碘过量对脂代谢的影响及机制研究
摘要
碘是合成甲状腺激素所必需的微量元素。甲状腺激素在调节机体物质代谢和生长发育中发挥重要作用。适宜的碘营养水平是维持甲状腺正常功能的重要基础。碘缺乏病(IDD)曾在世界范围内流行并严重危害健康,长久以来人们一直致力于研究碘缺乏对人群健康的影响及其防治措施。在1991年世界卫生组织(WHO)和国际控制碘缺乏病理事会(ICCIDD)推荐：以普遍食盐加碘(USI)为主要策略以实现消除碘缺乏病的目标。随后,食盐加碘的政策得到了有效推广和实施,碘营养水平在世界范围内显著提高,碘缺乏病得到了有效的控制。然而在防治碘缺乏病达标的同时,在近些年国内外关于碘过量摄入引起的各种甲状腺疾病的发病增加的报道逐年增加。碘过量及其对健康的危害成为一项新的公共卫生问题。
目前碘过量的危害研究多集中于对甲状腺功能的影响,对甲状腺外机体其他系统的损伤的研究比较少。但是本课题组在进行碘过量危害的毒理学研究时,发现碘过量会引起大鼠小鼠血脂代谢紊乱；国外学者也有报道碘过量导致母鸡血胆固醇水平升高。另外,2009年国内首次报道高水碘与人群血脂异常存在流行病学关联。越来越多的证据提示,碘过量可能与人群血脂异常有关,而相关研究缺乏。据中国居民营养与健康状况调查报告显示,我国成人高脂血症的患病率18.8%,估计全国血脂异常现患人数达1.6亿。高脂血症是心脑血管疾病最重要的危险因素。心血管疾病是我国居民健康的头号杀手,我国每年由于心血管疾病所花费的医疗费用及劳动力损失逾2000亿元,给社会和家庭造成沉重的负担。因此,除了近年来随着我国经济的快速发展,居民生活水平的不断提高,膳食模式西方化趋势明显,导致我国居民血脂异常患病率显著升高外,碘过量与血脂异常的关系值得高度关注和深入研究。
本研究结合动物学实验研究和人群流行病学调查,建立不同膳食模式下的碘过量动物模型,深入研究碘过量对血脂代谢影响的时间剂量效应及其机理；调查深圳市居民碘营养水平及血脂异常患病率,初步探索碘营养水平是否与血脂异常存在流行病学相关；开展问卷调查,对血脂异常的影响因素进行细致量化收集,采用多因素Logistic回归分析碘营养水平是否为血脂异常的影响因素。当前,我国面临食盐加碘政策的调整,本研究的开展为全面认识碘过量的危害,并为制定科学合理的碘营养政策提供理论依据。现将结果报告如下：
目的：建立碘过量小鼠动物模型,系统地观察碘过量致小鼠血脂代谢紊乱的特点及时间效应、剂量效应关系。观察碘过量对机体的氧化／抗氧化平衡、甲状腺功能、甲状腺激素代谢的影响、以及对肝脏甲状腺激素受体TRpl和肝脏脂代谢相关基因表达的影响,深入探讨碘过量所致小鼠脂代谢紊乱的机制。
方法：刚断乳的清洁级雌性BABL/C小鼠100只,体重10-13g。按体重随机分为10组(10只／组)。其中6组分别给予不同剂量的碘(0、300μg/L、600μg/L、1200μg／L、2400μg/L、4800μg／L)喂养一月；2组分别给予0、1200μg／L喂养三月；2组分别给与0、1200μg/L喂养六月。检测血脂、血甲状腺激素水平、氧化、抗氧化水平、脱碘酶1(D1)的活性；测定肝脏甲状腺激素受体TRpl和脂代谢相关基因LDLR、SR-BI的表达水平。
结果：①本实验结果表明,碘过量摄入导致小鼠血清总胆固醇水平、低密度脂蛋白胆固醇水平升高并呈剂量时间效应。②碘过量摄入导致甲状腺发生胶质潴留甲状腺肿的病理改变。随着碘剂量的增加,甲状腺滤泡增大。③碘过量摄入降低血清、肝脏的总抗氧化能力,并升高MDA水平,并呈剂量和时间效应。血清和肝脏的MDA水平与碘剂量呈显著正相关,当碘剂量达到2400μg/L时显著升高。1200μg／L摄入3、6月时MDA水平显著升高。在本实验条件下,血清甲状腺激素(TT4、TT3、TSH)水平无显著性改变；肝脏脱碘酶活性未发生显著性改变。④碘过量剂量依赖性和时间依赖性的摄入下调肝脏TRβ1和LDLR表达水平。与对照组相比,在2400μg／L和4800μg／L碘剂量组TRβ1和LDLR显著性降低,并与碘剂量显著性相关(LDLR:r=-0.748,<0.01；TRβ1:r=-0.847,P<0.01)；与对照组相比,1200μg/L碘摄入1月TRβ1、LDLR表达水平无显著变化,当摄入时间≥3月时TRβ1、LDLR表达水平显著性降低。
结论：本研究发现碘过量导致小鼠血清总胆固醇水平、低密度脂蛋白胆固醇水平升高,并呈剂量时间效应。在本实验条件下,甲状腺激素未发生改变时,血脂水平已发生改变,提示在碘过量摄入时,血脂的改变可能比甲状腺激素的改变更为敏感。肝脏TRpl和LDLR表达水平降低可能是碘过量导致血胆固醇升高的重要分子机制。
目的：建立碘过量联合高脂膳食小鼠动物模型,系统地观察在高脂膳食模式下,碘过量对小鼠血脂代谢影响的特点及时间、剂量效应关系。观察碘过量联合高脂膳食对机体的氧化／抗氧化平衡、甲状腺功能、甲状腺激素代谢的影响、以及对肝脏脂代谢相关基因表达的影响,进一步探讨碘过量联合高脂膳食对血脂代谢影响的机制。
方法：动物分组与碘剂量设置与第一部分相同。小鼠自由饮水、摄食。饲料为本实验室配制的高脂饲料。指标的检测方法与第一部分相同。
结果：①各碘过量联合高脂膳食组甲状腺出现胶质性甲状腺肿的改变,高剂量碘组动物甲状腺受损严重,出现了滤泡融合。高脂联合1200μg/L随时间的延长,甲状腺受损严重,出现了滤泡融合,部分滤泡破裂。②与正常饲料对照组相比,高脂饲料对照组氧化应激增加,高碘联合高脂膳食组,随着碘剂量的增加,机体氧化应激加剧。碘过量联合高脂膳食对机体氧化损伤具有协同作用。长期碘过量联合高脂膳食摄入降低小鼠SOD和GSH-Px活性,而升高MDA水平。③与高脂膳食对照组相比,高脂膳食联合碘剂量≤4800μg/L摄入1个月,小鼠血清中甲状腺激素、血脂水平未发生显著改变。1200μg／L联合高脂膳食≥3月时,小鼠血清中甲状腺激素改变表现为：总甲状腺激素(TT4)、总三碘甲状腺原氨酸(TT3)升高,促甲状腺激素(TSH)降低。血脂代谢改变的主要表现为：血清中总胆固醇、总甘油三酯、低密度脂蛋白胆固醇水平显著性降低。④与高脂膳食对照组相比,高脂膳食联合碘剂量≤4800μg／L摄入1个月,LDLR和SR-BI表达无显著改变。1200μg/L碘联合高脂膳食摄入一个月对LDLR和SR-BI表达无影响,随着时间的延长,当摄入3个月和6个月时,LDLR表达显著升高,并与TT3水平和血脂变化一致。
结论：长期碘过量联合高脂膳食,加剧机体氧化应激水平造成甲状腺损伤,导致甲状腺激素代谢紊乱(总甲状腺激素、总三碘甲状腺原氨酸升高,促甲状腺激素降低),继而引起血脂代谢改变(血清中总胆固醇、总甘油三酯、低密度脂蛋白胆固醇水平降低)。LDLR表达水平的升高可能是碘过量联合高脂膳食引起血脂代谢变化的分子机制。
目的：调查深圳市居民尿碘水平和血脂异常患病率,比较不同碘营养水平居民的血脂异常率,初步探索不同碘营养水平是否与血脂异常存在流行病学关联。开展问卷调查,对血脂异常的影响因素进行细致量化收集,采用多因素Logistic回归分析碘营养水平是否为血脂异常的影响因素。
方法：采取多级抽样的方法,随机抽取深圳市30岁以上326人作为调查对象。本次调查研究包括问卷调查(收集调查对象一般情况和各种食物的消费频率和消费量及身体活动情况等信息)、人体测量学指标测量(测量所有调查对象的身高、体重、腰围和血压)和实验室检测(采集所有调查对象的清晨空腹血液样本和清晨中段尿,测定空腹血糖,血脂以及尿碘水平)三部分内容。
结果：①本次抽样调查获得样本中,居民血脂异常患病率为33.72%,其中男性为39.02%,女性为31.28%。不同年龄血脂异常患病率差异显著,60-70岁年龄组血脂异常患病率最高为53.13%。②本次抽样调查获得样本总体尿碘中位数167.7μg/L。个体尿碘水平差异较大,尿碘最高者达到1705.5μg/L,尿碘最低为12μg/L。尿碘水平>300μg/L者占15.64%；尿碘水平200-300μg/L之间者占45.09%；③相关性分析表明,在尿碘水平<200μg/L时,高密度脂蛋白胆固醇异常降低与尿碘表现出线性负相关(rs=-0.164,p=0.031)；在尿碘水平>300μg/L时,高密度脂蛋白胆固醇异常降低与尿碘表现出线性正相关(rs=0.246,p=0.013)。其他血脂指标与尿碘无显著相关性。④多因素Logistic回归分析表明：年龄<60为血脂异常保护因素；高血糖、腹部肥胖为血脂异常危险因素。尿碘对血脂异常无显著性影响。
结论：深圳市居民血脂异常患病率较高,血脂异常防治工作十分迫切。深圳市居民尿碘水平在200μg/L以上的百分比较高,易引起碘过量的危害。本研究首次发现碘营养水平与HDL-C异常之间可能存在U型关系。尿碘水平在200-300μg/L之间时,血脂HDL-C异常的患病率最低,在尿碘水平<200μg/L或>300μg／L增加HDL-C异常的风险。碘营养水平是否为血脂异常的影响因素需要在大样本流行病学调查的基础上进一步研究。
Iodine is an essential trace element which is an essential constituent of the thyroid hormones.Thyroid hormones play an important role in the regulation of metabolism and growth. Adequate iodine intake lays solid foundation for maintaining normal thyroid function. Iodine deficiency disorders (IDD) have been prevalent in the world and created serious hazards to public health. The goal of eliminating iodine deficiency disease (IDD) has been achieved since Universal Salt Iodization (USI) policy has been widely carried out in many nations. With rapid global progress in correcting iodine deficiency, reports are increasingly appearing on the higher prevelance of all kinds of thyroid diseases caused by excessive iodine intake in the recent decades. Iodine excess and its health hazards are immerging as a new public health problem.
