植物化学物、氧化应激与抗氧化酶相关基因多态性对燃煤型氟中毒的影响

The most severe area of the coal-burning endemic fluorosis is located in Guizhou province of China. Fluorosis is the result of the combined effects of environmental and genetic. Studies suggest that oxidative stress is an important pathogenesis of chronic fluorosis. Phytochemicals exhibit strong antioxidant activity and are widespread present in our daily diet. Several studies have showed that phytochemicals attenuated oxidative damage induced by excessive fluoride in animal, which indicated that phytochemicals may prevent the risk of fluorosis. However, up to date, there are no epidemical studies have investigated the overall effect of multiple oxidantive phytochemicals on endemic fluorosis. Furthermore, no studies have examined the associations between antioxidant enzymes (SOD and GPx) gene polymorphism and endemic fluorosis and reported the influence of interaction to the susceptibility of fluorosis. To address this issue，we will perform a 1:1 matched case-control study, including 500 pairs of coal-burning endemic fluorosis case and control, to collect dietary intake et al by questionnaire, blood and urine samples. Dietary consumption of phytochemicals and blood or urine concentrations of phytochemicals will be assessed. Antioxidant enzymes gene polymorphisms and blood oxidative/anti-oxidative levels also will be examined. Our results will reveal the effects size and strenth of various phytochemicals on endemic fluorosis, and clarify the associations between antioxidant enzymes gene polymorphisms and endemic fluorosis, and explore influence of interaction between phytochemicals, urine fluorine and antioxidant enzymes gene polymorphisms to the susceptibility of fluorosis. Moreover, our findings will form a theoretical foundation for screening high risk population of endemic fluorosis and provide theoretical evidences for prevention and/or treatment of endemic fluorosis by via antioxidant approach.

贵州省是燃煤型氟中毒是严重的省份，氟中毒是环境与基因综合作用的结果。研究表明氧化应激是慢性氟中毒的重要发病机制，植物化学物具有较强的抗氧化活性且广泛存在日常膳食中。少量动物实验研究表明植物化学物可以拮抗过量氟所致的氧化损伤，提示植物化学物可能预防氟中毒，但尚无流行病学研究证据；亦无抗氧化酶（SOD和GPx）基因多态性与氟中毒的关联性及它们之间的相互作用对氟中毒易感性的影响报道。为此，本研究拟采用1:1病例对照研究，收集500对病例和对照的膳食等问卷资料及生物样本，检测分析膳食及血清植物化学物含量、氧化/抗氧化水平和抗氧化酶基因多态性，揭示植物化学物对氟中毒的作用性质和强度，阐明抗氧化酶基因多态性与氧化应激及氟中毒的关系，探索环境与抗氧化酶基因交互作用对氟中毒易感性的影响。为筛选氟中毒的高危人群提供理论基础，为从抗氧化途径选择针对性的措施预防和/或治疗氟中毒提供科学依据。

背景及主要研究内容：贵州省是燃煤型氟中毒是严重的省份，氟中毒是环境与基因综合作用的结果。少量动物实验研究表明植物化学物可以拮抗过量氟所致的氧化损伤，提示植物化学物可能预防氟中毒，但尚无流行病学研究证据探索植物化学物与氟中毒的关联及其与基因的交互作用对氟中毒的影响。本研究采用病例对照研究，收集1008名研究对象膳食等问卷资料及生物样本，分析膳食类胡萝卜素、大豆异黄酮、黄酮醇、黄烷醇、黄酮等植物化学物并构建膳食模式，检测血清类胡萝卜素含量、尿大豆异黄酮含量、血清氧化应激水平以及CAT、SOD、PON1等抗氧化酶基因多态性。.结果：膳食α、β-胡萝卜素、叶黄素/玉米黄质、番茄红素和总类胡萝卜素氟中毒呈负关联，血清β-隐黄质，叶黄素/玉米黄质和番茄红素水平越高，氟中毒风险越低；女性大豆异黄酮摄入量越来越高，燃煤型氟中毒发生的风险就越小，而在男性中不存在该负关联。黄烷醇中表儿茶素没食子酸酯、儿茶素、没食子儿茶素对氟中毒具有保护作用，表儿茶素没食子酸酯效应最强，而黄酮醇中槲皮素和山奈酚具有较强的保护效应；遵从DQI-I、aMED、AHEI膳食模式，燃煤形氟中毒的危险性则越低。此外，采用因子分析构建的高坚果-菌藻-奶类模式对燃煤型氟中毒具有保护作用，而高玉米-土豆-瓜类模式可能增加燃煤型氟中毒的风险。PON1 rs662位点单核苷酸多态性与氟中毒发生有关，氟暴露水平修饰该基因多态性与氟骨症的关联。CAT rs230182位点显性模式和累加模式与氟骨症有关，膳食钙在CAT rs2300182位点不同基因型中对氟斑牙的作用有所区别，不同类胡萝卜素针对不同基因型保护作用有所不同。意义：补充植物化学物如类胡萝卜素、大豆异黄酮、黄烷醇、黄烷酮、黄酮和黄酮醇等对燃煤型氟中毒的保护作用，证实膳食营养、基因、氟暴露水平存在交互作用，为筛选氟中毒的高危人群提供理论基础，为从抗氧化途径精准预防氟中毒提供了科学依据。本研究项目发表论文9篇，其中SCI 1篇，核心期刊5篇，培养研究生3名，本科生4名。