The Impact Of Iodine Deficiency And Iodine Excess On Thyroid Function And Its Regulation Mechanism

Iodine is an essential component for the synthesis of thyroid hormones. Thyroidfunction ultimately depends on appropriate iodine supply to the gland. Both iodinedeficiency and iodine excess will lead to thyroid dysfunction. Up to now, significantprogress has been accomplished in understanding the relationship between iodinedeficiency and thyroid disorders. However, the mechanism underlying the effect ofiodine excess on thyroid function remains unknown in part. Moreover, differentanimals show different ability to respond to iodine deficiency and iodine excess.Therefore, it is of great necessary to establish different animal models in vitro andtake a thorough evaluation of the impact of iodine intakes on thyroid function and itspossible regulation mechanism. In this study we tried to clarify these issues atdifferent levels and from various angles.After successfully establishing animal models of iodine deficiency and iodineexcess in Wistar rats and Babl/c mice, we examined the following parameters toinvestigate the thyroid function under different iodine nutritional status, i.e. iodinecontent in urine and thyroid tissue, thyroid hormones in serum and thyroid tissue, andthyroid morphology. Then by using the method of reverse-phase high performanceliquid chromatography (RP-HPLC) and ion-exchange chromatography combinedwith immunoassay, we measured the content of thyroid hormoneprecursors—monoiodothyronines (MIT) and diiothyronines (DIT) and the activity ofthyroid type 1 deiodinase respectively. The mRNA and protein expression level offour major proteins which direct the complex machinery of thyroid hormonesynthesis—sodium iodide sympoter (NIS), thyroid type 1 deiodinase (D1), thyroidperoxidase(TPO) and thyroglobulin (Tg) were determined by RT-PCR, real timequantitative PCR, western blotting and immunohistochemistry method. These studiesare pertinent to the understanding of the exact regulation mechanism by which iodineacts on thyroid function. Physiologically, thyroid function is controlled in two pathways, i.e.hypothalamic-pituitary-thyroid axis regulation and thyroid autoregulation. Our datashows that the fluctuation of iodine intakes will firstly result in the activation ofthyroid autoregulation. When the level of thyroid hormones in serum can not bemaintained, the hypothalamic-pituitary-thyroid axis will also be switched on to keepthe normal thyroid function. If this still doesn't work, the synthesis of thyroidhormones will be impaired and will lead to hypothyroidism. From the findings in thisresearch, we could draw the following conclusions:1. The impact of iodine deficiency on thyroid function1.1 Less iodine excreted through urine In both Wistar rats and Babl/c mice,the urinary iodine content in low iodine (LI) group was significantly lower than thatin normal iodine (NI) group.1.2 Increased iodide trapping The simulation of iodide uptake was due to anincrease in both NIS mRNA and protein expression levels. Furthermore,immunohistochemistry analysis indicates that most NIS was located at the basolateralmembrane of thyrocyte, which means they had the activity to transport iodide. Theimprovement of iodide uptake will keep the balance of iodine content in thyroid andmaintain the normal synthsis of thyroid, which has critical significance for the bodyto compensate for short-term iodine deficiency. When faced with long-term andsevere iodine deficiency, the iodine content in thyroid will finally decreased, whichcan be observed in LI groups in rats and mice.1.3 Increased T₃/T₄ ratio In case of iodine deficiency, the synthesis of MITand DIT was greatly decreased. At the same time, the D1 mRNA expression and itsactivity were remarkably elevated which prompt the conversion of T₄ to T₃. As aresult, though T₄ and T₃ was significantly lower in LI than that in NI, the T₃/T₄ ratioin LI was higher. The shift to increasing T₃ secretion may be very important for theadaptation to iodine deficiency because T₃ possesses about four times the metabolicpotency of T4 but requires only 75ï¼…as much iodine for synthesis. The assay ofthyroid hormone in serum indicated that during the early period of iodine deficiency, TT₃and FT₃ was lightly increased. When long-term and severe iodine deficiencyexists, thyroid function will not be maintained and manifestation of hypothyroidismwill finally occur.1.4 Up-regulated TPO expression This will accelerate iodide activation,organization and coupling of