Present studies on the hazard effects of iodine excess were focus on its effect on thyroid function. Wheras studies on the extrathyroidal effects of the iodine excess are rare. However, our group has found the dyslipidemia caused by iodine excess in both rats and mice during the toxicological study of excessive iodine intake. In addition, the dose-dependent hypercholesterol effect of iodine excess has also been reported in laying hens by foreign scholars. Moreover, the first report on the epidemiological correlation between high water iodine and dyslipideima was published in domestic in 2009. Increasing evidences have suggested that iodine excess may have a potential effect on dyslipideima. Prevalence of dyslipidemia in China significantly increased in recent decades due to rapid economic growth, the higher living standards, as well as evident trends in Western dietary pattern. According to The Chinese Nutrition and Health Survey, prevalence of hyperlipidemia in adult was 18.8%, patients with hyperlipidemia were up to 160 million. Hyperlipidemia is the most important risk factor for cardiovascular disease. Every year China spends more than 200 billion yuan on medical expenses and labor costs due to cardiovascular diseases and it is also a heavy burden both to society and to the family. Therefore, the relationship between Iodine excess and dyslipidemia deserves more attention and further study.
Animal experiments and epidemiological study are combined in the present study. To investigate the time and dose effect of iodine excess on lipid metabolism and its underlying mechanism in animal models of iodine excess under different dietary patterns; To investigate the correlation between different iodine nutrition and the prevalence of dyslipidemia and further to determine wether the iodine nutrition is the risk factor for dyslipidemia. At present China is facing the adjustment of the strategy of Universal Salt Iodization, this study will further expand our knowledge on the potential hazards of iodine excess on health and the results will be instructive for reasonable iodine intake.
Aim of study:The aim of this study is to illustrate the physiological effects and potential mechanisms of excessive iodine intake on lipid metabolism.
Methods:Balb/c mice were given drinking water containing different levels of iodine for one month and treated with 1200μg/L iodine for different period time respectively. Plasma lipid parameters and serum thyroid hormones were measured. Hepatic type 1 deiodinase activity and oxidative stress parameters were evaluated. Expressions of hepatic genes were detected by real time polymerase chain reactions and Western blot.
Results:①Dose-dependent hypercholesterolemic effects were detected in mice (TC:r= 0.615, P＜0.01). Drinking 1200μg/L iodine water for 1 month had no significant effect on serum lipid metabolism while prolonged exposure induced an increase of serum cholesterol.②An obvious colloid goiter was observed in thyroid of mice exposed to high doses of iodine.The diameter of the thyroid Follicular gradually increased as the dosage of iodine increased.③Serum thyroid hormones were not affected by iodine throughout the study. Excessive iodine intake decreased the TAOC antioxidant ability and increased the MDA content in serum and liver mice in a dose-dependant manner. MDA level in serum and liver elevated obviously when iodie dosage was up to 2400μg/L. drinking 1200μg/L iodine water for 1 month did not affect oxidative stress parameters while prolonged exposure induced an increase of MDA level in serum and liver. Hepatic D1 activity was not affected by iodine throughout the study.④A dose-dependent attenuation of hepatic Low Density Lipoprotein receptor (LDLR) and Thyroid hormone receptorβ1 (TRβ1) expression were detected in parallel to the change of serum cholesterol. Treatment with 1200μg/L iodine water for 1 month did not affect LDLR and TRβ1 expression, while 3 months or 6 months exposure resulted in a decrease of their expression.
Conclusion:Present findings demonstrated a dose and time dependent hypercholesterolemic effects of iodine excess. Furthermore, our data suggests that TRβ1 mediated down regulation of hepatic LDLR gene may play a critical role in iodine excess induced hypercholesterolemic effects.
Aim of study:The aim of this study is to illustrate the combined effect of iodine excess and high fat diet on lipid metabolism and its mechanism.
Methods:Balb/c mice were given drinking water containing different levels of iodine for one month and treated with 1200μg/L iodine for different period time respectively. Animals were feed with high fat diet which was made in our laboratory.Plasma lipid parameters and serum thyroid hormones were measured. Expressions of hepatic genes were detected by real time polymerase chain reactions and Western blot.
Results:①an obvious colloid goiter was observed in thyroid of mice exposed to excessive iodine combined high fat diet.The weight of the thyroid gradually increased as the dosage of iodine increased. Follicular fusion and part of the Follicular rupture occurred in the 2400μg/L and 4800μg/L iodine combined high fat diet groups. The damage in the thyroid were gradually serious with prolonged exposure to 1200μg/L iodine combined high fat diet.②Iodine excess combined high fat diet led to a synergistic effect on oxidative damage in mice. Chronic iodine excess combined high fat diet intake resulted in a decrease of the SOD and GSH-Px activity and an increase of MDA level.③Compared with the high fat diet group, Iodine intake (≤4800μg/L) in drinking water combined high fat diet for 1 month had no effect on serum thyroid hormones (TT4,TT3,TSH) and serum lipids. Exposure to 1200μg/L iodine combined high fat diet for 3、6 month resulted in abnormal thyroid hormone metabolism (TT4、TT3 elevated,TSH dereased) and abnormal serum lipid metabolism (TC, TG, LDL-C decreased).④Compared with the high fat diet group, exposure to iodine excess combined high fat diet for 1 month (iodine dosage≤4800μg/L) did not affect LDLR and SR-BI expression; exposure to 1200μg/L iodine water combined high fat diet for 1 month did not affect LDLR and SR-BI expression, while 3 months or 6 months exposure resulted in an increase of LDLR expression.
Conclusion:Present findings demonstrated iodine excess combined high fat diet could cause damage to the thyroid and lead to thyroid hormone disorder. Those in turn resulted in the changes in serum lipids. Up regulation of hepatic LDLR gene might be an important molecular mechanism of the changes in serum lipids induced by iodine excess combined high fat diet.
Aim of study:To investigate the association between different iodine nutriton and the prevelance of dyslipidemia in a representative sample of subjects in Shenzhen and to investigate whether the abnormal iodine nutrition is the risk factor for dyslipidemia.
Study design:A total of 326 adult from 2 dififerent communities in shenzhen, aged 30 to 85 years were included in the study. Body weight and height were measured, the urine iodine concertration and serum lipid and serum glucose level were measued. A questionnaire was given to the subject about general information and risk factors for dyslipidemia.
Results:①the prevalence of dyslipidemia in the sample was 33.72%, males 39.02% and females 31.28%. The prevalence of dyslipidemia was significantly different among different age groups. The highest prevalence of dyslipidemia was 53.13% in 60 to 70 age group.②the median urinary iodine in the sample was 167.7μg/L. there were large individual differences in level of urinary iodine, with the 15.64%; urinary iodine concentration 200-300μg/L accounted for 45.09% in the sample.③when the urine iodine concentration<200μg/L,There is a reverse relationship between iodine nutrition and prevalence of HDL-C(rs=-0.164,p=0.031); when the urine iodine concentration>300μg/L,There is a positive relationship between iodine nutrition and prevalence of HDL-C(rs=0.246,p=0.013); there was no significant correlation between Other lipid parameters and urinary iodine concentration.④Multivariate Logistic regression analysis showed that:Age, high blood glucose, abdominal obesity was significantly related the prevalence of dyslipidemia; urine iodine concentration was no significant correlation the prevalence of dyslipidemia.
