高碘补充对母体及其子代甲状腺功能的影响及干预治疗改善疾病表现的实验研究

Iodine supplementation in severely iodine deficient areas is beneficial for improving maternal thyroid function. However, epidemiological studies indicate that excessive iodide intake during pregnancy and/or lactation period may lead to thyroid dysfunction. .Recently, we have identified a direct correlation between high iodide intake throughout pregnancy and lactation and autoimmune thyroiditis in maternal Wistar rats and their offspring (Journal of Trace Elements in Medicine and Biology, 2018.1.31, 47: 89-97). Interventional treatments targeting the basic etiology of iodine-induced thyroid diseases (namely through the adjustment of high iodide intake to normal iodide intake), and targeting on the decrease of vitamin D levels in serum and the infiltration of CD4+T lymphocytes which express vitamin D receptor (1,25(OH)₂D₃ administration), may improve the manifestations of the disease..Based on this, we propose to do the following:.(1).Establish a model of iodine-induced thyroid disease in maternal rats and their offspring, and establish methods for evaluating the function of thyroid, brain and heart, which closely related to clinical development..(2).In order to investigate the effects and mechanisms of different intervention treatments on iodine-induced thyroid disease models in maternal rats and their offspring at their different developmental stages (lactation day 21 in maternal rats, postnatal day 21 and 90 in the offspring), the levels of thyroid hormones and autoantibodies, the %thyroid uptake measured by quantitative SPECT, the proportion of CD4+T lymphocytes differentiation and cytokines, genomes and epigenetics were analyzed. We also plan to explore the effects of fertility of maternal rats and their offspring following different treatments. This study will pave a new way for theoretical basis and strategy on the improvement of iodine-induced thyroid disease at different developmental stages, and serve for scientific iodide supplementation, eugenics and childbirth.

补碘可改善严重碘缺乏地区孕产妇的甲状腺功能，而流行病学调查显示：孕期和/或哺乳期过量碘摄入易导致母体或子代甲状腺功能障碍。我们发现：孕期、哺乳期高碘摄入可导致母鼠及其子代自身免疫性甲状腺炎（2018发表），靶向碘致性甲状腺疾病病因的干预治疗（高碘调整为适碘）；靶向甲状腺浸润的CD4+T淋巴细胞共表达维生素D受体的干预治疗（给予1,25(OH)₂D₃）可改善疾病表现。基于此，我们拟利用孕期、哺乳期高碘补充所致的母体和子代碘致性甲状腺疾病模型，确立与临床密切相关的甲状腺、脑、心脏功能的评价方法，揭示干预治疗对不同发育阶段（母鼠哺乳21天及其子代出生后21天、90天）的影响和机制，特别是对甲状腺自身抗体、SPECT甲状腺摄取率、CD4+T细胞亚群及分泌细胞因子比例、基因组和表观遗传学的影响，并观察干预后母体二次生育和子代生育情况，为碘致性甲状腺疾病提供新的治疗策略，为科学补碘、优生优育服务。

我们率先报道正常成年Wistar大鼠短期碘过量摄入，甲状腺功能仍然可维持正常，体内过量碘可激活Nrf2并维持正常的甲状腺功能，Nrf2激活在碘过量诱导的甲状腺氧化应激和抗氧化防御之间架起了一座桥梁，并得到国内外同行的关注、引用和认可。由于孕产妇和新生儿是碘过量的易感人群，我们建立了母鼠孕期、哺乳期100倍高碘补充，子代继续高碘摄入至180天或120天或90天的动物模型，此模型可出现FT3、FT4水平降低，TSH水平升高伴自身抗体增高，维生素D3(VD3)水平下降，肝脂、血脂增高，心功能中代表心室收缩功能的LVEF和LVFS显著降低；脑功能改变表现为水迷宫的空间学习记忆能力下降，可能与甲状腺激素与TET3、TRβ1相互作用有关；血清脂肪酸谱分析发现PGs的增加和8,9-DHET水平的降低可能参与了高碘引起的甲状腺功能减退诱导的心脏功能障碍、高血压和血脂异常的进展。我们还建立了母鼠孕期、哺乳期5倍和10倍高碘，子代继续高碘摄入至产后16天或21天的动物模型，发现此模型母鼠和子鼠的FT3、FT4水平升高；血清和肝脂质 LDL-C、TG、TC 水平降低，可能和甲状腺激素影响脂质合成基因 ME、SREBP 1c mRNA和脂质清除基因 LDLR mRNA有关；脑海马和小脑中KLF9、TRα、TRβ和BDNF的表达增强，子代大鼠（尤其是5倍高碘组）的DHA和EPA代谢产物增加；心脏KLF9表达升高，抗氧化基因Txnrd2表达和血清5，6-EET降低。碘调整和/或补充1,25(OH)2D3对母鼠孕期、哺乳期100倍高碘补充，子代继续高碘摄入至90天的动物模型干预研究发现：碘调整4周后尿碘中位数发生显著改变，碘调整和/或补充1,25(OH)2D3可改善SPECT甲状腺摄取率，提高血清FT3和VD3的水平，抑制促炎细胞因子（IFNγ和IL-17A）的表达，增强抗炎细胞因子（IL-10）的表达，有助于SPECT甲状腺摄取率的改善；高碘调整为适碘和/或1,25(OH)2D3补充可改善高碘引起的甲状腺功能减退、肝脂代谢功能障碍和心肌收缩力下降，脂肪酸谱中EET和HETEs的增加可能有助于改善这些并发症。课题还通过复发性流产患者甲状腺相关基因多态性及受体表达分析及评价冠心病病人亚临床甲减的危险因素将基础研究与临床结合。