Induction of chronic oxidative stress, chronic inflammation and aberrant patterns of DNA methylation in the liver of titanium-exposed CBA/CaJ mice

Abstract

Purpose: To investigate the biological effects of titanium (⁴⁸Ti, one of the important heavy ions found in space) in the liver of exposed-mice.

Materials and methods: We gave adult male CBA/CaJ mice a whole-body exposure to a total dose of 0, 0.1, 0.25 or 0.5 Gy of ⁴⁸Ti ions. The liver was collected at 1 week, 1 month, and 6 months post-irradiation (five mice per treatment-group at each harvest-time). Three biological endpoints were used for evaluating the effects of ⁴⁸Ti ions: Oxidative-stress, inflammatory responses, and DNA-methylation (5-methylcytosine and 5-hydroxymethylcytosine).

Results: Our data clearly demonstrated dose-dependent increases in oxidative stress and inflammatory responses in the liver of exposed mice at all time-points (Analysis of Variance or ANOVA, p < 0.05). Significant dose-dependent increases in the levels of 5-methylcytosine were detected at 1 week and 1 month (ANOVA, p < 0.05). At 6 months post-irradiation, a significant increase in the level of 5-methylcytosine was found only in 0.5-Gy-⁴⁸Ti-ion-exposed mice. In contrast, dose-dependent decreases in 5-hydroxymethylcytosine levels were found in the liver of exposed mice (ANOVA, p < 0.05) at all time-points.

Conclusions: Chronic oxidative-stress, chronic inflammation, and persistent aberrant DNA-methylation occurred in the liver of ⁴⁸Ti-exposed mice. Hence, exposure to ⁴⁸Ti ions in space may pose health risks.

Keywords::

• In vivo oxidative stress
• inflammatory responses
• 5-methylycytosine
• 5-hydroxymethylcytosine
• titanium
• liver

Acknowledgements

This research was supported by the National Aeronautics and Space Administration (NASA) Grant # NNX11AK91G. We thank Dr Peter Guida and his team for logistic support, MaryAnn Petry and her staff at Brookhaven Laboratory Animal Facilities (BLAF) for their assistance in animal handling. We also thank Drs Adam Rusek and Michael Sivertz for dosimetry support. Editorial help from Dr Marinel M. Ammenheuser of the University of Texas Medical Branch in Galveston, TX, and from Mrs Louise Honikel of Stony Brook University is greatly appreciated.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.