| ObjectiveIodine is an essential element for thyroid hormone synthesis and iodine deficiency disorders (IDD) can seriously threaten the health of mankind. Universal Salt Iodization ( USI) has been recommended by international authoritative organizations to eliminate IDD, but excessive iodine has appeared with the elimination of IDD. In 2001, WHO and other international organizations put forward the evaluating standards of the iodine nutritional status according to median urinary iodine (MUI) of school -age children as follows: 100 - 199μg/L as adequate iodine intake, 200 -300μg/L as more than adequate iodine intake, and more than 300μg/L as excessive iodine intake.Our epidemiological study in three rural communities with different iodine intakes ( MUI are 103μg/L, 374μg/L and 615μg/L, respectively) showed that with the increment of iodine intake the prevalence of overt and .subclinical hypothyroidism increased. This indicated that the excessive iodine intake with MUI 300μg/L -600μg/L might lead to hypothyroidism.However, besides iodine, other trace elements such as selenium and zinc can also influence the thyroid function. In order to evaluate the effects of iodine, selenium and zinc status on hypothyroidism, serum selenium and zinc concentrations were measured in the patients with overt and subclinical hypothyroidism founded in the above 3 communities. 264 normal inhabitants (normal thyroid function and morphology, negative thyroid autoantibodies and blank personal and family history of thyroid diseases) were also included, and multifactor analysis was performed.Our epidemiological study found 121 cases of subclinical hypothyroidism, in which only 30% had positive thyroid autoantibodies. This suggested that the non - autoimmune factors might play an important role in the mechanism of iodine - induced hypothyroidism. In order to probe into the non - autoimmune mechamism of hypothyroidism caused by iodine excess with MUI 300u,g/L -600(xg/L, Wistar rats were chosen as study objects, since they have no tendency of autoimmunity. And the effects of iodine excess equal to 3 ~6 times physiological need on thyroid function and 5' deiodinase activity in several tissues of Wistar rats were observed. In addition, Wistar rats were also used to form iodine deficient animal models by iodine deficient diet. And the changes of thyroid function and 5' deiodinase activity were observed after iodine supplementation of 3 ~ 6 times physiological need, in order to evaluate the safety of 3 ~ 6 times iodine supplementation.MothodsEpidemiological study1. Subjects and indexes; Panshan, Zhangwu and Huanghua communities are mild iodine deficient, more than adequate iodine intake and excessive iodine intake areas, respectively. 3761 inhabitants from these 3 communities were examined for serum TSH, FT3, FT4, TPOAb, TgAb levels and urinary iodine concentration. Serum selenium and zinc concentrations were measured by atom absorption method in 158 patients with overt and subclinical hypothyroidism and 264 normal inhabitants (normal thyroid function and morphology, negative thyroid autoantibodies and blank personal and family history of thyroid diseases) founded in the above 3 communities.2. Diagnostic standard: Overt hypothyroidism can be diagnosed by TSH > 4. 8mU/L and FT4 < 10.3pmol/L; Subclinical hypothyroidism can be diagnosed by TSH > 4.8mU/L and FT4 > 10.3pmol/L.3. Statistical analysis: Data were inputted by EXCEL software, analyzed by SPSS11.5 software. x2testf ANOVA and t -test, were applied in single factor analysis. Logistic Regression and Multiple Linear Regression was applied formultifactor analysis.Animal experiment1. Groups and treatment of experimental animals(1) non - iodine deficient rats: 234 Wistar rats of 4 weeks age were provided by animal experiment center of China Medical University, male and female were equal in amount. All the animals were fed with normal diet and double distilled water ( DDW) for 3 months, then were divided into 3 groups, including normal control group, 3 - fold high iodine group and 6 - fold high iodine group. And they were fed with normal diet plus DDW, 300jxg/L and 660jAg/L iodine containing water, respectively. 12 rats of each group were killed at the 1st, 2" , 4th, 8th and 24th week after iodine supplementation, and 18 rats of each group were killed at the 12' week after iodine supplementation.