甲状腺激素调节脑发育的分子机制

本文复习了甲状腺功能减退时脑组织的病理变化和甲状腺激素影响脑发育的分子机制。     

甲状腺激素和脑发育

本文简介甲状腺激素对胎儿和婴幼儿脑发育的影响，作用机制及其临床意义。     

甲状腺激素对脑发育影响的研究进展

甲状腺激素(TH)在哺乳动物脑发育过程中具有重要作用。脑发育关键期TH缺乏,会造成一系列脑的生长发育障碍,表现为智力低下、运动失调以及瘫痪等临床症状。近年来,随着医学科学技术的迅猛发展,对甲状腺激素调控脑发育机制的研究已深入到分子水平,本文就甲状腺激素对脑发育的影响及其分子生物学研究现状的初步结果进行综述。1TH受体及其在脑内的分布甲状腺产生2种激素,即四碘甲状原氨酸(T4)和三碘甲状原氨酸(T3)。TH受体主要指三碘甲状原氨酸受体(T3R)。TH的作用是由T3R介导的,该受体在脑发育过程中的广泛表达对脑发育、分化及代谢具有…     

脑发育过程中的细胞凋亡与甲状腺激素的影响

甲状腺激素是维持脑发育的必需激素，甲状腺激素缺乏将导致脑发育障碍、脑细胞凋亡增加。甲状腺激素对脑细胞凋亡的影响可能是通过影响神经营养因子及其受体的表达与合成、也可能是通过直接ｂｃｌ－２／ｂａｘ等与凋亡有关的基因的表达与合成来实现。     

甲状腺功能减退对新生早期大鼠各脑区甲状腺激素受体mRNA表达的影响

目的探讨甲状腺功能减退（甲减）对新生早期大鼠各脑区甲状腺激素受体（TR）mRNA表达的影响。方法建立甲减Wistar大鼠动物模型，分别于仔鼠0、14、21、45d，用实时荧光定量PCR方法检测大脑、小脑、脑干和海马TR mRNA的表达。结果与对照组相比，各时间点甲减仔鼠各脑区TRα1 mRNA的表达量呈总体下调趋势，而甲减0d仔鼠大脑、小脑、脑干TRα2 mRNA表达量明显增高（t=8．18、6．23、3．68，P〈0．01），且45d仔鼠各脑区TRα2 mRNA表达量仍高于对照组（t大脑=5．50、t小脑=5．46、t脑干=4．10、t海马=11．83，P〈0．01），TRα1、TRα2 mRNA表达峰（21d）均延迟于对照组（14d）出现。甲减仔鼠TRβ1 mRNA表达变化趋势与对照组相一致，但45d仔鼠各脑区TRβ1 mRNA表达量均低于对照组（t大脑=4．64、t小脑=2．73、t脑干=3．90、t海马=5．07，P〈0．01或〈0．05）。结论甲减时甲状腺激素受体mRNA表达峰值的延迟出现以及异常的表达变化与克汀病脑损伤机制密切相关。     

妊娠期亚临床甲减大鼠对子代学习记忆能力及脑发育相关基因表达的影响

目的 通过建立妊娠期亚临床甲状腺功能减退(甲减)孕鼠动物模型,观察母鼠亚临床甲减对仔鼠行为学改变的影响,并从脑发育相关基因表达方面探讨母体亚临床甲减导致胎儿脑发育障碍的机制.方法将60只SPF级雌性成年Wistar大鼠随机分成3组(每组n=20):(1)亚临床甲减组:手术切除甲状腺,于背部皮下植入微渗泵,L-T4装入泵中持续泵入;(2)甲减组:手术完全切除甲状腺,术后注入等量生理盐水,作为阳性对照;(3)正常对照组(假手术组):行甲状腺切除假手术,术后注入等量生理盐水.取仔鼠出生后第3、7及21天海马组织,以实时定量PCR法检测各时间点脑源性神经营养因子(BDNF)、神经细胞黏附分子(NCAM)mRNA表达;以Western印迹法检测BDNF、Rap1的蛋白含量;第40天仔鼠进行Morris水迷宫学习与记忆测试.结果(1)与正常对照组比较,亚临床甲减组的仔鼠第3天BDNF mRNA和蛋白表达减弱(均P＜0.05),NCAM mRNA表达差异无统计学意义(P＞0.05);第21天Rap1蛋白表达明显增强(P＜0.05);水迷宫结果显示第44天逃避潜伏期明显高于对照组,第49天长时记忆试验中在目标象限游泳时间明显低于对照组(均P＜0.05).(2)与甲减组比较,亚临床甲减组的仔鼠出生后各时点BDNFmRNA及蛋白表达明显增强(P＜0.05或P＜0.01).Rap1蛋白表达明显降低(P＜0.05);水迷宫结果显示第44天逃避潜伏期明显低于甲减组,第49天长时记忆试验中在目标象限游泳时间明显高于甲减组(均P＜0.05).结论母体亚临床甲减的仔鼠空间学习能力及空间记忆能力均下降,其作用机制可能与甲状腺激素调控基因BDNF表达下调、Rap1表达升高有关.     

