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

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.