Phthalate Exposure and Mechanisms of Action in the Neonatal Intensive Care Unit

项目总结 在美国，每年有超过30万名新生儿被送入新生儿重症监护病房(NICU)， 在那里，他们暴露在化学密集型医院环境中。大多数NICU住院患者都是 因早产儿管理而入院。在NICU，婴儿面临着传递高剂量暴露的治疗 对邻苯二甲酸酯，一种普遍存在的扰乱内分泌的有机化学增塑剂家族，在生命阶段 相当于第三个月的宫内发育。我们知道，增加邻苯二甲酸盐的暴露在 在子宫发育窗口期，同样的情况会导致神经行为、生长发育和肺功能欠佳 足月出生儿童的结局。过去的研究表明，早产儿也有很大的风险 早期接触邻苯二甲酸盐可能会影响多系统的不良后果。我们的团队已经花了 在过去的十年中，研究了医院内邻苯二甲酸盐暴露对不良后果的贡献 早产儿。通过强有力的流行病学研究，我们已经证明了基于NICU的邻苯二甲酸酯 暴露改变了早产期神经发育和体重增加的轨迹。新兴数据 提示邻苯二甲酸盐暴露可能导致早产儿慢性肺部疾病的发生。 然而，关于早产儿邻苯二甲酸酯代谢的药代动力学仍有许多基本问题。 婴儿，允许邻苯二甲酸盐暴露的特定护理做法，以及邻苯二甲酸二甲酯的作用机制 早产儿疾病中的物种。我们建议通过以下具体目标来解决这些问题： 目的1.测定常用邻苯二甲酸酯类药物的药代动力学 不同月经后和不同年龄新生儿单酯代谢物的研究 输血的“自然实验”作为哨兵静脉注射暴露。 目的2.测试五种常用呼吸回路以确定邻苯二甲酸盐的相对含量 由每个人传达的曝光。 目的3：使用啮齿动物模型研究吸入邻苯二甲酸盐对小鼠的影响。 早产儿慢性肺部疾病的病理生物学研究。 拟议的研究将提供可操作的数据，这些数据可以迅速转化为NICU实践的改进 为今后的临床研究提供便利。

PROJECT SUMMARY Each year in the United States, over 300,000 newborns are admitted to a neonatal intensive care unit (NICU), where they are exposed to a chemical-intensive hospital environment. The majority of NICU inpatients are admitted for management of prematurity. In the NICU, infants face treatments that convey high-dose exposure to phthalates, a family of ubiquitous endocrine-disrupting organic chemical plasticizers, during a life stage equivalent to the third trimester of in utero development. We know that elevated exposure to phthalates during the same in utero developmental window can result in suboptimal neurobehavioral, growth, and pulmonary outcomes among term-born children. Past research shows that preterm infants are also at significant risk of adverse multisystem outcomes potentially impacted by early life phthalate exposure. Our group has spent the past decade investigating the contribution of in-hospital phthalate exposure to adverse outcomes among preterm infants. Through robust epidemiological studies, we have demonstrated that NICU-based phthalate exposure alters the trajectory of neurodevelopment and weight gain during the preterm period. Emerging data indicates that phthalate exposure may contribute to the development of chronic lung disease of prematurity. Yet many fundamental questions remain about the pharmacokinetics of phthalate metabolism in preterm infants, specific care practices that confer phthalate exposure, and the mechanism of action of major phthalate species in preterm infant disease. We propose to address these questions through the following Specific Aims: Aim 1. Determine the pharmacokinetic profile of common phthalate diesters and their monoester metabolites in neonates of varying postmenstrual and chronological ages using the “natural experiment” of blood transfusion as a sentinel intravenous exposure. Aim 2. Test five commonly used respiratory circuits to determine the relative phthalate exposure conveyed by each. Aim 3: Use a rodent model to examine the effects of inhalational phthalate exposure on the pathobiology of chronic lung disease of prematurity. The proposed study will provide actionable data that can rapidly translate into improvements in NICU practice and facilitate future clinical investigation.