妊娠早期母亲亚临床甲状腺功能减退症对其后代脑发育影响的前瞻性研究

目的 研究妊娠早期母亲亚临床甲状腺功能减退症(甲减)对其20～30月龄后代智力和运动发育的影响.方法对来自沈阳市10家医院的妊娠8周左右的妇女1 761名,测定血清TSH、FT4、甲状腺过氧化物酶抗体(TPOAb)及尿碘水平.以TSH≥2.5 mIU/L为切点筛查到亚临床甲减孕妇38例,采用妊娠特异性甲状腺功能参考范围将其进一步分为两个亚组:A组(2.5 mIU/L≤TSH＜3.93 mIU/L),18例;B组(TSH≥3.93 mIU/L),20例.同时选择同一队列中30名甲状腺功能正常、TPOAb阴性的妊娠妇女作为对照组.对研究对象的后代在20～30月龄时进行智力和运动发育指数测评.结果妊娠早期母亲亚临床甲减组及A、B亚组后代平均智力评分分别比对照组低6.55、3.39和9.40分(P=0.001、P=0.125及P＜0.001),平均运动评分分别比对照组低6.31、4.35和8.07分(P=0.003、P=0.070及P=0.001).智力评分和运动评分与母亲血清TSH水平呈明显负相关(r=-0.425,P＜0.001;r=-0.394,P=0.001).多组间比较显示不同水平TSH影响后代智力和运动评分(F=9.277,P＜0.001;F=5.909,P=0.004).有序logistic回归分析显示母亲血清TSH≥3.93 mIU/L导致后代智力和运动评分降低的风险分别是对照组的8.66、6.27倍(OR=8.66,95%CI 2.72～27.57;OR=6.27,95%CI 2.03～19.34).结论采用妊娠特异性的诊断标准诊断的妊娠早期母亲亚临床甲减是其20～30月龄后代智力和运动发育评分减低的独立危险因素.     

甲状腺激素缺乏对发育期鼠脑蛋白激酶C活性的影响

目的 研究甲状腺激纱缺乏对发育期大鼠脑蛋白激素Ｃ（ＰＫＣ）活性的影响,以探讨甲状腺激素调节脑发育的机制。方法 以丙基硫氧嘧啶溶液灌胃造成大鼠围生期甲状模型,部分甲状仔嫌每日腹腔注射Ｔ４２μｇ／１００ｇ体重。收集５天、１５天和２５天的正常、甲减及Ｔ４－替代治疗仔鼠脑组织、测定脑组织胞液和膜ＰＫＣ活性。结果 生后５天、１５天和２５天的甲减仔鼠脑胞液ＰＫＣ活性组织,测定脑组织胞液和膜ＰＫＣ活性。结果 和     

甲状腺激素对体外培养大鼠脑细胞Ⅱ、Ⅲ型脱碘酶mRNA表达的影响

目的观察体外培养的大脑细胞Ⅱ、Ⅲ型脱碘酶(D2、D3)mRNA在甲状腺激素的作用下其表达量的变化。方法取胎龄15～18d Wistar大鼠脑组织,机械分散后接种细胞,培养12d后分成4组,按组分别加入100 nmol／L T3、T4、地塞米松,对照组不做处理。在培养的不同时间收集细胞提取RNA,半定量RT-PCR方法分析D2-mRNA和D3-mRNA的变化。结果 T3作用1、2、4、6 h后,D2-mRNA表达量比对照组降低9％- 11％(t值分别为13．94、5．76、15．01、12-30,p<0．05)。D3-mRNA表达量在作用4、6 h后有明显增加,电泳条带从无到较为清晰。T4作用后,D2-mRNA、D3-mRNA的表达量在各时间点未见明显的变化;地塞米松作用1、2、4、 6 h后,D2-mRNA表达量比对照组上调18％～26％(t值分别为14．29、10．89、15．55、10．38,P<0．05)。结论大鼠脑细胞在体外培养时,T3对D2-mRNA的表达有抑制的作用,对D3-mRNA的表达有促进作用;T4对D2- mRNA、D3-mRNA的表达无明显影响;地塞米松有促进D2-mRNA表达的作用,但不影响D3-mRNA的表达。     

