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

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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.