Prenatal programming of adult thyroid function by alcohol and thyroid hormones

Increasing evidence associates environmental challenges early in life with permanent alterations of physiological functions in adulthood. These changes in fetal environment can trigger physiological adaptations by the fetus, called fetal programming, which may be beneficial before birth but permanently influence the physiology of the organism. In this study, we investigated the potential connection between alcohol-induced decreased maternal thyroid function and the hypothalamic-pituitary-thyroid (HPT) function of adult rat offspring. Plasma 3,5,3'-triiodothyronine (T(3)), thyroxine (T(4)), and thyroid-stimulating hormone (TSH) levels were decreased in alcohol-consuming (E) dams on gestational day 21 compared with ad libitum- (C) and pair-fed (PF) controls. No significant differences were found in HPT function in young offspring (3 wk of age) between diet groups. However, adult fetal alcohol-exposed (FAE) offspring had significantly decreased levels of T(3) along with elevated TSH compared with control offspring. T(4) administration to the mother did not normalize the hypothyroid state of the adult FAE offspring. Interestingly, administration of T(4) to control pregnant dams decreased plasma T(3) of the adult female offspring only, whereas T(4) together with maternal alcohol consumption or pair-feeding led to decreased TSH and T(4) in the adult female offspring. Our results suggest that ethanol consumption and T(4) administration alter maternal HPT function, leading to prenatally programmed permanent alterations in the thyroid function of the adult offspring.     

Association between postpartum thyroid dysfunction and thyroid antibodies and depression.

OBJECTIVE--To define the relation between mood and autoimmune thyroid dysfunction during the eight months after delivery. DESIGN--Double blind comparison of the psychiatric status of women positive and negative for thyroid antibodies. Clinical examination and blood sampling for free triiodothyronine and thyroxine, thyroid stimulating hormone, and thyroid antibody concentrations at four weekly intervals. Psychiatric assessment at six, eight, 12, 20, and 28 weeks post partum. SETTING--Outpatient department of district hospital. PATIENTS--145 antibody positive women and 229 antibody negative women delivering between August 1987 and December 1989. MAIN OUTCOME MEASURES--Thyroid status. Number of cases of mental ill health by the general health questionnaire, research diagnostic criteria, Hamilton 17 item depression scale, hospital anxiety and depression scale, and Edinburgh postnatal depression scale. RESULTS--Six weeks after delivery the general health questionnaire showed 62 (43%) antibody positive women and 65 (28%) antibody negative women had mental ill health (chi 2 = 8.18, p less than 0.005). Follow up of 110 antibody positive and 132 antibody negative women showed significantly greater depression by research diagnostic criteria in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). CONCLUSION--Depressive symptoms are associated with positive thyroid antibody status in the postpartum period.     

甲状腺癌患者血清促甲状腺激素和甲状腺激素表达水平及临床意义

目的:探讨甲状腺癌患者血清促甲状腺激素和甲状腺激素表达水平及临床意义。方法:应用电化学发光方法检测甲状腺癌组、甲状腺良性病变组和正常对照组血清促甲状腺激素(TSH)和甲状腺激素(TT3、FT3、TT4、FT4)水平。结果:①血清TSH在三组中比较有统计学意义(P〈0.001),甲状腺癌组血清TSH水平(3.56±0.93ulU/ml)明显高于甲状腺良性病变组(2.82±0.70ulU/ml)和正常对照组(2.04±0.56ulU/ml);TSH与肿瘤病理分期和肿瘤大小呈正相关(P<0.05)。②血清FT3、FT4水平在三组中有统计学意义(均P〈0.001),甲状腺癌组FT3、FT4水平处于较低水平,二者均明显低于甲状腺良性病变组和正常对照组(P<0.001);FT3与肿瘤病理分期和淋巴结转移呈负相关(P<0.05)。③TT3和TT4水平在三组之间比较均无统计学意义(P>0.05)。结论:高水平TSH可增加甲癌复发的危险性。低甲状腺激素水平在甲状腺癌形成中可能起到一定的作用,因此可以将其作为预测甲癌复发的重要指标之一。     