Regulation of thyroid hormone availability in liver and brain by glucocorticoids

Glucocorticoids as well as thyroid hormones are essential for normal brain development. Exogenous glucocorticoids stimulate 3,3',5-triiodothyronine (T(3)) availability in circulation of birds and similar effects have been observed in sheep. Chicken data indicate that glucocorticoid administration also stimulates thyroid hormone metabolism in brain but the effects on local thyroid hormone concentrations are not known. Therefore, the current study: (1) determined local thyroid hormone availability in separate brain areas of 18-day-old embryonic chickens (E18) after injection of dexamethasone (DEX), and (2) investigated the impact on the thyroid hormone metabolic pathways in these brain parts and compared the results with the hepatic situation. For this, E18 chicken embryos were treated with a single intravenous dose of DEX (25 microg). Despite the decreased 3,5,3',5-tetraiodothyronine (T(4)) availability in the liver of the DEX treated embryos, the T(3) content was strongly increased, parallel to the plasma T(3) surge. This T(3) surge was primarily related to a fall in hepatic T(3) breakdown through a downregulation of the type III deiodinase (D3). The sulfation pathway in liver seems not to be affected by DEX. In all brain parts, DEX affects the T(3) production capacity by upregulation of the type II deiodinase (D2). This enables the brain to compensate for the decrease in T(4) availability, although the T(3) concentrations are not consistently increased like in plasma and liver. This observation points to the existence of a fine-tuning mechanism in brain that enables the brain to keep the T(3) concentrations within narrow limits.     

正常孕妇早中晚孕期的甲状腺激素参考值范围

目的 建立正常孕妇早、中、晚孕期的甲状腺激素参考值范围,为诊断、治疗、监测(或筛查)孕妇甲状腺疾病以及相关研究提供参考.方法 在碘营养充足地区一次性横断面调查孕妇及非妊娠妇女,通过统一设计的调查表和实验室检测结果严格筛选出505名不同孕期的正常孕妇和153名正常非妊娠妇女(作为对照),建立甲状腺激素参考值范围;甲状腺激素测定采用化学发光免疫测定方法,参考值范围采用中位数(P50)及双侧限值(P2.5和P97.5)表示.结果 进入本研究的所有妇女家庭均食用加碘盐,她们的尿碘中位数均达到了适宜水平,表明这些妇女不存在碘缺乏或碘过量.孕妇的TSH水平在孕早期明显低于非妊娠妇女(P<0.01),孕中期开始回升,但到孕晚期时仍未完全恢复到非妊娠水平;孕妇的FT4和FT3,随妊娠时间逐渐下降,孕中期和孕晚期均明显低于非妊娠妇女(P<0.01);孕妇的TT4和TT3自孕早期开始即明显升高(P<0.01),至孕中期达峰值,大约是非妊娠的1.5倍.结论 孕妇的甲状腺激素水平不同于非妊娠妇女,早、中、晚孕期之间也存在明显差异.因此,建立正常孕妇早、中、晚孕期的甲状腺激素参考值范围具有临床意义.     

乳头状甲状腺癌术后131I治疗后短期内TSH和甲状腺激素水平变化及临床意义

目的 探讨乳头状甲状腺癌(PTC)患者首次131I治疗清除残余甲状腺组织(清甲治疗)后第5天血清甲状腺功能指标的变化及临床意义.方法 PTC术后患者74例,首次131I清甲治疗剂量3.7 GBq,分别于131I治疗前1 d及治疗后第5天监测PTC患者血清FT3、FT4、TSH.以治疗前TSH水平分A、B两组:A组TSH＜30 mIU/L 22例,B组TSH≥30 mIU/L 52例.统计分析采用配对资料的符号秩和检验及相关性分析.结果 A组在131I治疗后第5天TSH下降87%,FT4升高88%,FT3升高87%,3项指标前后变化均有统计学意义(均P＜0.05),其中45%(10/22)患者达一过性甲状腺毒症水平.B组治疗后第5天三指标变化个体差异大,TSH小幅上升6%(P＞0.05);而FT4下降13%,FT3下降14%,前后变化有统计学差异(均P＜0.05).结论 针对PTC患者首次清甲治疗后短期内,部分患者甲状腺功能指标会升高甚至出现一过性甲状腺毒症,而另一些患者甲状腺激素只轻微下降,个体变化差异大.所以针对清甲治疗后的甲状腺激素替代和抑制治疗宜根据血清甲状腺功能指标监测结果制定个性化治疗计划.     

