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

项目摘要/摘要 自闭症是一个日益严重的公共卫生问题，其经济成本也很高。自闭症谱系的迅速增加 疾病(ASD)的流行表明，非遗传因素可能是ASD病因的原因之一。 流行病学证据表明，孕期母亲甲状腺功能减退(甲状腺功能减退) 与儿童自闭症和其他神经发育障碍的风险增加有关。甲状腺过氧化物酶 作为甲状腺自身免疫标志的抗体(TPO-Ab)在自闭症先证者家族中也显著升高 而不是在比较对象中。甲状腺干扰物、高氯酸盐、硫氰酸盐和硝酸盐是为此而选择的 这是因为已知它们能抑制钠/碘同向转运体(NIS)的碘摄取。碘摄取率为 NIS对甲状腺激素的合成是必不可少的，因为孕期缺碘与 母亲和胎儿患甲状腺功能减退症的风险增加，甚至轻度缺碘也会导致 脑部受损。产前接触NIS抑制剂通过甲状腺功能障碍的潜在偶然途径 ASD的病因是概念化的，在实验和流行病学研究中有丰富的证据。因此，我们 建议检查产前暴露于高氯酸盐、硫氰酸盐和硝酸盐是否与 甲状腺功能障碍，导致患ASD的风险更大。为了检验我们的假设，我们计划利用 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“弹珠”(婴儿患自闭症风险的标记物-学习早期迹象)。 大理石是一项前瞻性调查，已经招募了520多名已经有孩子的孕妇 旨在通过利用家族性复发来确定ASD的原因和早期标志物 ~20%的比率。在弹珠中，我们有多种尿样和血液样本，这些样本是从 怀孕期间的母亲。为了实现我们的目标，我们将挑选250名母亲，她们同时提供尿液和 在怀孕期间采集血液样本，并生下最终确诊的孩子。用于产前暴露于NIS 我们将对250名母亲的750份尿样进行分析。为 甲状腺激素和TPO-Ab，我们将分析250名母亲的500份血液样本。那么，我们会 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)。我们会 还要确定产前暴露于NIS抑制剂或母亲甲状腺功能障碍是否与 增加自闭症风险(目标2)。为了发现暴露混合物对甲状腺功能障碍和自闭症的影响， 我们将应用各种尖端的建模策略。我们预计这个项目将利用RICH 一个严格的自闭症项目的资源将(1)产生关于潜在的偶然事件的可靠和丰富的信息。 从产前接触NIS抑制剂、甲状腺功能障碍到ASD病因学的途径；(2)确定 暴露于可能导致甲状腺功能障碍和/或自闭症的NIS抑制剂的关键时间窗口；以及(3) 发现暴露混合物对甲状腺功能障碍和/或自闭症的影响。

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.