Conclusion:the prevalence of dyslipdemia in Shenzhen is high, the prevention and treatment of dyslipidemia is in an urgent need. The percent of urinary iodine above 200μg/L is high in local residents and there may be a risk of iodine excess and its hazard effect. There may be a U typed relationship between iodine nutrition and the prevalence of HDL-C abnormality. Further studies are needed to make sure whether iodine nutrition is an influencing factor of dyslipidemia
目前碘过量的危害研究多集中于对甲状腺功能的影响,对甲状腺外机体其他系统的损伤的研究比较少。但是本课题组在进行碘过量危害的毒理学研究时,发现碘过量会引起大鼠小鼠血脂代谢紊乱；国外学者也有报道碘过量导致母鸡血胆固醇水平升高。另外,2009年国内首次报道高水碘与人群血脂异常存在流行病学关联。越来越多的证据提示,碘过量可能与人群血脂异常有关,而相关研究缺乏。据中国居民营养与健康状况调查报告显示,我国成人高脂血症的患病率18.8%,估计全国血脂异常现患人数达1.6亿。高脂血症是心脑血管疾病最重要的危险因素。心血管疾病是我国居民健康的头号杀手,我国每年由于心血管疾病所花费的医疗费用及劳动力损失逾2000亿元,给社会和家庭造成沉重的负担。因此,除了近年来随着我国经济的快速发展,居民生活水平的不断提高,膳食模式西方化趋势明显,导致我国居民血脂异常患病率显著升高外,碘过量与血脂异常的关系值得高度关注和深入研究。
本研究结合动物学实验研究和人群流行病学调查,建立不同膳食模式下的碘过量动物模型,深入研究碘过量对血脂代谢影响的时间剂量效应及其机理；调查深圳市居民碘营养水平及血脂异常患病率,初步探索碘营养水平是否与血脂异常存在流行病学相关；开展问卷调查,对血脂异常的影响因素进行细致量化收集,采用多因素Logistic回归分析碘营养水平是否为血脂异常的影响因素。当前,我国面临食盐加碘政策的调整,本研究的开展为全面认识碘过量的危害,并为制定科学合理的碘营养政策提供理论依据。现将结果报告如下：
目的：建立碘过量小鼠动物模型,系统地观察碘过量致小鼠血脂代谢紊乱的特点及时间效应、剂量效应关系。观察碘过量对机体的氧化／抗氧化平衡、甲状腺功能、甲状腺激素代谢的影响、以及对肝脏甲状腺激素受体TRpl和肝脏脂代谢相关基因表达的影响,深入探讨碘过量所致小鼠脂代谢紊乱的机制。
方法：刚断乳的清洁级雌性BABL/C小鼠100只,体重10-13g。按体重随机分为10组(10只／组)。其中6组分别给予不同剂量的碘(0、300μg/L、600μg/L、1200μg／L、2400μg/L、4800μg／L)喂养一月；2组分别给予0、1200μg／L喂养三月；2组分别给与0、1200μg/L喂养六月。检测血脂、血甲状腺激素水平、氧化、抗氧化水平、脱碘酶1(D1)的活性；测定肝脏甲状腺激素受体TRpl和脂代谢相关基因LDLR、SR-BI的表达水平。
结果：①本实验结果表明,碘过量摄入导致小鼠血清总胆固醇水平、低密度脂蛋白胆固醇水平升高并呈剂量时间效应。②碘过量摄入导致甲状腺发生胶质潴留甲状腺肿的病理改变。随着碘剂量的增加,甲状腺滤泡增大。③碘过量摄入降低血清、肝脏的总抗氧化能力,并升高MDA水平,并呈剂量和时间效应。血清和肝脏的MDA水平与碘剂量呈显著正相关,当碘剂量达到2400μg/L时显著升高。1200μg／L摄入3、6月时MDA水平显著升高。在本实验条件下,血清甲状腺激素(TT4、TT3、TSH)水平无显著性改变；肝脏脱碘酶活性未发生显著性改变。④碘过量剂量依赖性和时间依赖性的摄入下调肝脏TRβ1和LDLR表达水平。与对照组相比,在2400μg／L和4800μg／L碘剂量组TRβ1和LDLR显著性降低,并与碘剂量显著性相关(LDLR:r=-0.748,<0.01；TRβ1:r=-0.847,P<0.01)；与对照组相比,1200μg/L碘摄入1月TRβ1、LDLR表达水平无显著变化,当摄入时间≥3月时TRβ1、LDLR表达水平显著性降低。
结论：本研究发现碘过量导致小鼠血清总胆固醇水平、低密度脂蛋白胆固醇水平升高,并呈剂量时间效应。在本实验条件下,甲状腺激素未发生改变时,血脂水平已发生改变,提示在碘过量摄入时,血脂的改变可能比甲状腺激素的改变更为敏感。肝脏TRpl和LDLR表达水平降低可能是碘过量导致血胆固醇升高的重要分子机制。
目的：建立碘过量联合高脂膳食小鼠动物模型,系统地观察在高脂膳食模式下,碘过量对小鼠血脂代谢影响的特点及时间、剂量效应关系。观察碘过量联合高脂膳食对机体的氧化／抗氧化平衡、甲状腺功能、甲状腺激素代谢的影响、以及对肝脏脂代谢相关基因表达的影响,进一步探讨碘过量联合高脂膳食对血脂代谢影响的机制。
方法：动物分组与碘剂量设置与第一部分相同。小鼠自由饮水、摄食。饲料为本实验室配制的高脂饲料。指标的检测方法与第一部分相同。
结果：①各碘过量联合高脂膳食组甲状腺出现胶质性甲状腺肿的改变,高剂量碘组动物甲状腺受损严重,出现了滤泡融合。高脂联合1200μg/L随时间的延长,甲状腺受损严重,出现了滤泡融合,部分滤泡破裂。②与正常饲料对照组相比,高脂饲料对照组氧化应激增加,高碘联合高脂膳食组,随着碘剂量的增加,机体氧化应激加剧。碘过量联合高脂膳食对机体氧化损伤具有协同作用。长期碘过量联合高脂膳食摄入降低小鼠SOD和GSH-Px活性,而升高MDA水平。③与高脂膳食对照组相比,高脂膳食联合碘剂量≤4800μg/L摄入1个月,小鼠血清中甲状腺激素、血脂水平未发生显著改变。1200μg／L联合高脂膳食≥3月时,小鼠血清中甲状腺激素改变表现为：总甲状腺激素(TT4)、总三碘甲状腺原氨酸(TT3)升高,促甲状腺激素(TSH)降低。血脂代谢改变的主要表现为：血清中总胆固醇、总甘油三酯、低密度脂蛋白胆固醇水平显著性降低。④与高脂膳食对照组相比,高脂膳食联合碘剂量≤4800μg／L摄入1个月,LDLR和SR-BI表达无显著改变。1200μg/L碘联合高脂膳食摄入一个月对LDLR和SR-BI表达无影响,随着时间的延长,当摄入3个月和6个月时,LDLR表达显著升高,并与TT3水平和血脂变化一致。
结论：长期碘过量联合高脂膳食,加剧机体氧化应激水平造成甲状腺损伤,导致甲状腺激素代谢紊乱(总甲状腺激素、总三碘甲状腺原氨酸升高,促甲状腺激素降低),继而引起血脂代谢改变(血清中总胆固醇、总甘油三酯、低密度脂蛋白胆固醇水平降低)。LDLR表达水平的升高可能是碘过量联合高脂膳食引起血脂代谢变化的分子机制。
目的：调查深圳市居民尿碘水平和血脂异常患病率,比较不同碘营养水平居民的血脂异常率,初步探索不同碘营养水平是否与血脂异常存在流行病学关联。开展问卷调查,对血脂异常的影响因素进行细致量化收集,采用多因素Logistic回归分析碘营养水平是否为血脂异常的影响因素。
方法：采取多级抽样的方法,随机抽取深圳市30岁以上326人作为调查对象。本次调查研究包括问卷调查(收集调查对象一般情况和各种食物的消费频率和消费量及身体活动情况等信息)、人体测量学指标测量(测量所有调查对象的身高、体重、腰围和血压)和实验室检测(采集所有调查对象的清晨空腹血液样本和清晨中段尿,测定空腹血糖,血脂以及尿碘水平)三部分内容。
结果：①本次抽样调查获得样本中,居民血脂异常患病率为33.72%,其中男性为39.02%,女性为31.28%。不同年龄血脂异常患病率差异显著,60-70岁年龄组血脂异常患病率最高为53.13%。②本次抽样调查获得样本总体尿碘中位数167.7μg/L。个体尿碘水平差异较大,尿碘最高者达到1705.5μg/L,尿碘最低为12μg/L。尿碘水平>300μg/L者占15.64%；尿碘水平200-300μg/L之间者占45.09%；③相关性分析表明,在尿碘水平<200μg/L时,高密度脂蛋白胆固醇异常降低与尿碘表现出线性负相关(rs=-0.164,p=0.031)；在尿碘水平>300μg/L时,高密度脂蛋白胆固醇异常降低与尿碘表现出线性正相关(rs=0.246,p=0.013)。其他血脂指标与尿碘无显著相关性。④多因素Logistic回归分析表明：年龄<60为血脂异常保护因素；高血糖、腹部肥胖为血脂异常危险因素。尿碘对血脂异常无显著性影响。
结论：深圳市居民血脂异常患病率较高,血脂异常防治工作十分迫切。深圳市居民尿碘水平在200μg/L以上的百分比较高,易引起碘过量的危害。本研究首次发现碘营养水平与HDL-C异常之间可能存在U型关系。尿碘水平在200-300μg/L之间时,血脂HDL-C异常的患病率最低,在尿碘水平<200μg/L或>300μg／L增加HDL-C异常的风险。碘营养水平是否为血脂异常的影响因素需要在大样本流行病学调查的基础上进一步研究。
Iodine is an essential trace element which is an essential constituent of the thyroid hormones.Thyroid hormones play an important role in the regulation of metabolism and growth. Adequate iodine intake lays solid foundation for maintaining normal thyroid function. Iodine deficiency disorders (IDD) have been prevalent in the world and created serious hazards to public health. The goal of eliminating iodine deficiency disease (IDD) has been achieved since Universal Salt Iodization (USI) policy has been widely carried out in many nations. With rapid global progress in correcting iodine deficiency, reports are increasingly appearing on the higher prevelance of all kinds of thyroid diseases caused by excessive iodine intake in the recent decades. Iodine excess and its health hazards are immerging as a new public health problem.
Present studies on the hazard effects of iodine excess were focus on its effect on thyroid function. Wheras studies on the extrathyroidal effects of the iodine excess are rare. However, our group has found the dyslipidemia caused by iodine excess in both rats and mice during the toxicological study of excessive iodine intake. In addition, the dose-dependent hypercholesterol effect of iodine excess has also been reported in laying hens by foreign scholars. Moreover, the first report on the epidemiological correlation between high water iodine and dyslipideima was published in domestic in 2009. Increasing evidences have suggested that iodine excess may have a potential effect on dyslipideima. Prevalence of dyslipidemia in China significantly increased in recent decades due to rapid economic growth, the higher living standards, as well as evident trends in Western dietary pattern. According to The Chinese Nutrition and Health Survey, prevalence of hyperlipidemia in adult was 18.8%, patients with hyperlipidemia were up to 160 million. Hyperlipidemia is the most important risk factor for cardiovascular disease. Every year China spends more than 200 billion yuan on medical expenses and labor costs due to cardiovascular diseases and it is also a heavy burden both to society and to the family. Therefore, the relationship between Iodine excess and dyslipidemia deserves more attention and further study.
Animal experiments and epidemiological study are combined in the present study. To investigate the time and dose effect of iodine excess on lipid metabolism and its underlying mechanism in animal models of iodine excess under different dietary patterns; To investigate the correlation between different iodine nutrition and the prevalence of dyslipidemia and further to determine wether the iodine nutrition is the risk factor for dyslipidemia. At present China is facing the adjustment of the strategy of Universal Salt Iodization, this study will further expand our knowledge on the potential hazards of iodine excess on health and the results will be instructive for reasonable iodine intake.
Aim of study:The aim of this study is to illustrate the physiological effects and potential mechanisms of excessive iodine intake on lipid metabolism.
Methods:Balb/c mice were given drinking water containing different levels of iodine for one month and treated with 1200μg/L iodine for different period time respectively. Plasma lipid parameters and serum thyroid hormones were measured. Hepatic type 1 deiodinase activity and oxidative stress parameters were evaluated. Expressions of hepatic genes were detected by real time polymerase chain reactions and Western blot.