Side population cells in anaplastic thyroid cancer and normal thyroid

Comparison of studies of cells derived from normal and pathological tissues of the same organ can be fraught with difficulties, particular with cancer where a number of different diseases are considered cancer within the same tissue. In the thyroid, there are 4 main types of cancer, three of which arise from follicular epithelial cells; papillary and follicular which are classified as differentiated, and anaplastic which is classified as undifferentiated.One assay that can be utilised for isolation of cancer stem cells is the side population (SP) assay. However, SP studies have been limited in part due to lack of optimal isolation strategies and in the case of anaplastic thyroid cancer (ATC) are further compounded by lack of access to ATC tumors. We have used thyroid cell lines to determine the optimal conditions to isolate viable SP cells. We then compared SP cells and NSP cells (bulk tumour cells without the SP) of a normal thyroid cell line N-thy ori-3-1 and an anaplastic thyroid cancer cell line SW1736 and showed that both SP cell populations displayed higher levels of stem cell characteristics than the NSP. When we compared SP cells of the N-thy ori-3-1 and the SW1736, the SW1736 SP had a higher colony forming potential, expressed higher levels of stem cell markers and CXCR4 and where more migratory and invasive, invasiveness increasing in response to CXCL12.This is the first report showing functional differences between ATC SP and normal thyroid SP and could lead to the identification of new therapeutic targets to treat ATC.     

Hormonal regulation of thyroid peroxidase in normal and transformed rat thyroid cells

The hormonal induction of thyroid peroxidase (TPO) mRNA is studied in the functional rat thyroid cell line FRTL-5 and compared to the induction of thyroglobulin (TG) mRNA and I- uptake. TPO and TG mRNAs are regulated by TSH and by insulin-like growth factor I (IGF-I) and/or insulin. However, while TPO is more sensitive to TSH regulation (5- to 6-fold increase vs. 2- to 3-fold increase by IGF-I), TSH and IGF-I are equally potent in increasing TG mRNA levels (3- to 4-fold). Regulation of I- uptake appears to be different: thus TSH greatly (15-fold) increases I- uptake, while IGF-I or insulin are completely ineffective. TPO and TG mRNAs and I- transport display different sensitivity to transformation of rat thyroid cells. Thus, when another differentiated rat thyroid cell line, the PC cells, are transformed by human c-myc (PC myc), TPO and TG mRNAs are both present at normal levels, while I- uptake is slightly decreased; in the PC cells transformed by polyomavirus middle-T-antigen (PC PyMLV) TPO mRNA is undetectable and I- uptake is greatly decreased, while TG mRNA is present at normal levels. All three differentiated functions are switched off in PC cells transformed by the cooperation of c-myc and polyomavirus middle-T-antigen (PC myc + PyMLV).     

Immunoelectron microscopic demonstration of thyroglobulin and thyroid hormones in rat thyroid gland

We have developed a post-embedding immunogold technique for electron microscopic localization and quantitation of thyroglobulin (TG), thyroxine (T4), and triiodothyronine (T3) in rat thyroid. Labeling for TG was located on rough endoplasmic reticulum, Golgi apparatus, exocytotic vesicles, luminal colloid, colloid droplets, and lysosomes, whereas labeling for thyroid hormones was located on luminal colloid, colloid droplets, and lysosomes. We tested different procedures of fixation, dehydration, embedding, polymerization, and immunoincubation to optimize ultrastructural preservation and immunolabeling. Fixation with glutaraldehyde and osmium was possible with retained antigenicity. Dehydration temperature and the choice of embedding resin were the two crucial factors for good immunolabeling. Low-temperature dehydration greatly improved immunolabeling and could be combined with embedding in the methacrylate LR White or the epoxide Agar 100 (equivalent of Epon 812) polymerized at 40-60 degrees C, as the temperature during subsequent embedding and polymerization was of little importance for the immunoreactivity. Labeling on LR White sections was always higher than on Agar 100 sections. Various etching procedures were tested without improved specific labeling. Etching with hydrochloric acid gave nonspecific labeling of certain cell compartments.     

Patterns of expression of cytoskeletal proteins in human thyroid gland and thyroid carcinomas

By two-dimensional gel electrophoresis of proteins insoluble in detergents and high-salt buffer and immunofluorescence microscopy with a panel of polypeptide-specific antibodies to proteins of intermediate filaments (IF) and desmosomes, we have characterized the cytoskeletons of normal human thyroid gland, several kinds of benign lesion (goiter, Hashimoto's and Graves' diseases, adenomas), and the major thyroid carcinomas (follicular, papillary, medullary, and anaplastic). In all these tissues, desmoplakins and cytokeratins 7, 8, 18, and 19 were identified. While cytokeratins 8 and 18 occurred in all epithelial cells and cytokeratin 7 was also rather widespread, cytokeratin 19 occurred in amounts variable between the different types of tissues and in normal thyroid gland was restricted to certain clusters of follicular epithelial cells. Of all samples studied, in none did we detect cytokeratins commonly associated with stratified epithelia such as cytokeratins 4-6, 10, and 13-17, indicating that these are infrequent, if at all present, in such tissues. Coexpression of cytokeratins with vimentin appears to occur constitutively in follicular epithelial cells of normal thyroid gland and is also frequent in the diverse carcinomas, though to various degrees. Medullary carcinomas are exceptional, not only because they express neuroendocrine markers, but also because they coexpress combinations of cytokeratin IFs with neurofilaments and/or vimentin IFs in some cases, but not all. The results are discussed in relation to states of cell differentiation in normal and diseased thyroid gland and with respect to their value in tumor diagnosis.     

