-021-06593-6","article-title":"Pro-inflammatory cytokines and microRNAs in male infertility","volume":"48","author":"H Attia","year":"2021","journal-title":"Mol Biol Rep"},{"key":"pone.0282579.ref033","doi-asserted-by":"crossref","first-page":"e14023","DOI":"10.1111\/and.14023","article-title":"Sperm DNA damage and cytokines in varicocele: A case-control study","volume":"53","author":"R Finelli","year":"2021","journal-title":"Andrologia"},{"key":"pone.0282579.ref034","article-title":"Interleukin-6 disrupts blood-testis barrier through inhibiting protein degradation or activating phosphorylated ERK in Sertoli cells","volume":"4","author":"H Zhang","year":"2014","journal-title":"Sci Rep"},{"key":"pone.0282579.ref035","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in Inflammation, Immunity, and Disease","volume":"6","author":"T Tanaka","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"pone.0282579.ref036","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.lfs.2018.04.039","article-title":"Resistance exercise modulates male factor infertility through anti-inflammatory and antioxidative mechanisms in infertile men: A RCT","volume":"203","author":"B Hajizadeh Maleki","year":"2018","journal-title":"Life Sci"},{"key":"pone.0282579.ref037","unstructured":"2010 WHO laboratory manual for the examination and processing of human semen. https:\/\/apps.who.int\/iris\/handle\/10665\/44261. Accessed 15 Jan 2021"},{"key":"pone.0282579.ref038","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0009-8981(99)00144-8","article-title":"Improved determination of acetylcholinesterase activity in human whole blood","volume":"288","author":"F Worek","year":"1999","journal-title":"Clin Chim Acta Int J Clin Chem"},{"key":"pone.0282579.ref039","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"GL Ellman","year":"1961","journal-title":"Biochem Pharmacol"},{"key":"pone.0282579.ref040","doi-asserted-by":"crossref","first-page":"5444","DOI":"10.1093\/nar\/19.19.5444","article-title":"A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies","volume":"19","author":"DK Lahiri","year":"1991","journal-title":"Nucleic Acids Res"},{"key":"pone.0282579.ref041","first-page":"RA214","article-title":"Acetylcholinesterase and butyrylcholinesterase as possible markers of low-grade systemic inflammation","volume":"13","author":"UN Das","year":"2007","journal-title":"Med Sci Monit Int Med J Exp Clin Res"},{"key":"pone.0282579.ref042","doi-asserted-by":"crossref","unstructured":"Clement P, Giuliano F (2015) Chapter 3\u2014Anatomy and physiology of genital organs\u2013men. In: Vodu\u0161ek DB, Boller F (eds) Handbook of Clinical Neurology. Elsevier, pp 19\u201337","DOI":"10.1016\/B978-0-444-63247-0.00003-1"},{"key":"pone.0282579.ref043","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1111\/joim.13006","article-title":"Beyond neurotransmission: acetylcholine in immunity and inflammation","volume":"287","author":"MA Cox","year":"2020","journal-title":"J Intern Med"},{"key":"pone.0282579.ref044","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.mehy.2007.03.032","article-title":"Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer\u2019s disease","volume":"69","author":"AA Rao","year":"2007","journal-title":"Med Hypotheses"},{"key":"pone.0282579.ref045","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.2174\/1871527313666141023141545","article-title":"Status of Acetylcholinesterase and Butyrylcholinesterase in Alzheimer\u2019s Disease and Type 2 Diabetes Mellitus","volume":"13","author":"G Mushtaq","year":"2014","journal-title":"CNS Neurol Disord\u2014Drug Targets- CNS Neurol Disord"},{"key":"pone.0282579.ref046","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.cbi.2010.03.038","article-title":"Analysis of cholinesterases in human prostate and sperm. Implications in cancer and fertility","volume":"187","author":"S Nieto Cer\u00f3n","year":"2010","journal-title":"Chem Biol Interact"},{"key":"pone.0282579.ref047","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s00429-011-0376-z","article-title":"Hippocampal microRNA-132 mediates stress-inducible cognitive deficits through its acetylcholinesterase target","volume":"218","author":"G Shaltiel","year":"2013","journal-title":"Brain Struct Funct"},{"key":"pone.0282579.ref048","first-page":"278","article-title":"Serum cholinesterase activities distinguish between stroke patients and controls and predict 12-month mortality","volume":"16","author":"E Ben Assayag","year":"2010","journal-title":"Mol Med Camb Mass"},{"key":"pone.0282579.ref049","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/ni0805-756","article-title":"It takes nerve to dampen inflammation","volume":"6","author":"CN Metz","year":"2005","journal-title":"Nat Immunol"},{"key":"pone.0282579.ref050","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.immuni.2009.09.019","article-title":"MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase","volume":"31","author":"I Shaked","year":"2009","journal-title":"Immunity"},{"key":"pone.0282579.ref051","doi-asserted-by":"crossref","first-page":"5512","DOI":"10.1073\/pnas.0307659101","article-title":"Acetylcholinesterase\/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study","volume":"101","author":"EH Sklan","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0282579.ref052","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1007\/s12031-013-0176-4","article-title":"Cholinesterases as biomarkers for parasympathetic dysfunction and inflammation-related disease","volume":"53","author":"S Shenhar-Tsarfaty","year":"2014","journal-title":"J Mol Neurosci MN"},{"key":"pone.0282579.ref053","doi-asserted-by":"crossref","first-page":"E758","DOI":"10.3390\/biom10050758","article-title":"Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602","volume":"10","author":"T Furqan","year":"2020","journal-title":"Biomolecules"},{"key":"pone.0282579.ref054","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1095\/biolreprod52.5.1136","article-title":"Efferent innervation of the rat testis","volume":"52","author":"M Rauchenwald","year":"1995","journal-title":"Biol Reprod"},{"key":"pone.0282579.ref055","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1210\/en.2002-220392","article-title":"Anatomical and functional evidence for a neural hypothalamic-testicular pathway that is independent of the pituitary","volume":"143","author":"S Lee","year":"2002","journal-title":"Endocrinology"},{"key":"pone.0282579.ref056","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/j.1939-4640.1996.tb01765.x","article-title":"Cytokine levels in the seminal plasma of infertile males","volume":"17","author":"MS Gruschwitz","year":"1996","journal-title":"J Androl"},{"key":"pone.0282579.ref057","first-page":"51","article-title":"The role of IL-6, IL-10, TNF-alpha and its receptors TNFR1 and TNFR2 in the local regulatory system of normal and impaired human spermatogenesis","volume":"62","author":"M Bia\u0142as","year":"2009","journal-title":"Am J Reprod Immunol N Y N 1989"},{"key":"pone.0282579.ref058","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1684\/ecn.2018.0412","article-title":"Cytokines and male infertility","volume":"29","author":"V Syriou","year":"2018","journal-title":"Eur Cytokine Netw"},{"key":"pone.0282579.ref059","first-page":"123","article-title":"Impact of Inflammation on Male Reproductive Tract","volume":"16","author":"A Azenabor","year":"2015","journal-title":"J Reprod Infertil"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282579","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T10:44:51Z","timestamp":1702205091000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282579"}},"subtitle":[],"editor":[{"given":"Suresh","family":"Yenugu","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,7]]},"references-count":59,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0282579","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,7]]}}}