Results:①Dose-dependent hypercholesterolemic effects were detected in mice (TC:r= 0.615, P＜0.01). Drinking 1200μg/L iodine water for 1 month had no significant effect on serum lipid metabolism while prolonged exposure induced an increase of serum cholesterol.②An obvious colloid goiter was observed in thyroid of mice exposed to high doses of iodine.The diameter of the thyroid Follicular gradually increased as the dosage of iodine increased.③Serum thyroid hormones were not affected by iodine throughout the study. Excessive iodine intake decreased the TAOC antioxidant ability and increased the MDA content in serum and liver mice in a dose-dependant manner. MDA level in serum and liver elevated obviously when iodie dosage was up to 2400μg/L. drinking 1200μg/L iodine water for 1 month did not affect oxidative stress parameters while prolonged exposure induced an increase of MDA level in serum and liver. Hepatic D1 activity was not affected by iodine throughout the study.④A dose-dependent attenuation of hepatic Low Density Lipoprotein receptor (LDLR) and Thyroid hormone receptorβ1 (TRβ1) expression were detected in parallel to the change of serum cholesterol. Treatment with 1200μg/L iodine water for 1 month did not affect LDLR and TRβ1 expression, while 3 months or 6 months exposure resulted in a decrease of their expression.
Conclusion:Present findings demonstrated a dose and time dependent hypercholesterolemic effects of iodine excess. Furthermore, our data suggests that TRβ1 mediated down regulation of hepatic LDLR gene may play a critical role in iodine excess induced hypercholesterolemic effects.
Aim of study:The aim of this study is to illustrate the combined effect of iodine excess and high fat diet on lipid metabolism and its mechanism.
Methods:Balb/c mice were given drinking water containing different levels of iodine for one month and treated with 1200μg/L iodine for different period time respectively. Animals were feed with high fat diet which was made in our laboratory.Plasma lipid parameters and serum thyroid hormones were measured. Expressions of hepatic genes were detected by real time polymerase chain reactions and Western blot.
Results:①an obvious colloid goiter was observed in thyroid of mice exposed to excessive iodine combined high fat diet.The weight of the thyroid gradually increased as the dosage of iodine increased. Follicular fusion and part of the Follicular rupture occurred in the 2400μg/L and 4800μg/L iodine combined high fat diet groups. The damage in the thyroid were gradually serious with prolonged exposure to 1200μg/L iodine combined high fat diet.②Iodine excess combined high fat diet led to a synergistic effect on oxidative damage in mice. Chronic iodine excess combined high fat diet intake resulted in a decrease of the SOD and GSH-Px activity and an increase of MDA level.③Compared with the high fat diet group, Iodine intake (≤4800μg/L) in drinking water combined high fat diet for 1 month had no effect on serum thyroid hormones (TT4,TT3,TSH) and serum lipids. Exposure to 1200μg/L iodine combined high fat diet for 3、6 month resulted in abnormal thyroid hormone metabolism (TT4、TT3 elevated,TSH dereased) and abnormal serum lipid metabolism (TC, TG, LDL-C decreased).④Compared with the high fat diet group, exposure to iodine excess combined high fat diet for 1 month (iodine dosage≤4800μg/L) did not affect LDLR and SR-BI expression; exposure to 1200μg/L iodine water combined high fat diet for 1 month did not affect LDLR and SR-BI expression, while 3 months or 6 months exposure resulted in an increase of LDLR expression.
Conclusion:Present findings demonstrated iodine excess combined high fat diet could cause damage to the thyroid and lead to thyroid hormone disorder. Those in turn resulted in the changes in serum lipids. Up regulation of hepatic LDLR gene might be an important molecular mechanism of the changes in serum lipids induced by iodine excess combined high fat diet.
Aim of study:To investigate the association between different iodine nutriton and the prevelance of dyslipidemia in a representative sample of subjects in Shenzhen and to investigate whether the abnormal iodine nutrition is the risk factor for dyslipidemia.
Study design:A total of 326 adult from 2 dififerent communities in shenzhen, aged 30 to 85 years were included in the study. Body weight and height were measured, the urine iodine concertration and serum lipid and serum glucose level were measued. A questionnaire was given to the subject about general information and risk factors for dyslipidemia.
Results:①the prevalence of dyslipidemia in the sample was 33.72%, males 39.02% and females 31.28%. The prevalence of dyslipidemia was significantly different among different age groups. The highest prevalence of dyslipidemia was 53.13% in 60 to 70 age group.②the median urinary iodine in the sample was 167.7μg/L. there were large individual differences in level of urinary iodine, with the 15.64%; urinary iodine concentration 200-300μg/L accounted for 45.09% in the sample.③when the urine iodine concentration<200μg/L,There is a reverse relationship between iodine nutrition and prevalence of HDL-C(rs=-0.164,p=0.031); when the urine iodine concentration>300μg/L,There is a positive relationship between iodine nutrition and prevalence of HDL-C(rs=0.246,p=0.013); there was no significant correlation between Other lipid parameters and urinary iodine concentration.④Multivariate Logistic regression analysis showed that:Age, high blood glucose, abdominal obesity was significantly related the prevalence of dyslipidemia; urine iodine concentration was no significant correlation the prevalence of dyslipidemia.
Conclusion:the prevalence of dyslipdemia in Shenzhen is high, the prevention and treatment of dyslipidemia is in an urgent need. The percent of urinary iodine above 200μg/L is high in local residents and there may be a risk of iodine excess and its hazard effect. There may be a U typed relationship between iodine nutrition and the prevalence of HDL-C abnormality. Further studies are needed to make sure whether iodine nutrition is an influencing factor of dyslipidemia
引文
[1]Alsayed A, Gad AM, Abdel-Baset H, et al. Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women. Endocr J 2008,55:601-605.
[2]Camargo RY, Tomimori EK, Neves SC, et al. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol.2008,159:293-299.
[3]Izzeldin HS, Crawford MA, Jooste PL. Population living in the Red Sea State of Sudan may need urgent intervention to correct the excess dietary iodine intake. Nutr Health.2007,18:333-341.
[4]Seal AJ, Creeke PI, Gnat D, et al. Excess dietary iodine intake in long-term African refugees. Public Health Nutr.2006,9:35-39.
[5]Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006,354:2783-2793.
[6]肖东楼,孙殿军,白呼群等.《2005年中国碘缺乏病监测》.北京：人民卫生出版社,2007,3-4.
[7]Knobel M, Medeiros-Neto G. Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arq Bras Endocrinol Metabol.2007, 51:701-712.
[8]Rose NR, Bonita R, Burek CL. Iodine:an environmental trigger of thyroiditis. Autoimmun Rev.2002,1:97-103.
[9]Roti E, Uberti ED.Iodine excess and hyperthyroidism. Thyroid. 2001,11:493-500.
[10]Zhao J, Wang P, Shang L, et al. Endemic goiter associated with high iodine intake. Am J Public Health.2000,90:1633-1635.
[11]Guo H, Yang X, Xu J, Hou X, Sun X.Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res.2006,113:281-295.
[12]Lewis PD. Responses of domestic fowl to excess iodine:a review. Br J Nutr 2004,91:29-39.
[13]Yang XF, Xu J, Hou XH, et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol 2006,22:725-730.
[14]Kroupova V KP, Kaufmann S, Kursa J & Travnicek J. Metabolic effects of giving additional iodine to laying hens. In:Barcelona:Spanish Branch, World's Poultry Science Association. Vet Med (Praha) 1998, p207-212.
[15]Perry GC LPHM. Iodine supplementation from two sources and its effect on egg output. Br Poult Sci.1989,30:973-974.
[16]Perry GC LPHM. Responses of the laying hen to dietary iodine supplementation. In:Proceedings of the 8th European Poultry Conference.1990, p 384-387.
[17]杨雪锋,庞红,徐健,等.碘过量对大鼠血清TC和TG水平的影响.卫生研究,2006,35(1)：108-110.[18] 徐健,杨雪锋,郭怀兰,等.硒对小鼠碘过量性脂代谢紊乱的干预作用研究.卫生研究,2006,35：52-54.
[19]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method. Methods.2001, 25:402-408.
[20]施新猷.现代医学实验动物学.第1版.北京：人民军医出版社.2000,71-82；179-180.
[21]李英华,刘福英.不同浓度碘离子诱发小鼠甲状腺肿的实验研究.中国地方病防治杂志2000,15(3)：139-140.
[22]叶艳,王琨,张璐,等.不同碘摄入量对大鼠碘代谢及甲状腺功能影响.中国公共卫生.2007,23(6)：714-716.
[23]陈祖培,刘德润,杨英奎.高碘地区与地方性高碘甲状腺肿。中国地方病学杂志.1998,17(6)：385-388.
[24]高秋菊,张世勇.高碘对胚胎毒性的实验研究.中国地方病防治杂志.1998,13(5)：269-271.
[25]高博,尹桂山.高碘对小鼠脑发育的影响.中华预防医学志,1997,31：134-136.
[26]阎玉芹,陈祖培.正确和规范化使用“尿碘”这一生物学指标.中国地方病学杂志.2002,21(6)：512-514.
[27]Yang XF, Xu J, Guo HL, et al.Effect of excessive iodine exposure on the placental deiodinase activities and Hoxc8 expression during mouse embryogenesis. Br J Nutr.2007,98:116-122.
[28]Teng X, Shan Z, Teng W, et al. Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice. Clin Exp Med.2009,9:51-59.
[29]Li HS, Carayanniotis G. Induction of goitrous hypothyroidism by dietary iodide in SJL mice. Endocrinology.2007,148:2747-2752.
[30]Koenig RJ. Regulation of type 1 iodothyronine deiodinase in health and disease.Thyroid.2005,15(8):835-840.
[31]Zavacki AM,Ying H, Christoffolete MA, et al.Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. Endocrinology. 2005,146(3):1568-1575.
[32]徐韬,安家敖,胡俊峰.高碘致甲状腺损伤的机制研究进展.国外医学卫生学册,2003,30(6)：337-341.
[33]Joanta AE, Filip A, Clichici S, et al. Iodide excess exerts oxidative stress in some target tissues of the thyroid hormones. Acta Physiol Hung 2006,366 (93):347-359.
[34]Vitale M., Matola TD. And, D'Ascoli F. Iodide excessive induces apoptosis in thyroid cells throμgh a p53-independent mechanism involving oxidative stress.Endocrinology,2000,141:598-605.
