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目的:探讨砷暴露大鼠肝脏组蛋白H3第18位赖氨酸乙酰化（H3K18ac）水平与砷致肝损伤的关系，为砷中毒肝损伤机制及干预研究提供新靶点。方法:选取健康Wistar大鼠24只，雌雄各半，按体质量（80~100 g）采用随机数字表法分为对照组，低、中、高砷剂量组，每组6只。对照组给予去离子水灌胃，低、中、高砷剂量组按体质量用亚砷酸钠（NaAsOn 2，2.00 g/L）溶液灌胃（灌胃量依次为2.5、5.0、10.0 mg/kg·bw），每周染砷6 d，持续4个月。实验终末收集各组大鼠肝脏组织及外周血，采用电感耦合等离子体质谱仪（ICP-MS）检测肝砷含量；酸抽提法提取大鼠肝脏组蛋白，酶联免疫吸附试验（ELISA）检测H3K18ac水平；采用全自动生化分析仪检测大鼠血清总胆汁酸（TBA）及谷氨酰胺转移酶（γ-GT）水平。n 结果:对照组，低、中、高砷剂量组肝砷含量[中位数（四分位数间距）：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]比较差异有统计学意义（n H=18.98，n P < 0.01），低、中、高砷剂量组均高于对照组（ n P均< 0.05）；且大鼠肝砷含量随染砷剂量增加逐渐升高（n Z趋势=5.04，n P < 0.01）。对照组，低、中、高砷剂量组血清TBA、γ-GT水平比较差异有统计学意义（ n F=11.11、12.26，n P均< 0.05）；且大鼠血清TBA、γ-GT水平随染砷剂量增加逐渐升高（n F趋势=32.09、33.22，n P均< 0.01）。对照组，低、中、高砷剂量组肝组织H3K18ac水平比较差异有统计学意义（n F=4.62，n P < 0.05），中、高砷剂量组显著低于对照组（ n P均< 0.05）；且大鼠肝组织H3K18ac水平随染砷剂量增加逐渐降低（n F趋势=12.82，n P < 0.01）。相关性分析结果显示，大鼠肝砷含量与肝功能指标TBA、γ-GT水平呈正相关（ n r=0.631、0.863，n P均< 0.01），与H3K18ac水平呈负相关（n r=- 0.476，n P < 0.05）；H3K18ac水平与肝功能指标TBA、γ-GT水平呈负相关（ n r=- 0.628、- 0.544，n P均< 0.05）。H3K18ac对砷致肝损伤的中介效应检验结果显示，组蛋白H3K18ac在砷暴露对肝功能指标的影响中具有部分中介效应，其对TBA和γ-GT水平的中介效应分别占总效应的37.10%[95%置信区间（n CI）：9.71%~92.45%]和20.05%（95%n CI：2.61%~52.89%）。n 结论:大鼠肝脏H3K18ac水平不仅响应于砷暴露，还与砷诱导的肝损伤密切相关，提示H3K18ac可能作为砷中毒肝损伤机制及干预研究的新靶点。“,”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 (NaAsOn 2) by gavage according to their body weight for 6 days every week, the concentrations of NaAsOn 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.n 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 ( n H=18.98, n 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 ( n P < 0.05), and the arsenic content in liver increased gradually with the increase of arsenic dose ( n Ztrend=5.04, n 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 ( n F=11.11, 12.26, n P < 0.05). The TBA and γ-GT levels increased gradually with the increase of arsenic dose ( n Ftrend=32.09, 33.22, n P < 0.01). The difference of H3K18ac levels among the control group, low, medium and high arsenic dose groups was statistically significant ( n F=4.62, n P < 0.05). Compared with the control group, the levels of H3K18ac in the medium and high arsenic dose groups decreased ( n P < 0.05), and the level of H3K18ac in liver decreased gradually with the increase of arsenic dose ( n Ftrend=12.82, n 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( n r=0.631, 0.863, n P < 0.01), while the liver arsenic content were negatively correlated with H3K18ac level ( n r=- 0.476, n P < 0.05). And the level of H3K18ac were negatively correlated with the liver function indicators of TBA and γ-GT levels ( n r=- 0.628,-0.544, n 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 ( n CI): 9.71%-92.45%] and 20.05% (95%n CI: 2.61%-52.89%), respectively.n 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.