The association between histone modification of H3K18 acetylation and hepatic injury induced by arsenic in rats / 中华地方病学杂志

ABSTRACT

Objective:To explore the association between H3K18 acetylation (H3K18ac) and hepatic injury induced by arsenic in rats, which might to provide a new target for the study of mechanism and intervention of hepatic injury induced by arsenic.Methods:Twenty-four healthy Wistar rats, half male and half female, were selected and divided into control group, low, medium and high arsenic dose groups according to body weight (80-100 g) by random number table method, 6 rats in each group. The control group was given deionized water by gavage, and the low, medium and high arsenic dose groups were given 2.00 g/L sodium arsenite (NaAsO 2) by gavage according to their body weight for 6 days every week, the concentrations of NaAsO 2 in the low, medium and high arsenic dose groups were 2.5, 5.0 and 10.0 mg/kg·bw, respectively. After 4 months treatment, liver tissue and peripheral blood samples of rats were collected. The content of arsenic in liver was measured by inductively coupled plasma mass spectrometry (ICP-MS). Histone was extracted from the liver of rats by acid extraction, and the level of H3K18ac was measured with enzyme-linked immunesorbent assay (ELISA). The serum total bile acid (TBA) and γ-glutamyl transpeptidase (γ-GT) levels were measured by fully automatic biochemical instrument. Results:The difference of arsenic content in liver among the control group, low, medium and high arsenic dose groups [median (quartile range) 2.41 (1.83, 2.99), 62.64 (56.26, 65.17), 68.81 (62.58, 77.24), 88.48 (74.47, 98.99) μg/g] was statistically significant ( H=18.98, P < 0.01). The arsenic contents in liver in the low, medium and high arsenic dose groups were higher than that of the control group ( P < 0.05), and the arsenic content in liver increased gradually with the increase of arsenic dose ( Ztrend=5.04, P < 0.01). The differences of serum TBA and γ-GT levels among the control group and low, medium and high arsenic dose groups were statistically significant ( F=11.11, 12.26, P < 0.05). The TBA and γ-GT levels increased gradually with the increase of arsenic dose ( Ftrend=32.09, 33.22, P < 0.01). The difference of H3K18ac levels among the control group, low, medium and high arsenic dose groups was statistically significant ( F=4.62, P < 0.05). Compared with the control group, the levels of H3K18ac in the medium and high arsenic dose groups decreased ( P < 0.05), and the level of H3K18ac in liver decreased gradually with the increase of arsenic dose ( Ftrend=12.82, P < 0.01). The results of correlation analysis showed that there were positive correlation between liver arsenic content and the liver function indicators of TBA and γ-GT levels( r=0.631, 0.863, P < 0.01), while the liver arsenic content were negatively correlated with H3K18ac level ( r=- 0.476, P < 0.05). And the level of H3K18ac were negatively correlated with the liver function indicators of TBA and γ-GT levels ( r=- 0.628,-0.544, P < 0.05). The results of the mediating effect analysis showed that the H3K18ac had a partly mediating effect on the effect of arsenic exposure on liver function indicators of TBA and γ-GT, and the proportion of mediating effect on TBA and γ-GT to total effect was 37.10% [95% confidence interval ( CI) 9.71%-92.45%] and 20.05% (95% CI 2.61%-52.89%), respectively. Conclusion:The level of H3K18ac in the liver of rats is not only respond to arsenic exposure, but is also closely related to hepatic injury induced by arsenic, suggesting that H3K18ac may be used as a new target for the study of liver injury mechanism and intervention of hepatic injury induced by arsenic.