[35]项建梅,陈祖培,邸红军,等.高碘对小鼠抗氧化能力的影响.中国地方病学杂志,1999,18(4)：245-249.
[36]Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 1993,34:1637-1659.
[37]Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996,271:518-520.
[38]Covey SD, Krieger M, Wang W, et al. Scavenger receptor class B type I-mediated protection against atherosclerosis in LDL receptor-negative mice involves its expression in bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2003,23:1589-1594.
[39]Bhattacharya S, Balasubramaniam S, Simons LA. Regulation of low-density-lipoprotein metabolism in the rat. Biochem J 1986,234:493-496.
[40]Rudling M, Angelin B. Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice. FASEB J 2001,15:1350-1356.
[41]Lopez D, Abisambra Socarras JF, Bedi M, et al.Activation of the hepatic LDL receptor promoter by thyroid hormone. Biochim Biophys Acta 2007, 1771:1216-1225.
[42]Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986,232:34-47.
[43]Wade DP, Knight BL, Soutar AK. Hormonal regulation of low-density lipoprotein (LDL) receptor activity in human hepatoma Hep G2 cells. Insulin increases LDL receptor activity and diminishes its suppression by exogenous LDL. Eur J Biochem 1988,174:213-218.
[44]Gullberg H, Rudling M, Salto C, et al. Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice. Mol Endocrinol 2002,16:1767-1777.
[45]Oetting A, Yen PM. New insights into thyroid hormone action. Best Pract Res Clin Endocrinol Metab2007,21:193-208.
[46]Huang W, Wood C, L'Abbe MR, et al. Soy protein isolate increases hepatic thyroid hormone receptor content and inhibits its binding to target genes in rats. J Nutr 2005,135:1631-1635.
[47]Ness GC, Lopez D. Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone. Arch Biochem Biophys.1995,323:404-408.
[48]李书国,薛文通,李雪梅,等.我国居民膳食营养不平衡原因分析及对策.中国食物与营养2005,(10)：7-9.
[49]刘淼,李素梅,李秀维,等.高水碘摄入与血脂异常流行病关联的探索性研究.中华流行病学杂志2009,30(7)：699-701.
[50]阎玉芹,陈祖培.正确和规范化使用“尿碘”这一生物学指标.中国地方病学杂志.2002,21(6)：512-514.
[51]Mogami T, Andrus SB, Paolucci AM, et al. Effects of cholesterol and cholic acid supplements on rats fed low iodine diets. J Nutr.1963,81:39-47.
[52]Girard A, Andrus SB, Hegsted DM. Excretion of labeled thyroxine in the presence of cholesterol-cholic acid supplements. Metabolism 1966,15:714-719.
[53]Poncin S, Gerard AC, Boucquey M, et al. Oxidative Stress in the Thyroid Gland: From Harmlessness to Hazard Depending on the Iodine Content. Endocrinology,2008,149(1):424-433.
[54]Bednarczuk T., Pietrzykowski A., Slon M., et al. Pharmacologic effect of excess iodine on type I thyroxine 5'-deiodinase activity in rat thyroid. Endokrynol Pol, 1993,44:405-412.
[55]吴泰相,王家良,刘关键.高碘甲肿及碘致甲亢机制新假说：脱碘酶障碍学说.华西医学,2000,15：405-408.
[56]张文杰,宋光耀,王敬等.高脂饮食对老年大鼠氧化应激及脂质代谢的影响.中国老年学杂志.2007,27(16)：1567-1568.
[57]杨瑞丽,施用晖,李武等.硫辛酸对高脂饲料小鼠氧化应激与糖、脂代谢基因表达的影响.卫生研究.2008,37(5)：560-562.
[58]Issandou M. Pharmacological regulation of low density lipoprotein receptor expression:Current status and future developments. Pharmacol Ther,2006, 111(2):424-433.
[59]Yesilaltay A, Morales MG, Amigo L, et al. Effects of hepatic expression of The HDL-Receptor SR-BI on lipoprotein metabolism and female ferbility. Endocrinology,2006,147(4); 1577-1588.
[60]Roine P, Pekkarinen M, Karvonen MJ, et al. Diet arid cardiovascular disease in Finland. Lancet 1958,2:173-175.
[61]中国成人血脂异常防治指南制订联合委员会中国成人血脂异常防治指南2007中华心血管病杂志2007,35(5)：390-419.
[62]WHO, UNICEF, ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination:a guide for programme managers (Second edition) Geneva:World Health Organization.2001,36.
[63]王文《中国高血压防治指南》2005年修订版要点解析.医学与哲学：临床决策论坛版.2006,27(4)；9-13.
[64]卫生部疾病控制司中华医学会糖尿病学分会《中国糖尿病防治指南》(节选)中国慢性病预防与控制2004,12(6)：283-285.
[65]中国肥胖问题工作组数据汇总分析协作组.我国成人体重指数和腰围对相关疾病危险因索异常的预测价值：适宜体重指数和腰围切点的研究[J].中华流行病学杂志.2002,23(1)：5-10.
[66]李书国,薛文通,李雪梅等.我国居民膳食营养不平衡原因分析及对策.中国食物与营养2005,(10)：7-9.
[67]赵盘华,张坚,由悦等.中国15岁及以上人群血脂异常流行特点研究.中华预防医学杂志,2005,39(5)：306-310.
[68]国家“九五”科技攻关课题协作组我国中年人群心血管病主要危险固素流行现状放从80年代初至90年代未的变化趋势.中华心血管病杂志,2001,2(2)：74-79.
[69]张根红,李素梅.水源性高碘研究进展.河南预防医学杂志.2006,17：48-50.
[70]全国水源性高碘地区集中分布于黄泛区.中国地方病学杂志.2006,25：267-267.
[71]于志恒,陈崇义,等.中国高碘地方性甲状腺肿的发现历程和分布概况.中华预防医学杂志.2001,35：351-352.
[72]张红宇,罗若荣,邓辉萍.碘摄入量对妇女碘营养水平的影响.中国卫生工程学2005,4(4)：219-221.
[73]Suzuki H, Higushi T, Sawa K, et al.Endemic coast goiter in Hokkaido, Japan. Acta Endocrinol 1965,87:1020-1022.
[1]de Benoist B, McLean E, Andersson M, et al. Iodine deficiency in 2007: global progress since 2003. Food Nutr Bull,2008,29:195-202.
[2]Seal AJ, Creeke PI, Gnat D, et al. Excess dietary iodine intake in long-term African refugees. Public Health Nutr,2006,9:35-39.
[3]Camargo RY, Tomimori EK, Neves SC, et al. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol,2008,159:293-299.
[4]Alsayed A, Gad AM, Abdel-Baset H, et al. Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women. Endocr J,2008,55:601-6055.
[5]Izzeldin HS, Crawford MA, Jooste PL. Population living in the Red Sea State of Sudan may need urgent intervention to correct the excess dietary iodine intake. Nutr Health,2007,18:333-341.
[6]Silva KD, Munasinghe DL. Urinary iodine concentration of pregnant women and female adolescents as an indicator of excessive iodine intake in Sri Lanka. Food Nutr Bull,2006,27:12-18.
[7]Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med,2006,354:2783-2793.
[8]Duarte GC, Tomimori EK, Boriolli RA, et al. [Echographic evaluation of the thyroid gland and urinary iodine concentration in school children from various regions of the State of Sao Paulo, Brazil]. Arq Bras Endocrinol Metabol,2004, 48:842-848.
[9]Rasmussen LB, Larsen EH, Ovesen L. Iodine content in drinking water and other beverages in Denmark. Eur J Clin Nutr,2000,54:57-60.
[10]Nishiyama S, Mikeda T, Okada T, et al. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine
intake. Thyroid,2004,14:1077-1083.
[11]Pedersen KM, Laurberg P, Nohr S, et al. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol,1999,140:400-403.
[12]Li M, Liu DR., Qu CY, et al. Endemic goitre in central China caused by excessive iodine intake. Lancet,1987,2:257-259.
[13]Zhao J, Chen Z, Maberly G. Iodine-rich drinking water of natural origin in China. Lancet,1998,352:2024.
[14]Suzuki H HT, Sawa K KS, Koniuchi Y. Endemic coast goiter in Hokkaido, Japan. Acta Endocrinol,1965,87:1020-1022.
[15]张根红,李素梅.水源性高碘研究进展.河南预防医学杂志,2006,17：48-50.
[16]全国水源性高碘地区集中分布于黄泛区.中国地方病学杂志,2006,25：267-267.
[17]于志恒,陈崇义,等.中国高碘地方性甲状腺肿的发现历程和分布概况.中华预防医学杂志,2001,35：351-352.
[18]Cohen-Lehman J, Dahl P, Danzi S, et al. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol,2010,6:34-41.
[19]Wolff. Iodide. Iodide goiters and Pharmacologic effect of excess iodide. Am J Med,1969,47:101-124.
[20]Suzuki H. Etiology of endemic goiter and iodide excess. In:Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. Iodine nutrition in health and disease,1985:237-253.
[21]WHO, UNICEF, ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination:a guide for programme managers (Second edition) Geneva:World Health Organization.2001;36.
[22]Vought RL, London WT. Iodine intake, excretion and thyroidal accumulation in healthy subjects. J Clin Endocrinol Metab,1967,27:913-919.
[23]Shivaraj G, Prakash BD, Sonal V, et al. Thyroid function tests:a review. Eur Rev Med Pharmacol Sci,2009,13:341-349.
[24]Knobel M, Medeiros-Neto G. Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arq Bras Endocrinol Metabol,2007, 51:701-712.
[25]Rose NR, Bonita R, Burek CL. Iodine:an environmental trigger of thyroiditis. Autoimmun Rev,2002,1:97-103.
[26]Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid,2001, 11:493-500.
[27]Zhao J, Wang P, Shang L, et al. Endemic goiter associated with high iodine intake. Am J Public Health,2000,90:1633-1635.
[28]Dussault JH, Ruel J. Thyroid hormones and brain development. Annu Rev Physiol,1987,49:321-34.
[29]Delange F. Iodine deficiency as a cause of brain damage. Postgrad Med J. 2001.77(906):217-220.
[30]于志恒.高碘甲状腺肿.中国地方病学杂志,1983：248-255.
[31]孙晓楼.地方性甲状腺肿和地方性克汀病流行区7-14岁学生智力调查初报.地方病通讯,1984：44-49.