冠心病患者的血清甲状腺激素水平

冠心病伴心力衰竭患者血清FT3 水平显著降低 ,与射血分数呈正相关。冠心病患者血清FT3 水平下降并不是冠脉病变的直接后果 ,而与心功能障碍有关。     

Developmental changes of plasma inhibin, gonadotropins, steroid hormones, and thyroid hormones in male and female Shao ducks

Plasma samples from developing male and female Shao ducks were assayed for immunoreactive (ir-) inhibin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), steroid hormones, and thyroid hormones. In the male, plasma ir-inhibin significantly increased between 75 and 155 days posthatch, and then decreased slightly at day 165. Plasma FSH of male ducks decreased from day 35 to day 55, followed by progressive elevation until day 95. Plasma FSH of male ducks fell significantly at days 135 and 165, while plasma ir-inhibin rose to high level. In female ducks, plasma ir-inhibin remained low until the start of lay, and thereafter significantly increased at day 135. Plasma FSH fluctuated before day 95 and significantly rose at day 115, and decreased thereafter. In males, plasma LH did not vary significantly before day 135, however, plasma testosterone significantly increased from day 95 onwards. No changes in plasma LH were observed during development of female ducks. Plasma estradiol-17beta gradually increased reaching a peak level at day 135. Plasma progesterone did not vary significantly before day 135 and thereafter significantly increased. Both sexes showed a similar pattern in changes of plasma thyroid hormones during sexual development. There was a significant increase in plasma thyroxine (T4) at day 95, thereafter decreased. Plasma triiodothyronine (T3) was at high level at the earlier stage of development and significantly decreased at day 55. Significant increase in plasma T3 in male and female ducks was observed at 135 and 115 days, respectively. In conclusion, these results demonstrated that the rise in inhibin is correlated with age of sexual maturity in the female while the rise in inhibin significantly precedes sexual maturity in the male. There was a progressive increase in plasma steroid hormones towards sexual maturity, and there was no sex difference in the time course of thyroid hormones.     

The thyroid gland and thyroid hormones in Senegalese sole (Solea senegalensis) during early development and metamorphosis

We here describe the ontogeny and morphology of the thyroid gland in Senegalese sole (Solea senegalensis), and correlate these with whole body concentrations of thyroid hormones during early development and metamorphosis. Under our rearing conditions at 19.5 degrees C, most larvae entered metamorphosis in stage 1 at 15 days post-hatching (dph), and completed metamorphosis in stage 4 at 25dph. The onset of metamorphosis coincided with surges in whole body T4 and T3 concentrations. Crossmon's trichrome stain colored the lumen of follicular structures brightly red, and this co-localized with a T4-immunoreactivity. Thyroid follicles were first observed in stage 0 pre-metamorphic larvae at 5dph of age, and were detected exclusively in the subpharyngeal region, surrounding the ventral aorta. Increases in whole body thyroid hormone levels coincided with a 2(1/2)-fold increase in the total thyroidal colloid area in stage 1 larvae (aged 15dph) compared to stage 0 larvae (12dph). This was preceded by an approximately 40%-increase in the follicles' epithelial cell height in stage 0 larvae at 12dph compared to larvae at 5dph, and by an increase in the whole body T3/T4 ratio, indicative of an increase in outer ring deiodination. We conclude that in S. senegalensis there is a clear chronology in the activation of the thyroid gland that starts in early pre-metamorphic larvae.     

不同检测系统间甲状腺激素测定结果的偏倚分析及其可比性研究

利用4种化学发光检测系统测定患者新鲜血清中的甲状腺激素，探讨其结果的可比性和可接受性；研究表明个别的系统误差不能被接受，提示当同一检测项目存在两个以上的分析系统时，应进行方法比对和偏倚分析，以确保结果的准确稳定。