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.