[32]谢继良.水源性高碘地甲病区儿童智力调查研究.中国地方病防治杂志,1987：27-29.
[33]马洪涛,张华芳.高碘对儿童智力的影响.中国地方病防治杂志,1991,6：160-161.
[34]胡志忠,王兰英,林亮.高碘病区儿童智力水平调查.中国地方病学杂志,1994,13：167-168.
[35]赵金扣,张庆兰,尚莉,等.高碘摄入与儿童智力水平关系的研究.中国公共卫生,2004,20：516-518.
[36]Liu HL, Lam LT, Zeng Q, et al. Effects of drinking water with high iodine concentration on the intelligence of children in Tianjin, China. J Public Health
(Oxf),2009,31:32-38.
[37]王玲芳,王秀红,等.不同碘水平地区儿童智商与微量元素关系的研究.中国地方病防治杂志,2001,16：15-17.
[38]洪福贵,王会,等.沿海饮水型高碘病区儿童智力发育调查.中国公共卫生,2002,18：1490-1491.
[39]钱明,陈祖培,聂秀玲,等.碘过量对8-10岁学生智力发育的影响.中国公共卫生,2005,21：1064-1065.
[40]梁萍,任建庆.2000年江苏省徐州市高碘病区1631名中小学生智商调查.地方病通报,2005,20：111-111.
[41]高天舒,滕卫平,等.不同碘摄入量对农村学龄儿童甲状腺疾病及智商水平的影响.中华医学杂志,2001,81：453-456.
[42]王栋,刘澍平.高碘地区儿童的智力研究.中国地方病防治杂志.1987.2(6)：349-350.
[43]罗君,王传钢,孙宁.高碘地区不同碘摄入水平对儿童智力和精神运动功能的影响.中国地方病学杂志,2006,25：185-188.
[44]高博,尹桂山.高碘对小鼠脑发育的影响.中华预防医学杂志,1997,31：134-136.
[45]高秋菊,朱惠民.高碘对智力影响的实验观察.中国地方病学杂志,1999,18：104-106.
[46]李英华,朱惠民.高碘对仔鼠脑发育和智力的影响.中国地方病防治杂志,2000,15：10-11.
[47]李英华,朱惠民,郭影,等.高碘对多代仔鼠脑发育和智力影响的实验研究.中国地方病防治杂志,2000,15：68-70.
[48]周明,雷方,张富昌,等.大鼠孕期补碘性高碘对仔鼠脑发育的影响.中国地方病学杂志,2006,25：389-392.
[49]高秋菊,张世勇.高碘对小鼠大脑神经细胞超微结构的影响.中国地方病防治杂志,2000,15：270-272.
[50]周秀霞.高碘对脑、肾等组织损伤的研究.中国地方病学杂志.全国第五届
碘缺乏病学术会议论文专辑,1995：216.
[51]郭艺河,刘祥林.高碘性大、小鼠的大脑形态学观察.中国地方病防治杂志,1990,4：286-287.
[52]王世忠,康亚妮,刘皓,等.不同浓度碘酸钾对仔2代大鼠小脑Purkinje细胞的影响.中国临床解剖学杂志,2008,26：182-184.
[53]王俊艳,刘皓,刘金宝,等.碘过量对大鼠子代神经元特异性烯醇化酶表达的影响.中国地方病学杂志,2005,24：503-506.
[54]Kuiper GG, Kester MH, Peeters RP, et al. Biochemical mechanisms of thyroid hormone deiodination. Thyroid,2005,15:787-798.
[55]Bianco AC, Larsen PR. Cellular and structural biology of the deiodinases. Thyroid,2005,15:777-786.
[56]Guo H, Yang X, Xu J, et al. Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res,2006,113:281-295.
[57]PT Fox, ME Raichle, MA Mintun, et al. Nonoxidative glucose consumption during focal physiologic neural activity. Science,1988:462-463.
[58]崔红梅,梁玉,刘皓,等.碘缺乏和碘过量对成年大鼠海马神经元特异性烯醇化酶的影响.中国地方病防治杂志,2005,20：79-81.
[59]孙素菊,尹桂山,冯忠军.碘过量对仔鼠海马组织烯醇化酶活性的影响.中华预防医学杂志,2000,34：39-40.
[60]孙素菊,赵建宏.碘过量对仔鼠海马组织乙酰胆碱酯酶的影响.中国地方病学杂志,2000,19：174-176.
[61]高秋菊,刘爱国,刘辉,等.不同剂量碘对小鼠迷宫前、后大脑NO含量的影响.中国地方病防治杂志,2005,20：197-199.
[62]高秋菊,勾凌燕,王憬,等.不同剂量碘对迷宫前后鼠脑神经递质的影响.中国公共卫生,2005,21：710-711.
[63]王俊艳,刘皓,刘金宝,等.碘过量对后代鼠脑NSE和GFAP表达的影响.中国比较医学杂志,2007,17：18-21,10001.
[64]郭怀兰,冯景,杨雪锋,等.碘过量及补硒对仔鼠甲状腺激素水平及受体表达的影响.卫生研究,2007,36：175-177.
[65]帖利军,张瑞娟.高碘对新生鼠大脑神经生长相关蛋白表达的影响.中国地方病防治杂志,2000,15：332-334.
[66]侯晓晖,杨雪锋,孙秀发,等.硒对高碘仔鼠脑MBP基因表达的影响.卫生研究,2005,34：428-430.
[67]梁立武,张建荣,杨长春.高碘诱导脑细胞凋亡机制.武警医学院学报,2005,14：31-34.
[68]刘宇杰,肖建英,张欣,等.高碘对原代培养的大鼠皮层神经元细胞凋亡影响的实验研究.锦州医学院学报,2006,27：16-18.
[69]van TM, Blommaart PE, de Boer PA, et al. Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs. Dev Biol,2004,272:104-17.
[70]Dunn J, F. Damaged reproduction:the most important consequence of iodine deficiency. J Clin Endocr Metab.2001,86(6):2360-2363.
[71]Ammerman CB, Arrington LR, Warnick AC, et al. Reproduction and lactation in rats fed excessive iodine. J Nutr,1964,84:107-112.
[72]Arrington LR, Taylor RN Jr, Ammerman CB, et al. Effects of excess dietary iodine upon rabbits, hamsters, rats and swine. J Nutr,1965,87:394-398.
[73]Yang XF, Xu J, Hou XH, et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol, 2006,22:725-30.
[74]Yang XF, Xu J, Guo HL, et al. Effect of excessive iodine exposure on the placental deiodinase activities and Hoxc8 expression during mouse embryogenesis. Br J Nutr,2007,98:116-122.
[75]张建荣,杨长春,梁立武,等.碘过量对肾脏的损伤及机制初探.武警医学,2004,15：906-909.
[76]Pucci E, Chiovato L, Pinchera A. Thyroid and lipid metabolism. Int J Obes Relat Metab Disord,2000,24 Suppl 2:S109-112.
[77]刘淼,李素梅,李秀维,等.高水碘摄入与血脂异常流行病学关联的探索性研究.中华流行病学杂志,2009,30：699-701.
[78]徐健,杨雪锋,郭怀兰,等.硒对小鼠碘过量性脂代谢紊乱的干预作用研究.卫生研究,2006,35：52-54.
[79]杨雪锋,庞红,徐健,等.碘过量对大鼠血清TC和TG水平的影响.卫生研究,2006,35：108-110.
[80]Zhao LN, Xu J, Peng XL, et al. Dose and time-dependent hypercholesterolemic effects of iodine excess via TRbetal-mediated down regulation of hepatic LDLr gene expression. Eur J Nutr,2009.
[2]Camargo RY, Tomimori EK, Neves SC, et al. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol.2008,159:293-299.
[3]Izzeldin HS, Crawford MA, Jooste PL. Population living in the Red Sea State of Sudan may need urgent intervention to correct the excess dietary iodine intake. Nutr Health.2007,18:333-341.
[4]Seal AJ, Creeke PI, Gnat D, et al. Excess dietary iodine intake in long-term African refugees. Public Health Nutr.2006,9:35-39.
[5]Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med 2006,354:2783-2793.
[6]肖东楼,孙殿军,白呼群等.《2005年中国碘缺乏病监测》.北京：人民卫生出版社,2007,3-4.
[7]Knobel M, Medeiros-Neto G. Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arq Bras Endocrinol Metabol.2007, 51:701-712.
[8]Rose NR, Bonita R, Burek CL. Iodine:an environmental trigger of thyroiditis. Autoimmun Rev.2002,1:97-103.
[9]Roti E, Uberti ED.Iodine excess and hyperthyroidism. Thyroid. 2001,11:493-500.
[10]Zhao J, Wang P, Shang L, et al. Endemic goiter associated with high iodine intake. Am J Public Health.2000,90:1633-1635.
[11]Guo H, Yang X, Xu J, Hou X, Sun X.Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res.2006,113:281-295.
[12]Lewis PD. Responses of domestic fowl to excess iodine:a review. Br J Nutr 2004,91:29-39.
[13]Yang XF, Xu J, Hou XH, et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol 2006,22:725-730.
[14]Kroupova V KP, Kaufmann S, Kursa J & Travnicek J. Metabolic effects of giving additional iodine to laying hens. In:Barcelona:Spanish Branch, World's Poultry Science Association. Vet Med (Praha) 1998, p207-212.
[15]Perry GC LPHM. Iodine supplementation from two sources and its effect on egg output. Br Poult Sci.1989,30:973-974.
[16]Perry GC LPHM. Responses of the laying hen to dietary iodine supplementation. In:Proceedings of the 8th European Poultry Conference.1990, p 384-387.
[17]杨雪锋,庞红,徐健,等.碘过量对大鼠血清TC和TG水平的影响.卫生研究,2006,35(1)：108-110.[18] 徐健,杨雪锋,郭怀兰,等.硒对小鼠碘过量性脂代谢紊乱的干预作用研究.卫生研究,2006,35：52-54.
[19]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method. Methods.2001, 25:402-408.
[20]施新猷.现代医学实验动物学.第1版.北京：人民军医出版社.2000,71-82；179-180.
[21]李英华,刘福英.不同浓度碘离子诱发小鼠甲状腺肿的实验研究.中国地方病防治杂志2000,15(3)：139-140.