(2)Iodine deficient rats:234 Wistar rats of 4 weeks age with male and female equal in amount were fed with iodine - deficient diet and double distilled water( DDW)for 3 months, then were divided into 3 groups, including iodine -deficient control group, 1 - fold iodine supplement group and 3 - fold iodine supplement group. And they were fed with iodine - deficient diet plus DDW, 100}jLg/L and 330u>g/L iodine containing water, respectively. Another 78 rats of 4 weeks age with male and female equal in amount were continuously fed with normal diet and DDW, served as a normal control group. 12 rats of each group were killed at the 1st, 2" , 4' , 8' and 24th week after iodine supplementation, and 18 rats of each group were killed at the 12 th week after iodine supplementation.2. Animal sample collection and preparation(1) 24 - hour urine were collected before the rats were killed, and kept at 20T! to measure urinary iodine concentration.(2) Rats were anesthetized by aether after weighed, blood was collected from the heart. Serum was kept at - 20T:, to measure TT3, TT4, FT3, FT4, rT3andTSH.(3)Thyroid, pituitary, liver and kidney were separated and put in liquid nitrogen rapidly after weighed, then saved at - 70t to determine tissue T3, T4 and rT3 content and 5' deiodinase activity.3. Experimental methods(1) Urinary iodine concentration was determined with arsenic cerium luminosity catalysis.(2) Serum TT3, TT4, FT3, FT4, rT3, TSH and tissue T3, T4 and rT3 content were measured with RIA method.( 3) liver and kidney microsome fractions were prepared by differential cen-trifugation method.(4) Thyroid and pituitary homogenates were prepared on the day for deiodi-nase activity detection.(5) Bradford method was employed to determine the protein content in microsome fractions of liver and kidney and homogenates of thyroid and pituitary.(6)5' deiodinase activities were determined with outer - ring labeled I -rT3 as the substrate.4. Statistical analysis: Data were inputted by EXCEL software, analyzed by SPSS11. 5 software. Urine iodine concentrations were expressed by median. ANOVA were applied for means comparison.ResultsEpidemiological study1. MUI of 3 areas were 103.15|xg/L, 374.76jxg/L, and 614.61 jxg/L,respectively , and the differences were significant. For normal inhabitants of these 3 areas, serum selenium median were 91. 35|xg/L, 89.43|xg/L and 82. 23fig/ L, respectively; serum zinc median were 0. 892 mg/L,0. 883 mg/L and 0. 787mg/L, respectively, without significant difference between these 3 areas.2. The single factor analysis result of hypothyroidism: with the increase of iodine intake, prevalence of overt hypothyroid and sub - clinical hypothyroid increased. There was no significant difference of age, sex distribution and serum selenium and zinc levels between hypothyroidism patients (overt and sub - clinical ) and normal inhabitants from the same area. Prevalence of overt and sub -clinical hypothyroidism in TPOAb positive population were significantly higher than those in TPOAb negative population. In addition, prevalence of overt hypo-thyroidism in female was significantly higher than that in male, prevalence rate of overt hypothyroidism in population more than 35 years old was significantly higher than that in population less than 35 years old.3. Logistic regression analysis of hypothyroidism showed that more than adequate iodine intake, excessive iodine intake and TPOAb positive were risk factors of hypothyroidism (including overt and sub - clinical hypothyroidism). The OR values were 6.646 % 13.103 and 20.424, respectively. No significant interactions between the risk factors were found.4. The single factor analysis for the relationship between iodine, selenium, zinc status and serum TSH level of normal inhabitants: With the increment of iodine intake serum TSH level of normal population increased. Serum selenium and zinc levels were inversely related with serum TSH levels, and the TSH levels of the persons whose serum selenium concentration ^80u,g/L and serum zinc concentration^0.75mg/L were significantly higher than those of the others.5. Multiple linear regression analysis showed that serum TSH levels of normal inhabitants were positively related with iodine intake and negatively related with serum selenium levels.Animal experiment:Non -iodine deficient rats1. MUI of normal control rats was 139.43jxg/L. MUI of 3 - fold and 6 -fold high iodine group were about 3-6 times higher than that of normal control group.2. The differences of rats body weights and relative weights of thyroid, pituitary, liver and kidney between different groups were not significant.3. With the increment of iodine intake, T4NT3and rT3 content in thyroid increased significantly, and the T3/ T4 ratio decreased.4. There was no significant difference