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To evaluate the relationship between smoking and both antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb) positivity in subjects from Panshan, Zhangwu, and Huanghua with mildly deficient, more than adequate, and excessive iodine intake, respectively. Smoking-related data were collected by questionnaire, and laboratory measurements of TPOAb, TgAb, and thyrotropin (TSH) were determined at baseline and follow-up. (1) A 1.48-fold increased risk of TPOAb positivity was found in smokers than in non-smokers after adjusting for confounders (age, sex, and areas) (OR[95% CI] = 1.48[1.12-1.95], p = 0.01). (2) Among female subjects, the prevalence of thyroid autoantibodies in smokers was increased than that in non-smokers in Panshan, Zhangwu, and Huanghua (TPOAb): 16.79 vs. 8.89%, 14.14 vs. 11.09%, 19.53 vs. 9.57%; TgAb 15.32 vs. 9.29%, 12.79 vs. 11.94%, 17.19 vs. 10.55%, respectively). The difference was significant in Panshan after adjusting for age. (3) Female long-term smokers (> 20 years) had an increased frequency of thyroid autoantibody positivity than non-smokers after adjusting for confounders (TPOAb OR[95% CI] = 1.60[1.10-2.34]; TgAb OR[95% CI] = 1.31[0.88-1.94]). (4) There was no difference in the incidence of thyroid autoantibodies among non-smokers, new smokers, and long-term smokers at follow-up. (5) TSH was greater in TPOAb-positive subjects than in seronegative smokers (1.56 vs. 1.20 mU/L, p < 0.001) and non-smokers (1.97 vs. 1.58 mU/L, p < 0.001). However, TSH was also greater in non-smokers than in smokers, regardless of whether subjects were positive (1.97 vs. 1.56 mU/L, p = 0.04) or negative (1.58 vs. 1.20 mU/L, p < 0.001) for TPOAb. Long-term smoking could increase the prevalence of thyroid autoantibodies in a population with mildly deficient iodine intake. TSH levels were lesser in smokers than in non-smokers and greater in subjects with thyroid autoantibody positivity than in seronegative subjects. The influence of smoking on TSH levels was independent of thyroid autoantibody levels.

Many studies focused on the association between thyroid disease and pregnancy outcomes. The present study explored the effect of iodine nutrition during the first trimester on pregnancy outcomes. One thousand five hundred sixty-nine pregnant, euthyroid women at ≤12 weeks of gestation in an iodine-sufficient area in China were recruited. According to the World Health Organization (WHO) criteria for iodine nutrition during pregnancy, participants were divided into four groups: adequate iodine (median urinary iodine concentration (UIC), 150-249 μg/L), mild deficiency (UIC, 100-150 μg/L), moderate and severe deficiency (UIC, <100 μg/L), and more than adequate and excessive (UIC, ≥250 μg/L) groups. Pregnancy outcomes, including abortion, gestational hypertension, pre-eclampsia, gestational diabetes mellitus (GDM), placenta previa, placental abruption, preterm labor, low birth weight infants, macrosomia, breech presentation, and cord entanglement, were obtained during follow-up. The results showed that there was no significant difference in general characteristics, including age, body mass index, abdominal circumference, systolic blood pressure, diastolic blood pressure, heart rate, smoking rate, and drinking rate, among the four groups. In the more than adequate and excessive group, thyroid-stimulating hormone (TSH) was greater and free thyroxine (FT4) was lower than any other groups but still within normal range. The thyroglobulin (Tg) level was greater in the moderate and severe deficiency group. The incidence of GDM was significantly greater in women with mild iodine deficiency than in women with adequate iodine nutriture (18.38 vs. 13.70%, p < 0.05). Compared with the adequate group, incidence of macrosomia was significantly greater in the more than adequate and excessive group (12.42 vs. 9.79%, p < 0.05). Mild iodine deficiency was an independent risk factor for GDM (odds ratio = 1.566, 95% confidence interval = 1.060-2.313, p = 0.024); more than adequate and excessive iodine was an independent risk factor for macrosomia (OR = 1.917, CI = 1.128-3.256, p = 0.016). In summary, during 1st trimester, both mild iodine deficiency and excessive iodine intake had adverse impacts on pregnancy outcomes in an iodine-sufficient area.

