{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:02:27Z","timestamp":1789794147609,"version":"4.0.1"},"reference-count":66,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Cyproconazole (CYPRO), a widely used triazole fungicide, is detected across food and environmental matrices, raising concerns about chronic low\u2010dose human exposure. Its potential to disrupt the neuro\u2010immune interface, particularly the cross\u2010talk between cholinergic signaling and the NOD\u2010like receptor pyrin domain\u2010containing 3 (NLRP3) inflammasome, remains poorly characterized. The objective of this study is to establish an integrated neuro\u2010immunotoxicological profile of CYPRO in rats and explore molecular associations linking oxidative stress, inflammasome\u2010related signaling, and cholinergic disruption. Male Wistar rats received oral CYPRO (4, 8, 16 or 32\u2009mg\/kg body weight (bw)\/day) for 28\u2009days in a subacute exposure design. Endpoints comprised hematology, plasma lipid profile, tissue redox status, acetylcholinesterase (AChE) activity, NLRP3\/nuclear factor\u2010\u03baB (NF\u2010\u03baB)\u2010related gene expression, p53\/Caspase\u20103 immunohistochemistry, alkaline comet assay, brain and lymphoid histopathology, and in silico docking against eight inflammatory and apoptotic protein targets. CYPRO induced dose\u2010dependent dyslipidemia, complex leukocyte dysregulation (lymphocytosis, monocytosis, and neutropenia), and oxidative damage in the brain, spleen, and thymus. Systemic AChE inhibition extended to the lymphoid organs.\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    ,\n                    <jats:italic>Casp1<\/jats:italic>\n                    ,\n                    <jats:italic>Nfkb1<\/jats:italic>\n                    ,\n                    <jats:italic>Tnf\u03b1<\/jats:italic>\n                    ,\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    , and\n                    <jats:italic>Il18<\/jats:italic>\n                    mRNA were dose\u2010dependently upregulated, accompanied by p53 and Caspase\u20103 induction in lymphoid tissues and severe cortical and cerebellar lesions. DNA damage in the spleen and brain reached significance from the lowest dose tested (4\u2009mg\/kg\/day), below the current No Observed Adverse Effect Level (NOAEL). Docking predicted favorable binding of CYPRO to inducible nitric oxide synthase (iNOS), cyclooxygenase\u20102 (COX\u20102), tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), and NLRP3, with engagement of COX\u20102 (Tyr385 and Ser530) and Caspase\u20101 (Cys285) catalytic residues. Together, these findings suggest a plausible neuro\u2010immunotoxic profile for CYPRO, in which oxidative stress and AChE inhibition are associated with NLRP3\u2010related transcriptional responses and downstream genotoxic and apoptotic signals. A putative cholinergic\u2013inflammasome cross\u2010talk is proposed as a working hypothesis warranting direct mechanistic validation.\n                  <\/jats:p>","DOI":"10.1002\/jat.70424","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T04:30:45Z","timestamp":1789792245000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cyproconazole\u2010Induced Systemic Neuro\u2010Immunotoxicity: An Integrated In\u00a0Vivo and In Silico Study of Oxidative Stress, NLRP3\u2010Related Inflammatory Signaling, and Cholinergic Disruption"],"prefix":"10.1002","author":[{"given":"Mnassri","family":"Asma","sequence":"first","affiliation":[{"name":"Laboratory for Research on Biologically Compatible Compounds (LR01ES17), Faculty of Dental Medicine University of Monastir  Monastir Tunisia"},{"name":"Faculty of Science of Gafsa University of Gafsa  Gafsa Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-2634","authenticated-orcid":false,"given":"Horchani","family":"Mabrouk","sequence":"additional","affiliation":[{"name":"Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Medicinal Chemistry and Natural Products, Faculty of Sciences of Monastir University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rich","family":"Siwar","sequence":"additional","affiliation":[{"name":"Laboratory for Research on Biologically Compatible Compounds (LR01ES17), Faculty of Dental Medicine University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaabani","family":"Hanen","sequence":"additional","affiliation":[{"name":"Laboratory for Research on Biologically Compatible Compounds (LR01ES17), Faculty of Dental Medicine University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mokni","family":"Moncef","sequence":"additional","affiliation":[{"name":"Department of Pathology Farhat Hached University Hospital  Sousse Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omezzine","family":"Asma","sequence":"additional","affiliation":[{"name":"Biochemistry Department (LR12SP11) Sahloul University Hospital  Sousse Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben Jannet","family":"Hichem","sequence":"additional","affiliation":[{"name":"Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity (LR11ES39), Medicinal Chemistry and Natural Products, Faculty of Sciences of Monastir University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chouchene","family":"Saoussen","sequence":"additional","affiliation":[{"name":"Department of Hematology Fattouma Bourguiba University Hospital  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassine","family":"Mohsen","sequence":"additional","affiliation":[{"name":"Department of Hematology Fattouma Bourguiba University Hospital  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4965-5855","authenticated-orcid":false,"given":"Salwa","family":"Abid","sequence":"additional","affiliation":[{"name":"Laboratory for Research on Biologically Compatible Compounds (LR01ES17), Faculty of Dental Medicine University of Monastir  Monastir Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0253-6007","authenticated-orcid":false,"given":"Ayed\u2010Boussema","family":"Imen","sequence":"additional","affiliation":[{"name":"Laboratory for Research on Biologically Compatible Compounds (LR01ES17), Faculty of Dental Medicine University of Monastir  Monastir Tunisia"},{"name":"Faculty of Science of Gafsa University of Gafsa  Gafsa Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"issue":"3","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1007\/s10787-024-01461-8","article-title":"Neuroprotective Effect of Withania somnifera Leaves Extract Nanoemulsion Against Penconazole\u2010Induced Neurotoxicity in Albino Rats via Modulating TGF\u2010\u03b21\/Smad2 Signaling Pathway","volume":"32","author":"Abomosallam M.","year":"2024","journal-title":"Inflammopharmacology"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cbpc.2022.109440","article-title":"Thiobencarb Induces Phenotypic Abnormalities, Apoptosis, and Cardiovascular Toxicity in Zebrafish Embryos Through Oxidative Stress and Inflammation","volume":"261","author":"An G.","year":"2022","journal-title":"Comparative Biochemistry and Physiology. 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