{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:22:29Z","timestamp":1787566949355,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Disease-Free Animals and People Safe from Rabies project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Xenobiotics","JoX"],"abstract":"<jats:p>Genistein (GEN) exhibits concentration- and cell-type-dependent biological activities; however, the mechanisms underlying its cytotoxicity remain incompletely understood. This study investigated whether oxidative stress-mediated mitochondrial dysfunction contributes to GEN-induced apoptosis in TM4 mouse Sertoli cells and ELT3 rat leiomyoma cells. Cells were exposed to GEN (30 or 100 \u00b5M) for 48 h. Cytotoxicity, oxidative stress, mitochondrial function, and apoptosis were assessed by measuring cell viability, lactate dehydrogenase release, reactive oxygen species (ROS), malondialdehyde, glutathione reductase activity, mitochondrial membrane potential (\u0394\u03a8m), intracellular ATP, apoptosis-related gene expression, and caspase-3\/-9 activities. The involvement of oxidative stress was examined using N-acetyl-L-cysteine (NAC). GEN reduced cell viability, antioxidant capacity, \u0394\u03a8m, and ATP content while increasing membrane damage, ROS accumulation, and lipid peroxidation in both cell lines. These changes were accompanied by upregulation of Bax, Tp53, caspase-3, and caspase-9; downregulation of Bcl-2; and increased caspase-3\/-9 activities. NAC pretreatment attenuated these alterations, supporting ROS as an upstream mediator. Notably, TM4 cells were approximately 4.4-fold more sensitive to GEN than ELT3 cells at 48 h. Collectively, the findings support a ROS-dependent mitochondrial apoptotic response under elevated in vitro GEN exposure but do not establish selective antitumor cytotoxicity or direct physiological relevance.<\/jats:p>","DOI":"10.3390\/jox16050156","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:03:41Z","timestamp":1787558621000},"page":"156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oxidative Stress-Mediated Mitochondrial Dysfunction Drives Genistein-Induced Apoptosis in TM4 Sertoli and ELT3 Leiomyoma Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4851-1526","authenticated-orcid":false,"given":"Samak","family":"Sutjarit","sequence":"first","affiliation":[{"name":"Department of Veterinary Nursing, Faculty of Veterinary Technology, Kasetsart University, Bangkok 10900, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6489-1373","authenticated-orcid":false,"given":"Chainarong","family":"Sakulthaew","sequence":"additional","affiliation":[{"name":"Department of Veterinary Nursing, Faculty of Veterinary Technology, Kasetsart University, Bangkok 10900, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0098-2361","authenticated-orcid":false,"given":"Nattakan","family":"Meekhanon","sequence":"additional","affiliation":[{"name":"Department of Veterinary Nursing, Faculty of Veterinary Technology, Kasetsart University, Bangkok 10900, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5736-0598","authenticated-orcid":false,"given":"Kazuhiko","family":"Ochiai","sequence":"additional","affiliation":[{"name":"School of Veterinary Nursing and Technology, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo 180-8602, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1208\/ps050325","article-title":"Nutraceutical-definition and introduction","volume":"5","author":"Kalra","year":"2003","journal-title":"AAPS Pharm. 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