Intratracheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice

Abstract

An estimated 1% or less of nanoparticles (NPs) deposited in the lungs translocate to systemic circulation and enter other organs; however, this estimation may not be accurate given the low sensitivity of existing in vivo NP detection methods. Moreover, the biological effects of such low levels of translocation are unclear. We employed a nano-scale hyperspectral microscope to spatially observe and spectrally profile NPs in tissues and blood following pulmonary deposition in mice. In addition, we characterized effects occurring in blood, liver and heart at the mRNA and protein level following translocation from the lungs. Adult female C57BL/6 mice were exposed via intratracheal instillation to 18 or 162 µg of industrially relevant titanium dioxide nanoparticles (nano-TiO₂) alongside vehicle controls. Using the nano-scale hyperspectral microscope, translocation to heart and liver was confirmed at both doses, and to blood at the highest dose, in mice analyzed 24 h post-exposure. Global gene expression profiling and ELISA analysis revealed activation of complement cascade and inflammatory processes in heart and specific activation of complement factor 3 in blood, suggesting activation of an early innate immune response essential for particle opsonisation and clearance. The liver showed a subtle response with changes in the expression of genes associated with acute phase response. This study characterizes the subtle systemic effects that occur in liver and heart tissues following pulmonary exposure and low levels of translocation of nano-TiO₂ from lungs.

• Complement cascade
• gene expression
• hyperspectral microscopy
• inflammation
• nanoparticles
• translocation

Acknowledgements

We thank Michael Guldbrandsen, Lisbeth Meyer Petersen and Eva Terrida for their excellent technical assistance. We also thank Dr Michael Johnston and Dr Jonathan Glen Boucher for their helpful comments on the manuscript.

Declaration of interest

The authors declare that there are no conflicts of interest. This work was supported by the Health Canada's Genomics Research and Development Initiative and Chemicals Management Plan, as well as Danish Centre for Nanosafety, grant # 20110092173-3 and NanoKem, grant # 20060068816, both from the Danish Working Environment Research Foundation.

Supplementary material available online.

Supplementary Figure S1 and Supplementary Tables S1-S5.