Titanium dioxide nanoparticles activate the ATM-Chk2 DNA damage response in human dermal fibroblasts

Abstract

The use of nanoparticles in consumer products increases their prevalence in the environment and the potential risk to human health. Although recent studies have shown in vivo and in vitro toxicity of titanium dioxide nanoparticles (nano-TiO₂), a more detailed view of the underlying mechanisms of this response needs to be established. Here, the effects of nano-TiO₂ on the DNA damage response and DNA replication dynamics were investigated in human dermal fibroblasts. Specifically, the relationship between nano-TiO₂ and the DNA damage response pathways regulated by ATM/Chk2 and ATR/Chk1 was examined. The results show increased phosphorylation of H2AX, ATM, and Chk2 after exposure. In addition, nano-TiO₂ inhibited the overall rate of DNA synthesis and frequency of replicon initiation events in DNA-combed fibres. Taken together, these results demonstrate that exposure to nano-TiO₂ activates the ATM/Chk2 DNA damage response pathway.

Keywords::

• Nanotoxicology
• environmental toxicology
• mechanistic toxicology
• DNA damage response
• ATM

Acknowledgments

The authors would like to thank Dr. Jayne Boyer, Wallace Ambrose at the Chapel Hill Analytical and Nanofabrication Laboratory, and Stephanie Smith-Roe of the Kaufmann laboratory. In addition, we thank Mark Olorvida and Bentley Midkiff of the Translational Pathology Core Facility at Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill for assistance with the study. This Body on a Chip project was supported by a Gillings Innovation Laboratory award from the UNC Gillings School of Global Public Health. In addition, this research was supported in part by grants from the National Institute of Environmental Health Sciences (P30ES010126, ES019315, and P30ES010126) as well as a United States Public Health Service grant (grant number ES018918 (P.D.C.))