title: Inflammatory MAPK and NF-κB signaling pathways differentiated hepatitis potential of two agglomerated titanium dioxide particles.
abstract: TiO2 nanoparticles (TiO2NPs) consumption and deposit in liver have possible implications for hepatitis risks. Specific signal dysregulation at early inflammatory responses needs to be characterized in TiO2NP-induced hepatopathy. MAPK and NF-κB signaling pathways are known to participate in inflammation and respond sensitively to chemical agents, making them preferable biomarkers for hepatitis. In the present study, dynamic activation of MAPK and NF-κB pathways were explored by immunoblotting and NF-κB luciferase reporter assay depending on characterization of TiO2NP agglomeration in human HepG2 cells. Inflammatory and cytotoxic potential of TiO2NPs were determined by qRT-PCR and WST-1 assay. AFM and TEM analyses uncovered ultrastructure damages underlying hepatotoxicity of TiO2NPs. Rod-like rutile agglomerated smaller and induced more pronounced cytotoxicity and immunogenicity than anatase. Correspondingly, though both rutile and anatase significantly activated p38, ERK1/2 and NF-κB pathways, rutile accelerated the maximum phosphorylation of ERK1/2 and elevated the potency of IκBα phosphorylation to its bell curve shape in comparison with a lower and sigmoid type of IκBα phosphorylation for anatase. Furthermore, cell elasticity indicated by Young's modulus and adhesion force increased accompanied with mitochondria damage, contributing to signal dysregulation and hepatotoxicity. The results suggested that differential activation of MAPK and NF-κB pathways could be early predictors for distinct hepatitis risks of two agglomerated TiO2NPs.
authors.affiliation: Environmental Science Institute, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 21014013@zju.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Environmental Science Institute, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Organic Pollution Process and Control, Hangzhou, Zhejiang, China. Electronic address: zjy@zju.edu.cn.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Environmental Science Institute, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: cjm2012@zju.edu.cn.
authors.forename: Junmei
authors.initials: J
authors.lastname: Cao
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou, China. Electronic address: xia2010@zju.edu.cn.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Environmental Sciences, University of California, Riverside, CA, USA. Electronic address: jgan@ucr.edu.
authors.forename: Jay
authors.initials: J
authors.lastname: Gan
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006505:Hepatitis / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014025:Titanium / Q000737:chemistry / Q000633:toxicity*
chemical_list: D016328:NF-kappa B; C009495:titanium dioxide; D014025:Titanium; D020928:Mitogen-Activated Protein Kinases
keywords: Agglomeration; Cell elasticity; Hepatitis risk; NF-κB/MAPK pathways; TiO(2) nanoparticles