Early-life phthalate exposure, thyroid function and child cognitive development

描述（由申请人提供）：竞争性更新是对最近流行病学和实验证据的回应，表明某些邻苯二甲酸盐调节甲状腺功能并降低循环甲状腺激素水平。所涉及的邻苯二甲酸酯包括已经在现行RO1（产前邻苯二甲酸酯，胎盘功能和胎儿生长R01 ES013543， Robin Whyatt， PI）下研究的那些：邻苯二甲酸二（2-乙基己基）酯（DEHP），邻苯二甲酸丁苯酯（BBzP）和邻苯二甲酸二丁酯（DBP）。这些邻苯二甲酸盐的暴露在队列受试者中是大量的。我们提出的更新将确定这些暴露是否与从出生到10-11岁的儿童甲状腺功能紊乱有关。这项研究还将确定邻苯二甲酸盐是否与儿童神经心理功能缺陷有关，包括可能与邻苯二甲酸盐引起的甲状腺功能（智力、注意力、执行功能和运动技能）下降有关的领域。此外，考虑到邻苯二甲酸盐影响甲状腺水平的机制是通过调节甲状腺中碘化钠同调体（NIS）介导的碘吸收活性，我们还将评估产前邻苯二甲酸盐暴露是否会调节胎盘组织中NIS的表达。这一发现可能对胎儿甲状腺功能有重要意义，因为NIS是负责碘在胎盘中主动转移的转运基因。怀孕期间和幼儿时期的甲状腺激素对大脑发育至关重要，即使激素水平的适度降低也可能对儿童的精神、运动和神经心理功能产生长期影响。然而，虽然之前的研究已经评估了成人邻苯二甲酸盐和甲状腺激素之间的关系，但之前的研究没有评估儿童的这些关系，也没有评估产前和早期接触邻苯二甲酸盐对儿童神经心理功能的影响。在我们的初步分析中，我们发现母亲产前DEHP暴露与队列儿童3岁时的儿童智力发育之间存在显著的负相关。这项建议的更新将建立在这些初步发现的基础上，以评估产前和儿童早期邻苯二甲酸盐暴露对以下方面的作用：(1)从出生到11岁儿童甲状腺功能的测量；(2)儿童认知（语言、工作记忆、执行功能、问题解决）；(3)儿童行为（注意力和冲动）；(4)儿童运动发育（精细手控、手协调、身体协调、力量和敏捷性、运动速度和视觉扫描）和(5)胎盘组织中NIS的表达。

DESCRIPTION (provided by applicant): The competitive renewal is responsive to recent epidemiologic and experimental evidence indicating that certain phthalates modulate thyroid function and reduce circulating thyroid hormone levels. The phthalates implicated include those already being studied under the current RO1 (Prenatal Phthalates, Placental Function and Fetal Growth R01 ES013543, Robin Whyatt, PI): di(2-ethylhexyl) phthalate (DEHP), butylbenzyl phthalate (BBzP) and dibutyl phthalate (DBP). Exposures to these phthalates are substantial among cohort subjects. Our proposed renewal will determine whether these exposures are associated with perturbations in thyroid function in children followed from birth through age 10-11 years. The study will also determine whether the phthalates are associated with deficits in child neuropsychological function, including in domains that might be associated with phthalate-induced reductions in thyroid function (intelligence, attention, executive function and motor skills). In addition, given that the purported mechanism whereby phthalates affect thyroid levels is through modulation of the Sodium Iodide Symporter (NIS) mediated iodide uptake activity in the thyroid gland, we will also evaluate whether prenatal phthalate exposures modulate expression of the NIS in placental tissue. Such a finding could have important implications for fetal thyroid function, as the NIS is the transport gene responsible for the active transfer of iodide across the placenta. Thyroid hormones during pregnancy and early childhood are critical to brain development, and even modest reductions in hormone levels may have long-lasting effects on child mental, motor and neuropsychological function. However, while prior studies have assessed the relationship between phthalates and thyroid hormones in adults, no prior studies have assessed these relationships in children, or evaluated the effects of prenatal and early-life phthalates exposures on child neuropsychological function. In our preliminary analyses, we found a significant inverse association between maternal prenatal DEHP exposure and child mental development at age 3 years among cohort children. This proposed renewal will build on these preliminary findings to evaluate the role of prenatal and early childhood phthalate exposures on: (1) measures of thyroid function in children from birth through age 11 years; (2) child cognition (language, working memory, executive function, problem solving); (3) child behavior (attention and impulsivity ); (4) child motor development (fine manual control, manual coordination, body coordination, strength and agility, motor speed and visual scanning) and (5) expression of the NIS in placental tissue. PUBLIC HEALTH RELEVANCE: The competitive renewal is responsive to recent epidemiologic and experimental evidence indicating that certain phthalates modulate thyroid function and affect child cognitive development. The proposal will determine whether prenatal and early postnatal exposure to the phthalates are associated with perturbations in thyroid function and with deficits in child europsychological function (intelligence, attention, executive function and motor skills) in a cohort of 400 children followed from birth through age 10-11 years.