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：
10668541
负责人：
Hyeong-Moo Shin
金额：
$ 14.38万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668541
关键词：
3 year old 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 Hypothalamic structure Hypothyroidism Individual Intake Intervention Investigation Iodide Peroxidase Iodides Iodine 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 Sampling Sodium Testing Thiocyanates Thyroid Function Tests Thyroid Gland Thyroid Hormones Thyrotropin Thyroxine Time Triiodothyronine Urine Woman autism spectrum disorder autistic children 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 symporter 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.

项目摘要/摘要自闭症是日益增长的公共卫生问题，经济成本高。自闭症频谱的快速增加疾病（ASD）患病率表明，非可遗物因素可能导致ASD病因。流行病学证据表明，怀孕期间孕产妇甲状腺功能减退症（甲状腺不足）是与儿童ASD和其他神经发育障碍的风险增加有关。甲状腺过氧化物酶抗体（TPO-AB）是甲状腺自身免疫性的标志物，自闭症概率家族的抗体也明显更高为此选择甲状腺破坏者，高氯酸盐，硫代酯和硝酸盐项目是因为众所周知，它们会抑制钠/碘分支机（NIS）的碘化物摄取。碘化物的吸收 NIS对于甲状腺恐怖片的合成至关重要，因为怀孕期间的碘缺陷与众所周知，由于孕产妇和胎儿甲状腺功能减退症甚至轻度碘缺乏的风险增加脑损伤。潜在的休闲途径，从产前暴露于NIS抑制剂通过甲状腺功能障碍在实验和流行病学研究中，对ASD病因进行了概念化。提议检查产前暴露于高氯酸盐，硫氰酸酯和硝酸盐是否与甲状腺功能障碍，导致更大的ASD风险。为了检验我们的假设，我们计划利用大型自闭症流行病学项目在NIEHS资助的UC戴维斯儿童中心启动环境健康被称为“大理石”（婴儿的自闭症风险标记 - 学习早期迹象）。大理石是一项前瞻性投资，已经招募了520多名孕妇使用ASD，旨在通过大写家庭复发来识别ASD的原因和早期标记率〜20％。在大理石中，我们有多种尿液和血液样本前瞻性地收集怀孕期间的母亲。为了实现我们的目标，我们将选择250位提供尿液和尿液的母亲怀孕期间的血液样本，并有一个最终诊断的孩子。对于产前暴露于NIS 抑制剂和母体碘状况，我们将分析从250位母亲那里收集的750个尿液样本。为了甲状腺激素和TPO-AB，我们将分析从250位母亲那里收集的500个血液样本。然后，我们会的确定产前暴露于NIS抑制剂是否与甲状腺功能障碍有关（AIM 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增加了ASD的风险（AIM 2）。要发现暴露混合物对甲状腺功能障碍和ASD的影响，我们将采用各种尖端建模策略。我们预计这个项目利用Rich 严格的自闭症项目的资源将（1）产生有关潜在休闲的强大而丰富的信息通过甲状腺功能障碍到ASD病因从产前暴露于NIS抑制剂的途径；（2）确定暴露于NIS抑制剂的关键时间窗口可能导致甲状腺功能障碍和/或ASD；（3）发现暴露混合物对甲状腺功能障碍和/或ASD的影响。