{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T09:36:11Z","timestamp":1785576971902,"version":"3.56.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environmental Toxicology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Titanium dioxide (TiO<jats:sub>2<\/jats:sub>) is generally regarded as a nontoxic and nongenotoxic white mineral, which is mainly applied in the manufacture of paper, paint, plastic, sunscreen lotion and other products. Recently, TiO<jats:sub>2<\/jats:sub> nanoparticles (TiO<jats:sub>2<\/jats:sub> NPs) have been demonstrated to cause chronic inflammation and lung tumor formation in rats, which may be associated with the particle size of TiO<jats:sub>2<\/jats:sub>. Considering the important role of activator protein\u20101 (AP\u20101) in regulating multiple genes involved in the cell proliferation and inflammation and the induction of neoplastic transformation, we aimed to evaluate the potency of TiO<jats:sub>2<\/jats:sub> NPs (\u2264\u200920\u2009nm) on the activation of AP\u20101 signaling pathway and the generation of reactive oxygen species (ROS) in a mouse epidermal cell line, JB6 cells. MTT, electron spin resonance (ESR), AP\u20101 luciferase activity assay in vitro and in vivo, and Western blotting assay were used to clarify this problem. Our results indicated that TiO<jats:sub>2<\/jats:sub> NPs dose\u2010dependently caused the hydroxyl radical (\u00b7OH) generation and sequentially increased the AP\u20101 activity in JB6 cells. Using AP\u20101\u2010luciferase reporter transgenic mice models, an obvious increased AP\u20101 activity was detected in dermal tissue after exposure to TiO<jats:sub>2<\/jats:sub> NPs for 24\u2009h. Interestingly, TiO<jats:sub>2<\/jats:sub> NPs increased the AP\u20101 activity via stimulating the expression of mitogen\u2010activated protein kinases (MAPKs) family members, including extracellular signal\u2010regulated protein kinases (ERKs), p38 kinase, and C\u2010Jun N\u2010terminal kinases (JNKs). Of note, the AP\u20101 activation induced by TiO<jats:sub>2<\/jats:sub> NPs could be blocked by specific inhibitors (SB203580, PD98059, and SP 600125, respectively) that inhibit ERKs and p38 kinase but not JNKs. These findings indicate that ROS generation is involved in TiO<jats:sub>2<\/jats:sub> NPs\u2010induced AP\u20101 activation mediated by MAPKs signal pathway.<\/jats:p>","DOI":"10.1002\/tox.23393","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T12:50:01Z","timestamp":1635943801000},"page":"237-244","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["ROS generation is involved in titanium dioxide nanoparticle\u2010induced AP\u20101 activation through p38 MAPK and ERK pathways in JB6 cells"],"prefix":"10.1002","volume":"37","author":[{"given":"Lu","family":"Kong","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Medicine and Engineering, Ministry of Education; School of Public Health Southeast University  Nanjing China"},{"name":"Toxicology and Molecular Biology Branch, Health Effects Laboratory Division National Institute for Occupational Safety and Health  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