Prenatal Exposure to NIS inhibitors, Iodine Deficiency, and Thyroid Dysfunction

项目总结/摘要 自闭症是一个日益严重的公共卫生问题，经济成本很高。自闭症谱系的快速增长 ASD患病率表明，非遗传因素可能导致ASD病因。 流行病学证据表明，母亲在怀孕期间甲状腺功能减退（甲状腺功能减退）， 与儿童ASD和其他神经发育障碍的风险增加有关。甲状腺过氧化物酶 一种甲状腺自身免疫的标志物TPO-Ab在孤独症先证者的家族中也明显较高 比对照组更好。甲状腺干扰物，高氯酸盐，硫氰酸盐和硝酸盐被选择用于此 因为已知它们抑制钠/碘同向转运体（NIS）的碘摄取。碘吸收. NIS对甲状腺激素合成至关重要，因为妊娠期间碘缺乏与 与母亲和胎儿甲状腺功能减退症的风险增加，甚至轻度碘缺乏症是已知的原因， 脑损伤产前暴露于NIS抑制剂通过甲状腺功能障碍的潜在因果途径 ASD病因学的概念化在实验和流行病学研究中有丰富的证据。因此我们 建议检查产前接触高氯酸盐、硫氰酸盐和硝酸盐是否与 甲状腺功能障碍，导致ASD的风险更大。为了验证我们的假设，我们计划利用一个 由NIEHS资助的加州大学戴维斯分校儿童中心发起的大型自闭症流行病学项目 环境健康被称为“大理石”（标记自闭症风险的婴儿-学习早期迹象）。 MARBLES是一项前瞻性研究，招募了520多名已有孩子的孕妇 旨在通过利用家族性复发来确定ASD的病因和早期标志物， 率~ 20%。在MARBLES，我们有多个尿液和血液样本，前瞻性地收集自 母亲在怀孕期间。为了实现我们的目标，我们将选择250名母亲， 怀孕期间的血液样本，并有一个孩子的最终诊断。产前暴露于NIS 抑制剂和母体碘状态，我们将分析从250名母亲收集的750份尿液样本。为 甲状腺激素和TPO-Ab，我们将分析从250名母亲那里收集的500份血液样本。那就 确定产前暴露于NIS抑制剂是否与甲状腺功能障碍有关（目标1）。我们将 还确定产前暴露于NIS抑制剂或母体甲状腺功能障碍是否与 ASD风险增加（目标2）。为了发现暴露混合物对甲状腺功能障碍和ASD的影响， 我们将采用各种先进的建模策略。我们预计，这个项目利用丰富的 一个严格的自闭症项目的资源将（1）产生关于一个潜在的偶然的强大和丰富的信息 从产前暴露于NIS抑制剂通过甲状腺功能障碍到ASD病因的途径;（2）确定 暴露于可能导致甲状腺功能障碍和/或ASD的NIS抑制剂的关键时间窗;和（3） 发现暴露混合物对甲状腺功能障碍和/或ASD的影响。

Project Summary/Abstract Autism is a growing public health concern with a high economic cost. The rapid increase in autism spectrum disorder (ASD) prevalence suggests that non-heritable factors are likely contributing to ASD etiology. Epidemiologic evidence has shown that maternal hypothyroidism (underactive thyroid) during pregnancy is associated with increased risk of child ASD and other neurodevelopmental disorders. Thyroid peroxidase antibody (TPO-Ab), a marker of thyroid autoimmunity, is also significantly higher in families of autism probands than in comparison subjects. Thyroid disruptors, perchlorate, thiocyanate, and nitrate are chosen for this project because they are known to inhibit iodide uptake at the sodium/iodide symporter (NIS). Iodide uptake at the NIS is essential for thyroid hormone synthesis because iodine deficiency during pregnancy is associated with increased risk of maternal and fetal hypothyroidism and even mild iodine deficiency is known to cause brain damage. A potential casual pathway from prenatal exposure to NIS inhibitors through thyroid dysfunction to ASD etiology is conceptualized with rich evidence in experimental and epidemiologic research. Thus, we propose to examine whether prenatal exposure to perchlorate, thiocyanate, and nitrate is associated with thyroid dysfunction, resulting in greater risk of ASD. To test our hypothesis, we plan to take advantage of a large autism epidemiology project initiated under the NIEHS-funded UC Davis Center for Children's Environmental Health known as “MARBLES” (Markers of Autism Risk in Babies – Learning Early Signs). MARBLES is a prospective investigation that has enrolled over 520 pregnant women who already have a child with ASD and is designed to identify causes and early markers of ASD by capitalizing on a familial recurrence rate of ~20%. In MARBLES, we have available multiple urine and blood samples prospectively collected from the mother during pregnancy. To achieve our goals, we will select 250 mothers who provided both urine and blood samples during pregnancy and have a child with a final diagnosis. For prenatal exposure to NIS inhibitors and maternal iodine status, we will analyze 750 urine samples collected from 250 mothers. For thyroid hormones and TPO-Ab, we will analyze 500 blood samples collected from 250 mothers. Then, we will determine whether prenatal exposure to NIS inhibitors is associated with thyroid dysfunction (Aim 1). We will also determine whether prenatal exposure to NIS inhibitors or maternal thyroid dysfunction is associated with increased risk of ASD (Aim 2). To discover the impact of exposure mixtures on thyroid dysfunction and ASD, we will apply various cutting-edge modelling strategies. We anticipate that this project leveraging rich resources of a rigorous autism project will (1) yield robust and rich information about a potential casual pathway from prenatal exposure to NIS inhibitors through thyroid dysfunction to ASD etiology; (2) identify the critical time window of exposure to NIS inhibitors that may lead to thyroid dysfunction and/or ASD; and (3) discover the impact of exposure mixtures on thyroid dysfunction and/or ASD.