[22]叶艳,王琨,张璐,等.不同碘摄入量对大鼠碘代谢及甲状腺功能影响.中国公共卫生.2007,23(6)：714-716.
[23]陈祖培,刘德润,杨英奎.高碘地区与地方性高碘甲状腺肿。中国地方病学杂志.1998,17(6)：385-388.
[24]高秋菊,张世勇.高碘对胚胎毒性的实验研究.中国地方病防治杂志.1998,13(5)：269-271.
[25]高博,尹桂山.高碘对小鼠脑发育的影响.中华预防医学志,1997,31：134-136.
[26]阎玉芹,陈祖培.正确和规范化使用“尿碘”这一生物学指标.中国地方病学杂志.2002,21(6)：512-514.
[27]Yang XF, Xu J, Guo HL, et al.Effect of excessive iodine exposure on the placental deiodinase activities and Hoxc8 expression during mouse embryogenesis. Br J Nutr.2007,98:116-122.
[28]Teng X, Shan Z, Teng W, et al. Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice. Clin Exp Med.2009,9:51-59.
[29]Li HS, Carayanniotis G. Induction of goitrous hypothyroidism by dietary iodide in SJL mice. Endocrinology.2007,148:2747-2752.
[30]Koenig RJ. Regulation of type 1 iodothyronine deiodinase in health and disease.Thyroid.2005,15(8):835-840.
[31]Zavacki AM,Ying H, Christoffolete MA, et al.Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. Endocrinology. 2005,146(3):1568-1575.
[32]徐韬,安家敖,胡俊峰.高碘致甲状腺损伤的机制研究进展.国外医学卫生学册,2003,30(6)：337-341.
[33]Joanta AE, Filip A, Clichici S, et al. Iodide excess exerts oxidative stress in some target tissues of the thyroid hormones. Acta Physiol Hung 2006,366 (93):347-359.
[34]Vitale M., Matola TD. And, D'Ascoli F. Iodide excessive induces apoptosis in thyroid cells throμgh a p53-independent mechanism involving oxidative stress.Endocrinology,2000,141:598-605.
[35]项建梅,陈祖培,邸红军,等.高碘对小鼠抗氧化能力的影响.中国地方病学杂志,1999,18(4)：245-249.
[36]Dietschy JM, Turley SD, Spady DK. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res 1993,34:1637-1659.
[37]Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996,271:518-520.
[38]Covey SD, Krieger M, Wang W, et al. Scavenger receptor class B type I-mediated protection against atherosclerosis in LDL receptor-negative mice involves its expression in bone marrow-derived cells. Arterioscler Thromb Vasc Biol 2003,23:1589-1594.
[39]Bhattacharya S, Balasubramaniam S, Simons LA. Regulation of low-density-lipoprotein metabolism in the rat. Biochem J 1986,234:493-496.
[40]Rudling M, Angelin B. Growth hormone reduces plasma cholesterol in LDL receptor-deficient mice. FASEB J 2001,15:1350-1356.
[41]Lopez D, Abisambra Socarras JF, Bedi M, et al.Activation of the hepatic LDL receptor promoter by thyroid hormone. Biochim Biophys Acta 2007, 1771:1216-1225.
[42]Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986,232:34-47.
[43]Wade DP, Knight BL, Soutar AK. Hormonal regulation of low-density lipoprotein (LDL) receptor activity in human hepatoma Hep G2 cells. Insulin increases LDL receptor activity and diminishes its suppression by exogenous LDL. Eur J Biochem 1988,174:213-218.
[44]Gullberg H, Rudling M, Salto C, et al. Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice. Mol Endocrinol 2002,16:1767-1777.
[45]Oetting A, Yen PM. New insights into thyroid hormone action. Best Pract Res Clin Endocrinol Metab2007,21:193-208.
[46]Huang W, Wood C, L'Abbe MR, et al. Soy protein isolate increases hepatic thyroid hormone receptor content and inhibits its binding to target genes in rats. J Nutr 2005,135:1631-1635.
[47]Ness GC, Lopez D. Transcriptional regulation of rat hepatic low-density lipoprotein receptor and cholesterol 7 alpha hydroxylase by thyroid hormone. Arch Biochem Biophys.1995,323:404-408.
[48]李书国,薛文通,李雪梅,等.我国居民膳食营养不平衡原因分析及对策.中国食物与营养2005,(10)：7-9.
[49]刘淼,李素梅,李秀维,等.高水碘摄入与血脂异常流行病关联的探索性研究.中华流行病学杂志2009,30(7)：699-701.
[50]阎玉芹,陈祖培.正确和规范化使用“尿碘”这一生物学指标.中国地方病学杂志.2002,21(6)：512-514.
[51]Mogami T, Andrus SB, Paolucci AM, et al. Effects of cholesterol and cholic acid supplements on rats fed low iodine diets. J Nutr.1963,81:39-47.
[52]Girard A, Andrus SB, Hegsted DM. Excretion of labeled thyroxine in the presence of cholesterol-cholic acid supplements. Metabolism 1966,15:714-719.
[53]Poncin S, Gerard AC, Boucquey M, et al. Oxidative Stress in the Thyroid Gland: From Harmlessness to Hazard Depending on the Iodine Content. Endocrinology,2008,149(1):424-433.
[54]Bednarczuk T., Pietrzykowski A., Slon M., et al. Pharmacologic effect of excess iodine on type I thyroxine 5'-deiodinase activity in rat thyroid. Endokrynol Pol, 1993,44:405-412.
[55]吴泰相,王家良,刘关键.高碘甲肿及碘致甲亢机制新假说：脱碘酶障碍学说.华西医学,2000,15：405-408.
[56]张文杰,宋光耀,王敬等.高脂饮食对老年大鼠氧化应激及脂质代谢的影响.中国老年学杂志.2007,27(16)：1567-1568.
[57]杨瑞丽,施用晖,李武等.硫辛酸对高脂饲料小鼠氧化应激与糖、脂代谢基因表达的影响.卫生研究.2008,37(5)：560-562.
[58]Issandou M. Pharmacological regulation of low density lipoprotein receptor expression:Current status and future developments. Pharmacol Ther,2006, 111(2):424-433.
[59]Yesilaltay A, Morales MG, Amigo L, et al. Effects of hepatic expression of The HDL-Receptor SR-BI on lipoprotein metabolism and female ferbility. Endocrinology,2006,147(4); 1577-1588.
[60]Roine P, Pekkarinen M, Karvonen MJ, et al. Diet arid cardiovascular disease in Finland. Lancet 1958,2:173-175.
[61]中国成人血脂异常防治指南制订联合委员会中国成人血脂异常防治指南2007中华心血管病杂志2007,35(5)：390-419.
[62]WHO, UNICEF, ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination:a guide for programme managers (Second edition) Geneva:World Health Organization.2001,36.
[63]王文《中国高血压防治指南》2005年修订版要点解析.医学与哲学：临床决策论坛版.2006,27(4)；9-13.
[64]卫生部疾病控制司中华医学会糖尿病学分会《中国糖尿病防治指南》(节选)中国慢性病预防与控制2004,12(6)：283-285.
[65]中国肥胖问题工作组数据汇总分析协作组.我国成人体重指数和腰围对相关疾病危险因索异常的预测价值：适宜体重指数和腰围切点的研究[J].中华流行病学杂志.2002,23(1)：5-10.
[66]李书国,薛文通,李雪梅等.我国居民膳食营养不平衡原因分析及对策.中国食物与营养2005,(10)：7-9.
[67]赵盘华,张坚,由悦等.中国15岁及以上人群血脂异常流行特点研究.中华预防医学杂志,2005,39(5)：306-310.
[68]国家“九五”科技攻关课题协作组我国中年人群心血管病主要危险固素流行现状放从80年代初至90年代未的变化趋势.中华心血管病杂志,2001,2(2)：74-79.
[69]张根红,李素梅.水源性高碘研究进展.河南预防医学杂志.2006,17：48-50.
[70]全国水源性高碘地区集中分布于黄泛区.中国地方病学杂志.2006,25：267-267.
[71]于志恒,陈崇义,等.中国高碘地方性甲状腺肿的发现历程和分布概况.中华预防医学杂志.2001,35：351-352.
[72]张红宇,罗若荣,邓辉萍.碘摄入量对妇女碘营养水平的影响.中国卫生工程学2005,4(4)：219-221.
[73]Suzuki H, Higushi T, Sawa K, et al.Endemic coast goiter in Hokkaido, Japan. Acta Endocrinol 1965,87:1020-1022.
[1]de Benoist B, McLean E, Andersson M, et al. Iodine deficiency in 2007: global progress since 2003. Food Nutr Bull,2008,29:195-202.
[2]Seal AJ, Creeke PI, Gnat D, et al. Excess dietary iodine intake in long-term African refugees. Public Health Nutr,2006,9:35-39.
[3]Camargo RY, Tomimori EK, Neves SC, et al. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol,2008,159:293-299.
[4]Alsayed A, Gad AM, Abdel-Baset H, et al. Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women. Endocr J,2008,55:601-6055.
[5]Izzeldin HS, Crawford MA, Jooste PL. Population living in the Red Sea State of Sudan may need urgent intervention to correct the excess dietary iodine intake. Nutr Health,2007,18:333-341.
[6]Silva KD, Munasinghe DL. Urinary iodine concentration of pregnant women and female adolescents as an indicator of excessive iodine intake in Sri Lanka. Food Nutr Bull,2006,27:12-18.
[7]Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med,2006,354:2783-2793.
[8]Duarte GC, Tomimori EK, Boriolli RA, et al. [Echographic evaluation of the thyroid gland and urinary iodine concentration in school children from various regions of the State of Sao Paulo, Brazil]. Arq Bras Endocrinol Metabol,2004, 48:842-848.
[9]Rasmussen LB, Larsen EH, Ovesen L. Iodine content in drinking water and other beverages in Denmark. Eur J Clin Nutr,2000,54:57-60.
[10]Nishiyama S, Mikeda T, Okada T, et al. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine
intake. Thyroid,2004,14:1077-1083.
[11]Pedersen KM, Laurberg P, Nohr S, et al. Iodine in drinking water varies by more than 100-fold in Denmark. Importance for iodine content of infant formulas. Eur J Endocrinol,1999,140:400-403.
[12]Li M, Liu DR., Qu CY, et al. Endemic goitre in central China caused by excessive iodine intake. Lancet,1987,2:257-259.
