title: Sheet-type titania, but not P25, induced paraptosis accompanying apoptosis in murine alveolar macrophage cells.
abstract: In this study, we identified the toxic effects of sheet-type titania (TNS), which are being developed as a material for UV-blocking glass, comparing with P25, a benchmark control for titania, in MH-S cells, a mouse alveolar macrophage cell line. After 24 h exposure, the TNS-exposed cells formed large vacuoles while the P25-exposed ones did not. The decreased levels of cell viability were similar between the P25 and TNS groups, but ATP production was clearly lower in cells exposed to the TNS. P25 decreased the expression of calnexin protein, an endoplasmic reticulum (ER) membrane marker, and increased the number of cells generating ROS in a dose dependent manner. Meanwhile, TNS dilated the ER and mitochondria and increased the secretion of NO and pro-inflammatory cytokines, but not of ROS. Subsequently, we studied the molecular response following TNS-induced vacuolization. TNS started to form vacuoles in the cytosol since 20 min after exposure, and the expression of the mitochondria function-related genes were down-regulated the most in the cells exposed for 1 h. After 24 h exposure, the number of apoptotic cells and the relative levels of BAX to Bcl-2 increased. The expression of SOD1 protein, but not of SOD2, also dose-dependently increased with an increase in caspase-8 activity. Additionally, the MAPK pathway was significantly activated, even though the expression of p-EGFR did not change significantly. Furthermore, the number of apoptotic cells increased rapidly with time and with the inhibition of vacuole formation. Taken together, we suggest that P25 and TNS may target different organelles. In addition, TNS, but not P25, induced paraptosis accompanied by apoptosis in MH-S cells, and the formation of the cytoplasmic vacuoles allowed delay apoptosis following TNS exposure.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: pejtoxic@hanmail.net.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Seung Yun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: School of Civil, Environmental and Architectural Engineering, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Gwang-Hee
authors.initials: GH
authors.lastname: Lee
authors.affiliation: School of Civil, Environmental and Architectural Engineering, Korea University, Seoul 136-713, Republic of Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Chemical Engineering, Kwangwoon University, Seoul 139-701, Republic of Korea.
authors.forename: Younghun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: jhkim@ajou.ac.kr.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D037281:Calnexin / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles; D009569:Nitric Oxide / Q000378:metabolism; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014025:Titanium / Q000633:toxicity*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D037281:Calnexin; C009495:titanium dioxide; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D014025:Titanium
keywords: Apoptosis; P25; Paraptosis; Sheet; Titanium dioxide nanoparticles; Vacuoles