Purpose: MicroRNA-326 (miR-326), as a member of the microRNA (miRNA) family, which includes endogenous single-stranded, conserved, noncoding small RNAs, has been reported to play important roles in autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus. However, few studies of the role of miR-326 in autoimmune thyroiditis (AIT) have been published. Here, we explored the roles of miR-326 and the involved pathway in iodine-induced AIT., Methods: NOD.H-2 h4 mice, which are a model of human AIT, were randomly divided into a normal water control group and a high-iodine group. Mice in the high-iodine group were administered 0.05% NaI (~1000 times the normal daily iodine intake), and mice in the control group received sterile water. Furthermore, we evaluated small interfering RNA (siRNA) interference in spleen mononuclear cell experiments in vitro., Results: In this study, we found that Th17 cells were significantly increased with a high expression of miR-326 in an iodine-induced thyroiditis NOD.H-2 h4 mouse model. In addition, the expression of Ets-1 protein, a negative regulator of Th17 differentiation, was significantly decreased. Intriguingly, our analysis showed that Ets-1 protein expression was negatively correlated with miR-326 levels in AIT mice (r = -0.814, p < 0.01). Our study indicated that miR-326 inhibited Ets-1 protein expression and promoted the differentiation of Th17 cells during the onset and development of AIT. The addition of a miR-326 inhibitor reversed Th17 cell production and Ets-1 protein expression, supporting this hypothesis., Conclusions: The results of our study suggest that miR-326 may target the Ets-1 protein to contribute to iodide-induced thyroiditis, providing a new theoretical basis for the use of miRNA targeting therapy for the treatment of autoimmune diseases.

The purpose of this study is to determine the effect of prolonged iodine overdose on type 2 iodothyronine deiodinase (D2) ubiquitination-related enzymes. Male Wistar rats were fed different doses of iodine and were then euthanized at the 4, 8, 12, or 24 weeks (4w, 8w, 12w, or 24w) after iodine administration. Urinary iodine concentration (UIC), thyroid-stimulating hormone (TSH), total thyroxine (TT4), and total triiodothyronine (TT3) were determined. Real-time quantitative RT-PCR and Western blot were used to measure mRNA and protein expression levels of pituitary D2 as well as two D2-specific ubiquitin ligases [WD repeat and SOCS box-containing protein 1 (WSB-1), membrane-associated ring finger (C3HC4) 6 (MARCH6 or TEB4)] and two D2-specific deubiquitinating enzymes [ubiquitin-specific peptidase 20 (USP20) and ubiquitin-specific peptidase 33 (USP33)]. The mRNA and protein expression levels of USP19, a TEB4-specific deubiquitinating enzyme, were also measured. Prolonged high iodine intake significantly increased TSH expression. At 12w, TSH was 1.57-, 1.44-, and 2.11-fold of NI group in 6HI, 10HI, and 50HI groups, respectively. At 24w, TSH had increased to 2.11-fold in the 50HI group. The pituitary D2 protein level decreased at 12w and 24w; though the mRNA level did not change. Prolonged iodine intake increased mRNA and protein expression levels of pituitary WSB-1 and TEB4. High iodine intake had no discernible effects on USP20. Temporary increases in USP33 and USP19 mRNA levels were observed. The enzymes related to D2 ubiquitination change with prolonged high iodine intake. Increased D2 ubiquitination suppresses the activity of D2, causing a decrease in negative feedback of the hypothalamic-pituitary-thyroid axis.

Expression of the oncogene Twist1 is correlated with tumor development and metastasis. Recent studies have suggested that the epithelial-to-mesenchymal transition (EMT) is necessary for tumor progression and metastases. Little is known concerning the role of Twist1 and EMT in thyroid cancer. In the present work, the expression levels of Twist1 and one marker of EMT, vimentin, were measured in papillary thyroid carcinoma (PTC). The results showed Twist1 expression to be correlated only with cancer lymph node metastases (P = 0.004) and not with other clinicopathological indicators. Moreover, Twist1 expression was positively correlated with the expression of vimentin (r = 0.408, P = 0.003). In vitro studies further indicated that reducing Twist1 expression using short hairpin RNA against Twist1 can decrease the invasive and metastatic properties of PTC cells and that the down-regulation of Twist1 can reverse EMT by increasing the expression of E-cadherin and down-regulating the expression of vimentin in the PTC cell line IHH-4. To investigate the effects on Twist1, the PTC cell lines TPC-1 and BCPAP were treated with TNF-α, resulting in Twist1 up-regulation that was dependent on NF-κB activation. After the inhibition of NF-κB activity with Bay11-7082, the Twist1 mRNA and protein levels could not be increased. The decline in the Twist1 mRNA and protein levels rendered the cancer cells less invasive. Thus, we conclude that Twist1 plays an important role in the EMT of PTC via the NF-κB pathway.