[13]Zhao J, Chen Z, Maberly G. Iodine-rich drinking water of natural origin in China. Lancet,1998,352:2024.
[14]Suzuki H HT, Sawa K KS, Koniuchi Y. Endemic coast goiter in Hokkaido, Japan. Acta Endocrinol,1965,87:1020-1022.
[15]张根红,李素梅.水源性高碘研究进展.河南预防医学杂志,2006,17：48-50.
[16]全国水源性高碘地区集中分布于黄泛区.中国地方病学杂志,2006,25：267-267.
[17]于志恒,陈崇义,等.中国高碘地方性甲状腺肿的发现历程和分布概况.中华预防医学杂志,2001,35：351-352.
[18]Cohen-Lehman J, Dahl P, Danzi S, et al. Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol,2010,6:34-41.
[19]Wolff. Iodide. Iodide goiters and Pharmacologic effect of excess iodide. Am J Med,1969,47:101-124.
[20]Suzuki H. Etiology of endemic goiter and iodide excess. In:Stanbury JB, Hetzel BS, eds. Endemic goiter and endemic cretinism. Iodine nutrition in health and disease,1985:237-253.
[21]WHO, UNICEF, ICCIDD. Assessment of the iodine deficiency disorders and monitoring their elimination:a guide for programme managers (Second edition) Geneva:World Health Organization.2001;36.
[22]Vought RL, London WT. Iodine intake, excretion and thyroidal accumulation in healthy subjects. J Clin Endocrinol Metab,1967,27:913-919.
[23]Shivaraj G, Prakash BD, Sonal V, et al. Thyroid function tests:a review. Eur Rev Med Pharmacol Sci,2009,13:341-349.
[24]Knobel M, Medeiros-Neto G. Relevance of iodine intake as a reputed predisposing factor for thyroid cancer. Arq Bras Endocrinol Metabol,2007, 51:701-712.
[25]Rose NR, Bonita R, Burek CL. Iodine:an environmental trigger of thyroiditis. Autoimmun Rev,2002,1:97-103.
[26]Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid,2001, 11:493-500.
[27]Zhao J, Wang P, Shang L, et al. Endemic goiter associated with high iodine intake. Am J Public Health,2000,90:1633-1635.
[28]Dussault JH, Ruel J. Thyroid hormones and brain development. Annu Rev Physiol,1987,49:321-34.
[29]Delange F. Iodine deficiency as a cause of brain damage. Postgrad Med J. 2001.77(906):217-220.
[30]于志恒.高碘甲状腺肿.中国地方病学杂志,1983：248-255.
[31]孙晓楼.地方性甲状腺肿和地方性克汀病流行区7-14岁学生智力调查初报.地方病通讯,1984：44-49.
[32]谢继良.水源性高碘地甲病区儿童智力调查研究.中国地方病防治杂志,1987：27-29.
[33]马洪涛,张华芳.高碘对儿童智力的影响.中国地方病防治杂志,1991,6：160-161.
[34]胡志忠,王兰英,林亮.高碘病区儿童智力水平调查.中国地方病学杂志,1994,13：167-168.
[35]赵金扣,张庆兰,尚莉,等.高碘摄入与儿童智力水平关系的研究.中国公共卫生,2004,20：516-518.
[36]Liu HL, Lam LT, Zeng Q, et al. Effects of drinking water with high iodine concentration on the intelligence of children in Tianjin, China. J Public Health
(Oxf),2009,31:32-38.
[37]王玲芳,王秀红,等.不同碘水平地区儿童智商与微量元素关系的研究.中国地方病防治杂志,2001,16：15-17.
[38]洪福贵,王会,等.沿海饮水型高碘病区儿童智力发育调查.中国公共卫生,2002,18：1490-1491.
[39]钱明,陈祖培,聂秀玲,等.碘过量对8-10岁学生智力发育的影响.中国公共卫生,2005,21：1064-1065.
[40]梁萍,任建庆.2000年江苏省徐州市高碘病区1631名中小学生智商调查.地方病通报,2005,20：111-111.
[41]高天舒,滕卫平,等.不同碘摄入量对农村学龄儿童甲状腺疾病及智商水平的影响.中华医学杂志,2001,81：453-456.
[42]王栋,刘澍平.高碘地区儿童的智力研究.中国地方病防治杂志.1987.2(6)：349-350.
[43]罗君,王传钢,孙宁.高碘地区不同碘摄入水平对儿童智力和精神运动功能的影响.中国地方病学杂志,2006,25：185-188.
[44]高博,尹桂山.高碘对小鼠脑发育的影响.中华预防医学杂志,1997,31：134-136.
[45]高秋菊,朱惠民.高碘对智力影响的实验观察.中国地方病学杂志,1999,18：104-106.
[46]李英华,朱惠民.高碘对仔鼠脑发育和智力的影响.中国地方病防治杂志,2000,15：10-11.
[47]李英华,朱惠民,郭影,等.高碘对多代仔鼠脑发育和智力影响的实验研究.中国地方病防治杂志,2000,15：68-70.
[48]周明,雷方,张富昌,等.大鼠孕期补碘性高碘对仔鼠脑发育的影响.中国地方病学杂志,2006,25：389-392.
[49]高秋菊,张世勇.高碘对小鼠大脑神经细胞超微结构的影响.中国地方病防治杂志,2000,15：270-272.
[50]周秀霞.高碘对脑、肾等组织损伤的研究.中国地方病学杂志.全国第五届
碘缺乏病学术会议论文专辑,1995：216.
[51]郭艺河,刘祥林.高碘性大、小鼠的大脑形态学观察.中国地方病防治杂志,1990,4：286-287.
[52]王世忠,康亚妮,刘皓,等.不同浓度碘酸钾对仔2代大鼠小脑Purkinje细胞的影响.中国临床解剖学杂志,2008,26：182-184.
[53]王俊艳,刘皓,刘金宝,等.碘过量对大鼠子代神经元特异性烯醇化酶表达的影响.中国地方病学杂志,2005,24：503-506.
[54]Kuiper GG, Kester MH, Peeters RP, et al. Biochemical mechanisms of thyroid hormone deiodination. Thyroid,2005,15:787-798.
[55]Bianco AC, Larsen PR. Cellular and structural biology of the deiodinases. Thyroid,2005,15:777-786.
[56]Guo H, Yang X, Xu J, et al. Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res,2006,113:281-295.
[57]PT Fox, ME Raichle, MA Mintun, et al. Nonoxidative glucose consumption during focal physiologic neural activity. Science,1988:462-463.
[58]崔红梅,梁玉,刘皓,等.碘缺乏和碘过量对成年大鼠海马神经元特异性烯醇化酶的影响.中国地方病防治杂志,2005,20：79-81.
[59]孙素菊,尹桂山,冯忠军.碘过量对仔鼠海马组织烯醇化酶活性的影响.中华预防医学杂志,2000,34：39-40.
[60]孙素菊,赵建宏.碘过量对仔鼠海马组织乙酰胆碱酯酶的影响.中国地方病学杂志,2000,19：174-176.
[61]高秋菊,刘爱国,刘辉,等.不同剂量碘对小鼠迷宫前、后大脑NO含量的影响.中国地方病防治杂志,2005,20：197-199.
[62]高秋菊,勾凌燕,王憬,等.不同剂量碘对迷宫前后鼠脑神经递质的影响.中国公共卫生,2005,21：710-711.
[63]王俊艳,刘皓,刘金宝,等.碘过量对后代鼠脑NSE和GFAP表达的影响.中国比较医学杂志,2007,17：18-21,10001.
[64]郭怀兰,冯景,杨雪锋,等.碘过量及补硒对仔鼠甲状腺激素水平及受体表达的影响.卫生研究,2007,36：175-177.
[65]帖利军,张瑞娟.高碘对新生鼠大脑神经生长相关蛋白表达的影响.中国地方病防治杂志,2000,15：332-334.
[66]侯晓晖,杨雪锋,孙秀发,等.硒对高碘仔鼠脑MBP基因表达的影响.卫生研究,2005,34：428-430.
[67]梁立武,张建荣,杨长春.高碘诱导脑细胞凋亡机制.武警医学院学报,2005,14：31-34.
[68]刘宇杰,肖建英,张欣,等.高碘对原代培养的大鼠皮层神经元细胞凋亡影响的实验研究.锦州医学院学报,2006,27：16-18.
[69]van TM, Blommaart PE, de Boer PA, et al. Prenatal exposure to thyroid hormone is necessary for normal postnatal development of murine heart and lungs. Dev Biol,2004,272:104-17.
[70]Dunn J, F. Damaged reproduction:the most important consequence of iodine deficiency. J Clin Endocr Metab.2001,86(6):2360-2363.
[71]Ammerman CB, Arrington LR, Warnick AC, et al. Reproduction and lactation in rats fed excessive iodine. J Nutr,1964,84:107-112.
[72]Arrington LR, Taylor RN Jr, Ammerman CB, et al. Effects of excess dietary iodine upon rabbits, hamsters, rats and swine. J Nutr,1965,87:394-398.
[73]Yang XF, Xu J, Hou XH, et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol, 2006,22:725-30.
[74]Yang XF, Xu J, Guo HL, et al. Effect of excessive iodine exposure on the placental deiodinase activities and Hoxc8 expression during mouse embryogenesis. Br J Nutr,2007,98:116-122.
[75]张建荣,杨长春,梁立武,等.碘过量对肾脏的损伤及机制初探.武警医学,2004,15：906-909.
[76]Pucci E, Chiovato L, Pinchera A. Thyroid and lipid metabolism. Int J Obes Relat Metab Disord,2000,24 Suppl 2:S109-112.
[77]刘淼,李素梅,李秀维,等.高水碘摄入与血脂异常流行病学关联的探索性研究.中华流行病学杂志,2009,30：699-701.
[78]徐健,杨雪锋,郭怀兰,等.硒对小鼠碘过量性脂代谢紊乱的干预作用研究.卫生研究,2006,35：52-54.
[79]杨雪锋,庞红,徐健,等.碘过量对大鼠血清TC和TG水平的影响.卫生研究,2006,35：108-110.
[80]Zhao LN, Xu J, Peng XL, et al. Dose and time-dependent hypercholesterolemic effects of iodine excess via TRbetal-mediated down regulation of hepatic LDLr gene expression. Eur J Nutr,2009.