职业性铝接触工人认知功能与H3K4me3和BDNF的关系

Association between H3K4me3/BDNF and the cognitive function of workers occupationally exposed to aluminum

目的探讨职业性铝接触对工人认知功能影响及其与外周血淋巴细胞组蛋白H3赖氨酸残基4位点三甲基化修饰（H3K4me3）、血浆脑源性神经生长因子（BDNF）蛋白水平的关系。方法于2015年9月，采用整群抽样的方式，选择山西某铝厂235例男性工人作为研究对象。采用简短精神状态量表（MMSE）、画钟试验（CDT）、数字广度测验[DST，包括正序测试（DSFT）和倒序测试（DSBT）]、物体记忆测验（FOME）、言语流畅性测验（VFT）等进行调查，收集研究对象的一般情况并进行认知功能评分；采用石墨炉原子吸收法测定血铝含量，以血铝水平的肘（P25，P75）分为低、中、高血铝组；酶联免疫吸附试验（ELISA）方法定量检测外周血淋巴细胞中H3K4me3水平和血浆BDNF蛋白水平。结果工人血铝水平M（P25，P75）为134．36（100．14，178．96）μg/L。高血铝组工人MMSE、DSFF、DSBT、DST平均得分分别为27．98±1．53、9．19±2．00、6．08±1．63、15．27±3．11，均低于低血铝组（28．83±1．25、10．64±2．87、7．19±3．07、17．81±4．72），差异均有统计学意义（均P〈0.05）。3个血铅组工人的CDT、FOME、VFT平均得分比较，差异均无统计学意义（均P〉0．05）。高血铝组工人外周血淋巴细胞H3K4me3水平为（18．45±9．81）ng/μg Pro、血浆BDNF蛋白水平为（26．07±10．18）ng／ml，均分别低于低血铝组[（23．76±9．89）ng/μg Pro、（31．66±9．24）ng/ml]，差异均有统计学意义（均P〈0．05）。Spearman秩相关分析结果显示，H3K4me3、BDNF、MMSE、DSFT和DST与血铝水平之间存在负相关（rs=-0．307、-0．214、-0．252、-0．197和-0．181，均P〈0.01）。结论长期职业性铝接触可能引起认知功能改变，并伴随外周血淋巴细胞H3K4me3水平和血浆BDNF蛋白表达降低。

Objective To investigate the influence of occupational aluminum exposure on cognitive function and its relationship with tri-methyl histone H3 lysine residues 4 points （H3K4me3） and brain-derived neurotrophic factor （BDNF） levels. Methods By cluster random sampling method,a total of 235 cases of male workers selected from a Shanxi aluminum factory were recruited in the study in September 2015. Used the occupational epidemiological investigation questionnaire, which included Mini-Mental State Examination （MMSE）, Clock Drawing Test （CDT）, Digit Span Test （DST, including forward test DSFT and backward test DSBT）, Fuild Object Memory Evaluation （FOME） and Verbal Fluency Test （VFT）, to collect workers＇ basic information and assess their cognitive function score. Detected the concentration of aluminum in plasma by graphite furnace atomic absorption spectrometry. Workers were divided into three groups by the 25 percentile and 75 percentile of the aluminum content, such as low, middle and high aluminum concentration groups. The concentrations of H3K4me3 in lymphocyte and BDNF in plasma were determined by enzyme-linked immunosorbent assay. Results The levels of aluminum in plasma was 134.36 （100.14,178.96） μg/L. The scores of MMSE, DSPF, DSBT, DST of high aluminum concentration group were lower than low aluminum group （27.98±1.25 vs 28.83±1.54, 9.19±2.00 vs 10.64±2.87,6.08±1.63 vs 7.19±3.07,15.27±3.11 vs 17.81±4.72, all P〈0.05 ）, the seores of CDT, FOME, VFT among three groups had no statistical significance （allP〉0.05 ）. The expression levels of H3K4me3 and BDNF of high aluminum eoneentration group were lower than the low group [ （18.45±9.81） ng/μg Pro vs （23.76±9.89） ng/μg Pro, （26.07±10.18） ng/ml vs （31.66±9.24） ng/ml, all P〈 0.05]. Multiple correlation analysis showed that aluminum coneentration were negatively correlated to H3K4me3, BDNF, MMSE, DSFT, DST, respectively （rs =-0.307, -0.214, -0.252, -0.197, -0.181, all P〈0.01）.Conclusion Exposure to occupational aluminum for a long time may change cognitive function, which go along with the decreasing of H3K4me3 level in lymphocyte and BDNF protein expression in plasma.