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

新生儿重症监护病房中邻苯二甲酸盐的暴露及其作用机制

• 批准号: 10736301
• 负责人: Annemarie Stroustrup
• 金额: $ 199.91万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736301
• 关键词: Address; Admission activity; Age; Angiogenic Factor; Animal Model; Animals; Architecture; Biological Markers; Birth; Birth Weight; Blood Transfusion; Bone Marrow; Bronchopulmonary Dysplasia; Caring; Cells; Chemicals; Child; Chronology; Clinical; Controlled Environment; Coupled; Data; Development; Disease; Dose; Drug Kinetics; Endocrine disruption; Environment; Equipment; Erythrocytes; Exposure to; Face; Family; Future; Genetic Predisposition to Disease; Gestational Age; Growth; Histopathology; Hospitalization; Hospitals; Hyperoxia; Infant; Infant Care; Inflammatory; Inhalation; Inhalation Exposure; Inpatients; Intravenous; Intravenous Bolus; Life; Link; Lung; Lung diseases; Measures; Medical; Metabolism; Modeling; Natural experiment; Nebulizer; Neonatal Intensive Care Units; Newborn Infant; Organic Chemicals; Outcome; Patients; Perinatal; Plasticizers; Plastics; Population; Population Heterogeneity; Premature Infant; Rattus; Research; Risk; Rodent Model; Role; Sentinel; Source; Sprague-Dawley Rats; System; Testing; Third Pregnancy Trimester; Toxic effect; Transfusion; Translating; Tube; United States; Weight Gain; Work; adverse outcome; blood product; clinical investigation; endotracheal; epidemiologic data; epidemiology study; exposure route; improved; improved outcome; in utero; insight; neonate; neurobehavioral; neurodevelopment; personal care products; phthalates; premature; pulmonary function; pup; respiratory; urinary

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.

项目摘要 在美国，每年有超过300，000名新生儿入住新生儿重症监护室（NICU）， 在那里他们暴露在化学密集的医院环境中。大多数NICU住院患者 因早产而入院治疗在新生儿重症监护室，婴儿面临着高剂量暴露的治疗， 邻苯二甲酸酯，一种普遍存在的内分泌干扰有机化学增塑剂， 相当于子宫内发育的第三个三个月。我们知道， 子宫内发育窗口期同样可导致次优神经行为、生长和肺 足月儿的结局。过去的研究表明，早产儿也有很大的风险， 早期邻苯二甲酸酯暴露可能会影响不良的多系统结局。我们的团队已经花了 在过去十年中，研究了医院内邻苯二甲酸酯暴露对不良结局的影响， 早产儿通过强有力的流行病学研究，我们已经证明，基于NICU的邻苯二甲酸酯 暴露会改变早产期间神经发育和体重增加的轨迹。新出现的数据 表明邻苯二甲酸酯暴露可能导致早产儿慢性肺病的发展。 然而，关于早产儿邻苯二甲酸酯代谢的药代动力学， 婴儿，导致邻苯二甲酸酯暴露的特定护理实践，以及主要邻苯二甲酸酯的作用机制 早产儿疾病的种类。我们建议通过以下具体目标解决这些问题： 目标1.确定常见邻苯二甲酸二酯及其 不同经后和实际年龄的新生儿单酯代谢物 输血作为一种哨点静脉暴露的“自然实验”。 目标2.测试五个常用的呼吸回路，以确定相对邻苯二甲酸酯 每个人的曝光度。 目的3：使用啮齿动物模型检查吸入性邻苯二甲酸酯暴露对 早产儿慢性肺病的病理生物学 拟议的研究将提供可操作的数据，可以迅速转化为改善新生儿重症监护室的做法 并促进未来的临床研究。