Titanium Dioxide Nanoparticles Induce Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death via Mitochondria-Associated Endoplasmic Reticulum Membrane Disruption in Normal Lung Cells

PLoS One. 2015 Jun 29;10(6):e0131208. doi: 10.1371/journal.pone.0131208. eCollection 2015.

Abstract

Nanomaterials are used in diverse fields including food, cosmetic, and medical industries. Titanium dioxide nanoparticles (TiO2-NP) are widely used, but their effects on biological systems and mechanism of toxicity have not been elucidated fully. Here, we report the toxicological mechanism of TiO2-NP in cell organelles. Human bronchial epithelial cells (16HBE14o-) were exposed to 50 and 100 μg/mL TiO2-NP for 24 and 48 h. Our results showed that TiO2-NP induced endoplasmic reticulum (ER) stress in the cells and disrupted the mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium ion balance, thereby increasing autophagy. In contrast, an inhibitor of ER stress, tauroursodeoxycholic acid (TUDCA), mitigated the cellular toxic response, suggesting that TiO2-NP promoted toxicity via ER stress. This novel mechanism of TiO2-NP toxicity in human bronchial epithelial cells suggests that further exhaustive research on the harmful effects of these nanoparticles in relevant organisms is needed for their safe application.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / drug effects*
  • Calcium / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Endoplasmic Reticulum Stress / drug effects*
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Homeostasis / drug effects
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism*
  • Intracellular Membranes / ultrastructure
  • Lung / pathology*
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Nanoparticles / toxicity*
  • Nanoparticles / ultrastructure
  • Reactive Oxygen Species / metabolism
  • Taurochenodeoxycholic Acid / pharmacology
  • Titanium / toxicity*

Substances

  • Reactive Oxygen Species
  • titanium dioxide
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • Titanium
  • Calcium

Grants and funding

This study was partially supported by funding provided to Myung-Haing Cho by the Research Institute for Veterinary Science, Seoul National University, and the BK21 PLUS Program for Creative Veterinary Science Research. KNY, SHC, SJP, J. Lim, J. Lee, TJY, JSK, MHC received funding from the Ministry of Science, ICT, & Future Planning (NRF-2015M3A7B6027957) (www.msip.go.kr). KNY, MHC received funding from the Ministry of Food and Drug Safety (14182MFDS977) (www.mfds.go.kr). Co-authors Soo Jin Park and Jun-Sung Kim are employed by R&D Center, Biterials, Co. Biterials Co. provided support in the form of salaries for authors SJP and J-SK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.