of T4%T3and rT3 content in pituitary, liver and kidney between high iodine groups and normal controls, but T3 content in pituitary and liver showed decreasing tendency after 24 - week high iodine intake.5. Short - term high iodine intake could lower thyroid 5' Dl activity and the activity kept in the lower stage. Long - term high iodine intake could also make pituitary 5' D2 activity and liver, kidney 5' Dl activity decrease, but pitu-itary 5' Dl activity didnt change significantly.6. Short - term high iodine intake could lower serum TT4, TT3and FT4 levels and increase serum TSH level. Long - term high iodine intake could increase serum TT4, rT3and TSH levels and decrease serum TT3 level, but serum FT4 and FT3 levels didn' t change significantly.Animal experiment;iodine deficient rats1. MUI of iodine deficient control rats was 14. 55jxg/L, which was much lower than 139. 43u,g/L of normal control rats. Iodine supplementation made MUI increase significantly; MUI of 1 - fold and 3 - fold iodine supplement group were about 1 and 3 times higher than that of normal control group, respectively.2. The relative weights of thyroids in iodine deficient group were much higher than those in control group. Iodine supplementation could make the enlarged thyroids become smaller but they were still bigger than the normal ones. There was no significant difference of pituitary, liver and kidney relative weights between different groups.3. T4 NT3 and rT3 content in thyroids of iodine deficient rats were much lower than those of normal control group. After 24 -week iodine supplementation, thyroid hormones content in the thyroids of 1 - fold iodine supplement group reached the level of normal control group, but thyroid T4 content of 3 - fold iodine supplement group exceeded the level of normal control group, and the T3/ T4 ratio decreased.4. There was no significant difference of T4 and rT3 content in pituitaries between different groups. Pituitary T3 content in iodine deficient rats were slightly higher than those in normal control rats, and iodine supplementation didnt cause significant change of pituitary T3 content.5. T4 content in liver and kidney of iodine deficient rats were much lower than those of normal control group. Long - term 3 - fold iodine supplementation made T4 content in liver and kidney exceed the level of normal control group. T3 content in liver and kidney of iodine deficient rats were slightly higher than those in normal control rats, and iodine supplementation didn' t cause significant change of the T3 content. There was no significant difference of liver and kidney rT3content between different groups.6. Thyroid 5' Dl and pituitary 5' D2 activities of iodine deficient rats increased and could be drawn back by iodine supplementation. And the pituitary 5' D2 activity of 3 - fold iodine supplement group after 24 - week iodine supplementation was even lower than that of control group. liver and kidney 5' Dl activities of iodine deficient rats decreased and kept in the lower stage after iodine supplementation. There was no significant difference of pituitary 5' Dl activity between different groups.7. Thyroid function(1) In iodine deficient rats, serum TT4, FT4 and rT3 levels decreased significantly, but serum TT3and FT3 levels were normal or slightly above normal, serum TT3/TT4ratio, FT3/FT4ratio and TSH level increased.(2) Iodine supplementation made serum TT4,FT4 and rT3levels increased in a dose - dependent pattern. Serum TSH level decreased after iodine supplementation and showed a tendency to below the level of normal control rats.(3) After long - term iodine supplementation, thyroid function indexes of 1 - fold iodine supplement group reached the normal level, except the slightly elevated serum TT4 and rT3 levels. But for 3 - fold iodine supplement group, serum TT4, FT4 and rT3 levels were much higher and serum FT3 levels were lower than those of normal control group.Conclusions1. Excessive iodine intake and TPOAb positive were risk factors of hypot-hyroidism.2. Selenium and zinc status of adults didn' t take part in the occurrence of hypothyroidism in the above 3 communities.3. Iodine intake was positively whereas serum selenium was negatively associated with serum TSH levels.4. Long - term 3 ~ 6 - fold iodine excess increased the synthesis of thyroid hormone and resulted in thyroid hormone retention in the thyroid of non - iodine deficient Wistar rats, but goitors didn' t appear.5. Long - term 3 ~ 6 — fold iodine excess could inhibit 5' deiodinase activi-...
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