iodothyronines to improve thyroid hormones synthesis.1.5 Follicular hyperplastic goiter Long-term iodine deficiency will inducetypical diffuse goiter with follicular proliferation in both rats and mice. This may beattributed to the more secretion of TSH when hypothyroidism tendency occurs.1.6 No difference in species by producting iodine deficiency animal modelsBoth Wistar rats and Babl/c mice are sensitive to iodine deficiency. In this regardthere is no obvious discrepancy in these two models. But because the genome of ratshas proven to be more coincidental with the genome of human beings, therefore,Wistar rats are more suitable for establishing iodine deficiency models.Take together, these data demonstrate that Wistar rats and Babl/c mice displaythe capability to adapt to early stage of iodine deficiency to a certain extent, mediatedby hypothalamic-pituitary-thyroid axis regulation and thyroid autoregulation. Butwhen long-term and severe iodine deficiency exists, thyroid function will not bemaintained and hypothyroidism will finally occur.2. The impact of iodine excess on thyroid function2.1 More iodine excreted through urine In both rats and mice, the urinary'iodine content in high iodine (HI) groups was significantly higher than that in N1group, and in good accordance with the level of iodine intakes.2.2 Decreased iodide trapping Compared with NI group, NIS mRNA andprotein expression was greatly down-regulated. In addition, NIS protein was foundmainly in intracellular vesicles, other than at the cell membrane, which might be theindication of the loss of its activity. This phenomenon constitutes a highly specializedintrinsic autoregulatory system that protects the thyroid from high doses of iodide, butat the same time ensures adequate iodide uptake for hormone biosynthesis. Thereforethe iodine content in thyroid tissue was only lightly increased (2-5 folds) and was not paralleled to the iodine intake levels (50-100 folds).2.3 Decreased T₃/T₄ ratio Because iodine is supplied sufficiently, thebiosynthesis of MIT and DIT, especially DIT, was increased. There was an obvioustendency of decreasing in MIT/DIT ratio with increased doses of iodine intakes. Onthe other hand, D1 mRNA expression (rats and mice) and D1 activity (rats) wassignificantly lower in HI groups. Thyroid tissue hormone assay revealed that therewas a tendency of decreasing in T₃/T₄ ratio in both rats and mice HI groups, butsignificance was only seen in rats. The inhibition of D1 expression and activity maybe taken as an effective way to protect organism from impairment caused by toomuch T₃.2.4 Thyroid morphology Long-term iodine excess induced a typical colloidgoiter in Babl/c mice. As for Wistar rats, no colloid goiter appeared in anatomy, buthistological examination indicated the colloid abundant and TStH stimulatingsymptom exhibition at the same time. The more doses of iodine intakes, the moreobvious the TSH stimulating symptom exists, which may be taken as a manifestationof the switched on of the hypothalamic-pituitary-thyroid axis regulation.2.5 Distinct difference in iodine excess animal models Wistar rats and Babl/cmice display different capability to resist iodine excess in the following aspects:2.5.1 Their ability to keep the stability of iodine content in thyroid tissue seemeddifferent. The thyroid iodine content increased 5-fold in 50HI group of Babl/c mice,but only increased 2-fold in 100HI group of Wistar rats.2.5.2 Iodine excess greatly inhibited thyroid D1 activity in Wistar rats, but hadno obvious effect on Babl/c mice.2.5.3 Long-term iodine excess induced typical colloid goiter in mice, but not inrats.In conclusion, both Wistar rats and Babl/c mice exhibit certain tolerance toiodine excess through adaptation mechanism. If the regulation mechanism works,organism will maintain the normal thyroid function. If it doesn't work,hypothyroidism will occur. Since Babl/c mice is more sensitive to iodine excess, it may be a better in vitro model to analyze the mechanism involved in iodine excessand thyroid function.In summary, in the present study we investigate the impact of iodine intakes onthyroid function from both body level and molecular level. Our observations wouldbe of potential value for understanding the mechanism by which iodine exert its effecton thyroid function. This study also lays a foundation of methodology in relatedresearch field. We hope our study can provide new insight into the relationshipbetween iodine and thyroid function with implications ranging from basic to clinicalresearch.