Thyroid hormone is indispensable for fetal brain development, and maternal thyroid hormone deficiency is thought to result in severe and irreversible brain impairments in learning and memory. Epidemiological and animal studies by our group had shown that maternal subclinical hypothyroidism had significant negative impact on neurodevelopment. But, the underlying mechanisms responsible for these neurological alterations remain unclear. In the present study, we performed thyroidectomy and injected L-T4 daily in Wistar rats to induce maternal subclinical hypothyroidism. Our data indicated that the pups from subclinical group showed prolonged latencies during the learning process in the Morris water maze as compared to the control group. Transcription factor cAMP response element-binding protein (CREB) signaling pathway is closely associated with synaptic plasticity, learning, and memory. Consistent with behavioral results, Western blotting also showed decreased activation of three important upstream modulators of CREB signaling pathway: phospho-mitogen-activated protein kinases (P-ERK1/2), phospho-calcium-dependent-calmodulin kinase IV (P-CaMKIV), phospho-serine/threonine protein kinase AKT(P-AKT), as well as total CREB and phospho-CREB as compared to the control at postnatal day 7 (PND 7) in hippocampus. Our findings suggested that decreased activation of the CREB signaling pathway in pups was related to impairments of cognitive function caused by maternal subclinical hypothyroidism.

In this study, we researched the pattern of thyroid function of subclinical hypothyroid (SCH) women with levothyroxine (LT4) throughout pregnancy and determined the optimal dosages of LT4 for such women. 56 SCH pregnant women were followed regularly prospectively. They were divided into three groups: group A (n = 29. Baseline TSH between 2.5 and 5.0 mIU/L) received 50 μg/day of LT4; group B (n = 17. Baseline TSH between 5.0 and 8.0 mIU/L) received 75 μg/day of L-T4; group C (n = 10. Baseline TSH >8.0 mIU/L) received 100 μg/day of LT4. All the patients started LT4 therapy around the 8th gestational week. Serum TSH, free T4, and free T3 were measured at 4-week intervals throughout pregnancy. Among the thyroid function indexes, serum TSH changed quickly and decreased significantly 4 weeks after LT4 therapy. The change of serum FT4 responded drastically at the 12th gestational week. We also found that serum FT3 did not change much after LT4 therapy. 50, 75, and 100 μg/day can maintain serum TSH level of 79.3, 82.4, and 90.0 % of SCH women in definitive therapeutic goal in group A, B, and C, respectively. The LT4 dose need to be adjusted one or more times in 20.7, 17.6, and 10.0 % of the SCH women in group A, B, and C, respectively. The different LT4 dose can be chosen according to the baseline TSH levels of SCH women. The constant LT4 dose can maintain serum TSH levels of 79.3-90 % patients in the ideal range. A small part of patients require adjust therapy also during the second and third trimester. Therefore, careful follow-up of SCH pregnant women should be taken, and thyroid function should be tested every month until the end of pregnancy.

Iodine is an essential trace element for thyroid hormone synthesis and metabolism, either low or high intake may lead to thyroid disease, but the pathogenetic mechanisms by which iodine interacts with the thyroid autoimmune are poorly understood. We investigated the dynamic changes of CD4(+)CD25(+) regulatory T cells in NOD.H-2(h4) mice with iodine-induced autoimmune thyroiditis (AIT), and explore potential immune mechanism of AIT induced by iodine. NOD.H-2(h4) mice were randomly divided into two groups, and received plain water or water containing 0.005% sodium iodide. Eight weeks after iodine provision, the incidences of thyroiditis, relative weights of thyroids, and serum thyroglobulin antibody titers in the iodine-supplied groups were significantly increased compared to the control groups (p < 0.05). The AIT mice had fewer CD4(+)CD25(+)Foxp3(+) T cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01), and maintained relatively low levels during the development of thyroiditis. The changes described above aggravated gradually with the extension of iodine treatment. These data suggest that CD4(+)CD25(+) regulatory T cells may be involved in the pathogenesis and development of AIT induced by iodine.