Generation of oxygen free radicals in thyroid cells and inhibition of thyroid peroxidase

We examined whether superoxide (O(2)(-)) is produced as a precursor of hydrogen peroxide (H(2)O(2)) in cultured thyroid cells using the cytochrome c method and the electron paramagnetic resonance (EPR) method. No O(2)(-) or its related radicals was detected in thyroid cells under the physiological condition. The presence of quinone, 2,3-dimethoxy-l-naphthoquinone (DMNQ), or 2-methyl-1, 4-naphthoquinone (menadione), in the medium produced O(2)(-) and hydroxyl radicals (OH*); the amount of H(2)O(2) generation was also increased. Incubation of follicles with DMNQ or menadione inhibited iodine organification (a step of thyroid hormone formation) and its catalytic enzyme, thyroid peroxidase (TPO). This inhibition should be caused by reactive oxygen species because the two quinones, particularly DMNQ, exert their effect through the generation of reactive oxygen species. It is speculated that the site-specific inactivation of TPO might have occurred at the heme-linked histidine residue of the TPO molecule, a critical amino acid for enzyme activity because OH* (vicious free radicals) can be formed at the iron-linked amino acid. TPO mRNA level and electrophoretic mobility of TPO were not inhibited by quinones. Our study suggests that thyroid H(2)O(2) is produced by divalent reduction of oxygen without O(2)(-) generation. If thyroid cells happen to be exposed to significant amount of reactive oxygen species, TPO and subsequent thyroid hormone formation are inhibited.     

Prostaglandins and the thyroid

Prostaglandins (PG), PGE in particular, exert an effect similar to the stimulating one of thyroidotropic hormone (TTH), a basic regulator of the thyroid function, on the thyroid gland cells. Specific finding of the above compounds with plasma membranes of the gland cells is the first stage of their action. In most cases formation of the PGE-receptor complexes, is followed by the corresponding increase in the intracellular content of cAMP due to adenylate cyclase activation. PGE can be regarded as original extracellular local regulating agents formed in neighbouring (or the same) cells under the TTH effect and modulating the action of the latter on the regulated gland. In this case the regulating action of the hormone and PGE can be realized through the same mechanisms. Under conditions of the thyroid gland pathology against the background of the thyrotropic control weakening it is impossible to exclude the possibility of the independent PGE action on different parameters of the thyroid function or their participation in realization of the effects of other regulating agents.     

碘与甲状腺疾病

碘是人体必需的微量元素,是合成甲状腺激素（thyroid hormone,TH）的主要原料。人体内的碘主要从饮水及食物中获取。碘的摄入缺乏或过量,不仅对TH的合成及分泌有至关重要的影响,而且与甲状腺形态及多种甲状腺疾病的发生、发展及转归密切相关。加碘盐的推广有效预防了碘缺乏可能引起的相关疾病;而碘过量导致的甲状腺疾病谱和发病率的急剧变化,也引起各界高度重视。流行病学调查表明,碘的摄入量与甲状腺功能亢进、自身免疫性甲状腺炎、甲状腺功能减退、甲状腺肿大和甲状腺癌等疾病的发病率密切相关。针对碘的相关生物学问题,对近年来的基础研究和人群研究进行综述,希望借此抛砖引玉,引起相关部门的重视,提高人民群众对碘营养的科学认识水平。     

Flavonoids and thyroid disease

The most potent natural plant-derived compounds that can affect thyroid function, thyroid hormone secretion and availability to tissues is the group of flavonoids, i.e. plant pigments. They are present in our daily food, such as vegetables, fruits, grains, nuts, wine, and tea. Epidemiological studies suggest beneficial effects on health of flavonoids, which are commonly attributed to their activity as antioxidants. Experimental studies in vitro, however, showed inhibition of organification in thyroid cells and follicles by several flavonoids. Studies in vivo and vitro with synthetic and natural flavonoids showed displacement of T4 from transthyretin leading to disturbances in thyroid hormone availability in tissues. Radioactive labeled flavonoids appeared to be eliminated rapidly from the body mainly through excretion in the feces. In pregnant rats synthetic flavonoids cross the placenta and accumulate in the fetal compartment, including the fetal brain. Therefore, a high intake of flavonoids is contraindicated. In conclusion: flavonoids show strong interference with many aspects of thyroid hormone synthesis and availability.