{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T09:42:16Z","timestamp":1760521336718,"version":"build-2065373602"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82460651","21966027"],"award-info":[{"award-number":["82460651","21966027"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The adverse effects of titanium dioxide nanoparticles (TiO<jats:sub>2<\/jats:sub> NPs) on the integrity of the blood\u2013testis barrier (BTB) are widely recognized. However, the underlying mechanisms remain incompletely understood. The integrity of the BTB is imperative for the preservation of male reproductive health. TM4 cells, which are major component of the BTB, play a critical role in its integrity. The apoptosis of TM4 cells is closely associated with the disruption of the BTB. Therefore, we selected TM4 cells as experimental models to investigate the apoptosis induced by TiO<jats:sub>2<\/jats:sub> NPs and the underlying mechanisms. Cell viability, excessive production of reactive oxygen species (ROS), activation of p38 mitogen\u2010activated protein kinase (MAPK) pathway, and apoptosis\u2010related protein expression levels were determined under various concentrations (50, 100, 150, and 200\u2009\u03bcg\/mL) of TiO<jats:sub>2<\/jats:sub> NPs exposure. The results indicate that TiO<jats:sub>2<\/jats:sub> NPs induced the overproduction of ROS and activated the p38 MAPK signaling pathway, which subsequently led to apoptosis. The ROS scavenger N\u2010acetylcysteine (NAC) was able to suppress the activation of p38 MAPK pathway induced by TiO<jats:sub>2<\/jats:sub> NPs, while the p38 MAPK inhibitor SB203580 mitigated TiO<jats:sub>2<\/jats:sub> NPs\u2010induced ROS overproduction and subsequent apoptosis, suggesting an interplay between ROS overproduction and p38 MAPK pathway activation. In summary, TiO<jats:sub>2<\/jats:sub> NPs induced mitochondrial apoptosis via the ROS\u2010p38 MAPK axis. A positive feedback regulatory mechanism exists between the two processes, promoting apoptosis in TM4 cells through a synergistic effect.<\/jats:p>","DOI":"10.1002\/jat.4789","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T04:53:01Z","timestamp":1744692781000},"page":"1521-1534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Effect of ROS and p38 MAPK in Apoptosis of TM4 Cells Induced by Titanium Dioxide Nanoparticles"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6227-0757","authenticated-orcid":false,"given":"Pengfei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Preventive Medicine\/the Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, the Xinjiang Production and Construction Corps, School of Medicine Shihezi University  Shihezi 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