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

产前接触 NIS 抑制剂、碘缺乏和甲状腺功能障碍

基本信息

批准号：
10453337
负责人：
Hyeong-Moo Shin
金额：
$ 28.4万
依托单位：
BAYLOR UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453337
关键词：
3 year old Accounting Antibodies Autoimmunity Blood specimen Brain Injuries Child Classification Detection Development Diagnosis Diagnostic Enrollment Environment Environmental Health Epidemiology Etiology Exposure to Family Functional disorder Funding Future Goals Gold Hypothalamic structure Hypothyroidism Individual Intake Intervention Investigation Iodide Peroxidase Iodides Iodine Lead Learning Modeling Mothers National Institute of Environmental Health Sciences Neurodevelopmental Disorder Nitrates Outcome Pathway interactions Perchlorates Population Pregnancy Pregnant Women Prevalence Prevention strategy Prospective cohort study Public Health Recurrence Research Resources Risk Risk Factors Role SLC5A5 gene Sampling Testing Thiocyanates Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyrotropin Thyroxine Time Triiodothyronine Urine Woman autism spectrum disorder autistic children base design economic cost environmental chemical exposure epidemiology study experimental study fetal improved inhibitor instrument iodine deficiency syndrome maternal risk pituitary thyroid axis prenatal prenatal exposure proband prospective thyroid disruption uptake

项目摘要

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.

项目概要/摘要自闭症是一个日益严重的公共卫生问题，其经济成本很高自闭症谱系的迅速增加。自闭症谱系障碍 (ASD) 的患病率表明，非遗传因素可能导致自闭症谱系障碍 (ASD) 病因。流行病学证据表明，妊娠期间母亲甲状腺功能减退症（甲状腺功能低下）与儿童自闭症谱系障碍和其他神经发育障碍的风险增加有关。甲状腺自身免疫标志物抗体（TPO-Ab）在自闭症先证者家族中也显着较高为此选择甲状腺干扰物、高氯酸盐、硫氰酸盐和硝酸盐。项目，因为已知它们可以抑制钠/碘同向转运体 (NIS) 的碘化物吸收。 NIS 对于甲状腺激素的合成至关重要，因为怀孕期间缺碘与母体和胎儿甲状腺功能减退症的风险增加，甚至轻度缺碘也会导致产前暴露于 NIS 抑制剂导致甲状腺功能障碍的潜在偶然途径。自闭症谱系障碍 (ASD) 病因学的概念已在实验和流行病学研究中得到了丰富的证据。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 风险增加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“MARBLES”（婴儿自闭症风险标记 - 学习早期迹象）。 MARBLES 是一项前瞻性调查，招募了超过 520 名已生孩子的孕妇患有自闭症谱系障碍（ASD），旨在通过利用家族复发来确定自闭症谱系障碍的原因和早期标志物在 MARBLES 中，我们有前瞻性地收集的多个尿液和血液样本。为了实现我们的目标，我们将选择 250 名提供尿液和怀孕期间的母亲。怀孕期间的血液样本和最终诊断的孩子用于产前暴露于 NIS。抑制剂和母亲的碘状况，我们将分析从 250 名母亲收集的 750 份尿液样本。甲状腺激素和 TPO-Ab，我们将分析从 250 名母亲采集的 500 份血液样本。确定产前接触 NIS 抑制剂是否与甲状腺功能障碍有关（目标 1）。还确定产前接触 NIS 抑制剂或母亲甲状腺功能障碍是否与 ASD 风险增加（目标 2）发现暴露混合物对甲状腺功能障碍和 ASD 的影响，我们将应用各种尖端的建模策略，我们预计该项目将利用丰富的资源。严格的自闭症项目的资源将（1）产生关于潜在的休闲者的可靠且丰富的信息从产前接触 NIS 抑制剂到甲状腺功能障碍到 ASD 病因的途径 (2) 确定接触 NIS 抑制剂可能导致甲状腺功能障碍和/或 ASD 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 ASD 的影响。