{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T02:27:46Z","timestamp":1786760866363,"version":"build-2736575974"},"reference-count":24,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFD1801100"],"award-info":[{"award-number":["2023YFD1801100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32172929"],"award-info":[{"award-number":["32172929"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32402958"],"award-info":[{"award-number":["32402958"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M741291"],"award-info":[{"award-number":["2023M741291"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Thiram is an agricultural fungicide known to disrupt cellular calcium homeostasis by inducing endoplasmic reticulum (ER) stress and mitochondrial calcium overload in hepatic and growth plate (GP) tissues. Current study investigated thiram\u2010induced alterations at mitochondria\u2010associated membranes (MAMs) and their impact on inter\u2010organ calcium signaling. Following thiram exposure in chickens, hepatic ER stress markers GRP78 and CHOP, along with key calcium\u2010transfer proteins mediating ER\u2010mitochondrial coupling, including inositol 1,4,5\u2010trisphosphate receptor 1 (IP3R1) and voltage\u2010dependent anion channel 1 (VDAC1), were significantly upregulated. Importantly, hepatic ER stress driven hyperactivation of IP3R1\/VDAC1 signaling was accompanied by parallel calcium dysregulation and mitochondrial stress responses in the tibial growth plate, providing direct evidence that liver ER stress acts upstream of skeletal calcium imbalance. These findings establish a previously unrecognized liver\u2010bone axis in which thiram\u2010induced hepatic ER stress propagates calcium signaling disturbances to the growth plate, thereby disrupting chondrocyte calcium homeostasis and bone development. Collectively, this study elucidates a mechanistic framework linking MAM\u2010mediated calcium\u2010transfer, ER stress, and cross\u2010organ communication, offering new insights into how toxicant\u2010induced hepatic stress orchestrates systemic calcium metabolism and skeletal pathology.<\/jats:p>","DOI":"10.1002\/tox.70182","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T01:55:17Z","timestamp":1786758917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thiram Disrupts Hepatic and Tibial Calcium Homeostasis via\n                    <scp>ER<\/scp>\n                    Stress\u2010Mediated\n                    <scp>IP3R1<\/scp>\n                    \/\n                    <scp>VDAC1<\/scp>\n                    Hyperactivation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-633X","authenticated-orcid":false,"given":"Shah","family":"Nawaz","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Mo","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Farhan","family":"Rahim","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0776-827X","authenticated-orcid":false,"given":"Farah","family":"Ijaz","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuxian","family":"Quan","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Asif","sequence":"additional","affiliation":[{"name":"Department of Clinical Surgery, Faculty of Veterinary Sciences Gomal University  D.I.Khan Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-6874","authenticated-orcid":false,"given":"Mudassar","family":"Iqbal","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9512-5230","authenticated-orcid":false,"given":"Md. F.","family":"Kulyar","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine State Research Institute Centre for Innovative Medicine  Vilnius Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-6648","authenticated-orcid":false,"given":"Jiakui","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Huazhong Agricultural University  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.tcb.2022.07.004","article-title":"Calcium Homeostasis and Cancer: Insights From Endoplasmic Reticulum\u2010Centered Organelle Communications","volume":"33","author":"Zheng S.","year":"2023","journal-title":"Trends in Cell Biology"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuro.2018.07.015","article-title":"Effects of Environmental Pollutants on Calcium Release and Uptake by Rat Cortical Microsomes","volume":"69","author":"Dusza H. 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F. e. A.","year":"2022","journal-title":"Phytomedicine"},{"issue":"3","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cmet.2015.06.010","article-title":"Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes","volume":"22","author":"Arruda A. P.","year":"2015","journal-title":"Cell Metabolism"},{"key":"e_1_2_9_9_1","first-page":"160","article-title":"Hypercalcemia: Other Causes Than Primary Hyperparathyroidism","volume":"1","author":"Rizzoli R.","year":"2018","journal-title":"Encyclopedia of Endocrine Diseases"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1042\/CS20200844","article-title":"Mitochondria\u2010Associated Membranes (MAMs): A Potential Therapeutic Target for Treating Alzheimer's Disease","volume":"135","author":"Yu W.","year":"2021","journal-title":"Clinical Science"},{"key":"e_1_2_9_11_1","article-title":"The Contribution of Mitochondria\u2010Associated Endoplasmic Reticulum Membranes (MAMs) Dysfunction in Alzheimer's Disease and the Potential Countermeasure","volume":"17","author":"Li Z.","year":"2023","journal-title":"Frontiers in Neuroscience"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"103919","DOI":"10.1016\/j.etap.2022.103919","article-title":"Triazole Fungicide Tebuconazole Induces Apoptosis Through ROS\u2010Mediated Endoplasmic Reticulum Stress Pathway","volume":"94","author":"Ben Othm\u00e8ne Y.","year":"2022","journal-title":"Environmental Toxicology and Pharmacology"},{"issue":"5","key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"e0115723","DOI":"10.1128\/mbio.01157-23","article-title":"Dynamic Calcium\u2010Mediated Stress Response and Recovery Signatures in the Fungal Pathogen, \n                     Candida albicans","volume":"14","author":"Giuraniuc C. V.","year":"2023","journal-title":"MBio"},{"issue":"1","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12964-023-01377-w","article-title":"Modulation of Apoptosis and Inflammasome Activation in Chondrocytes: Co\u2010Regulatory Role of Chlorogenic Acid","volume":"22","author":"Kulyar M. F. e. 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