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

描述(由申请人提供)：竞争更新是对最近的流行病学和实验证据做出反应，这些证据表明某些邻苯二甲酸盐调节甲状腺功能并降低循环中的甲状腺激素水平。涉及的邻苯二甲酸酯包括已在现行RO1(产前邻苯二甲酸盐、胎盘功能和胎儿生长R01 ES013543，Robin Whyatt，PI)下研究的邻苯二甲酸酯：邻苯二甲酸二异辛酯(DEHP)、邻苯二甲酸丁基苄酯(BBZP)和邻苯二甲酸二丁酯(DBP)。在队列受试者中，接触这些邻苯二甲酸盐的人数很多。我们建议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酯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导致的甲状腺功能(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的碘化钠转运体(NIS)介导的碘摄取活动，我们还将评估产前邻苯二甲酸盐暴露是否调节胎盘组织中NIS的表达。这一发现可能对胎儿甲状腺功能有重要影响，因为NIS是负责通过胎盘主动转移碘的运输基因。怀孕和儿童早期的甲状腺激素对大脑发育至关重要，即使激素水平略有下降，也可能对儿童的智力、运动和神经心理功能产生长期影响。然而，尽管之前的研究评估了邻苯二甲酸盐与成人甲状腺激素之间的关系，但还没有研究评估儿童的这种关系，也没有评估产前和早期邻苯二甲酸酯暴露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，在队列儿童中，母亲产前接触DEHP与3岁时儿童智力发展之间存在显著的负相关。这项拟议的更新将以这些初步发现为基础，评估产前和儿童早期邻苯二甲酸盐暴露的作用：(1)测量从出生到11岁儿童的甲状腺功能；(2)儿童认知(语言、工作记忆、执行功能、解决问题)；(3)儿童行为(注意力和冲动)；(4)儿童运动发育(精细手动控制、手动协调、身体协调、力量和敏捷性、运动速度和视觉扫描)和(5)NIS在胎盘组织中的表达。 公共卫生相关性：竞争更新是对最近的流行病学和实验证据做出反应的，这些证据表明，某些邻苯二甲酸盐调节甲状腺功能并影响儿童认知发育。该提案将确定出生前和出生后早期接触邻苯二甲酸酯是否与甲状腺功能紊乱以及儿童神经心理功能(智力、注意力、执行功能和运动技能)缺陷有关，该队列中的400名儿童从出生到10-11岁。

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.