| Objective: In recent years,the increase of thyroid stimulating hormone(TSH)level and the prevalence of subclinical hypothyroidism have become a phenomenon that cannot be ignored.However,the cause of this phenomenon is not clear.Age increase,thyroid antibody positive,BMI increase and abnormal iodine nutrition level are considered to be important related factors for the risk of increasing TSH and subclinical hypothyroidism.And abnormal sleep or circadian rhythm is also believed to affect thyroid function.However,in addition to thyroid antibody positive,other factors and the mechanism of TSH elevation have not been thoroughly studied.In the previous mechanism studies,there are few studies on the circadian rhythm of the hypothalamus-pituitary-thyroid axis.The influence of the circadian rhythm of the hypothalamus-pituitary-thyroid axis and the time difference of related hormones on the experimental results cannot be ruled out.The purpose of this study is to analyze the distribution characteristics of subclinical hypothyroidism in Chinese and American populations,and to find the factors related to the risk of TSH level and subclinical hypothyroidism。The study mainly studied the relationship between the biological clock and the rhythm of thyrotropin and thyroid hormone through the rat light-dark disorder model,Verify whether the abnormality of thyroid hormone synthesis related pathway caused by high iodine and high fat is related to the biological clock through the rat model of high iodine and high fat,inaddition,verify the relevant mechanism through the in vitro experiment.Method:Part I:The TIDE study included 74100 people and NHANES included 9058 people.All participants received questionnaires,thyroid and biochemical tests.Statistical analysis was carried out using the statistical method of complex sampling design.The generalized additive model is used to visualize the factors related to the increase of TSH level and the factors related to subclinical hypothyroidism.Part II: Build a rat model of light and dark disorder,detect the levels of TSH and thyroid hormone,and the expression levels of pituitary and thyroid biological clock and hormone synthesis-related genes.CUT&TAG sequencing was used to obtain the target gene of thyroid biological clock in rats.In vitro,human normal thyroid cell lines were interfered with CLOCK overexpression,CLOCK silencing and gradient concentration TSH,and the expression levels of thyroid biological clock related genes and hormone synthesis related genes were detected.Part III:The rats’ high iodine model and high fat model were constructed,and the levels of TSH and thyroid hormone,as well as the expression levels of pituitary and thyroid biological clock and hormone synthesis related genes were detected.The expression level of thyroid biological clock and hormone synthesis related genes was detected by iodine intervention with different gradient concentrations on human normal thyroid cell lines in vitro.Result:Part I: The prevalence of subclinical hypothyroidism in the Chinese population is13.04%,and the prevalence of subclinical hypothyroidism in the American population is 5.26%.Female,non-smoking,TPOAb positive,Tg Ab positive,BMI increase,age increase,urinary iodine concentration increase and triglyceride increase are common risk factors of subclinical hypothyroidism in the Chinese and American populations.The risk factors of Chinese population also include lower total cholesterol,lower high-density lipoprotein cholesterol,lower fasting blood glucose and higher diastolic blood pressure,while the risk factors of American population are also increased blood phosphorus and decreased blood chlorine.TSH,f T4,f T3 and t T4 are all related to sleep time.The prevalence of hypothyroidism,hyperthyroidism and subclinical hyperthyroidism in people who sleep for 7 to 8 hours is the lowest.The prevalence of hypothyroidism in people who sleep for a long time is higher than that in people who sleep for a short time.Part II:Compared with the normal group,the TSH and thyroid hormone levels of rats in the sleep deprivation group had no significant difference.The TSH levels of rats in the light-dark disorder group at 3 weeks were normal,and the TSH levels of rats in the light-dark disorder group at 3 months were increased.The expression of hormone synthesis genes in the pituitary and thyroid in the light-dark disorder group was abnormal and had rhythm disorder,and the expression of biological clock genes in the pituitary and thyroid were abnormal and had rhythm disorder.CUT&TAG sequencing identified potential transcriptional regulatory genes in rat thyroid gland.When CLOCK is silenced in human normal thyroid cell lines in vitro,the expression of CLOCK-regulated genes(PAX8,SCL5A5)decreases,When CLOCK is over-expressed,the expression of CLOCK-regulated genes(PAX8,SCL5A5)increases.Part III: Compared with the normal group,there was no significant difference in the TSH of the 10 times high iodine feeding group,the TSH of the 50 times high iodine feeding group was increased,and the TSH of the high fat group was not significantly different.The expression of hormone synthesis genes in the pituitary and thyroid of rats fed with high iodine was abnormal,but there was no rhythm disorder.The expression of biological clock genes in the pituitary and thyroid was abnormal,but there was no rhythm disorder.The expression and rhythm of thyroid hormone synthesis gene in rats fed with high fat were abnormal,and the expression and rhythm of thyroid biological clock gene were normal.In vitro,the expression of biological clock genes and some genes related to thyroid hormone synthesis in human normal thyroid cell lines decreased during the intervention of high iodine.Conclusion : We found that the prevalence of subclinical hypothyroidism in the Chinese population is much higher than that in the United States.We found new risk factors for subclinical hypothyroidism,such as increased triglyceride,increased blood phosphorus,decreased blood chlorine,and decreased high-density lipoprotein.We confirmed that sleep is associated with thyroid function and thyroid dysfunction.Thyroid hormone disorder may be partly caused by the disorder of TSH rhythm,and partly by the disorder of thyroid’s own biological clock.The disorder of TSH may also be affected by upstream hormones and the disorder of the pituitary’s own biological clock,but it needs further verification.Chronic iodine excess can lead to the increase of TSH level in rats,but it does not affect the rhythm of TSH and thyroid hormone,nor the rhythm of pituitary and thyroid biological clock,but the expression of biological clock transcription complex is reduced.The inhibition of high iodine on thyroid may be partly caused by thyroid biological clock.High fat inhibited the rhythm fluctuation of thyroid hormone synthesis gene in rats,but the effect of high fat on thyroid may have nothing to do with thyroid biological clock. |
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