Placental Responses to Environmental Chemicals - Diversity Supplement 2

胎盘对环境化学物质的反应 - 多样性补充 2

• 批准号: 10360791
• 负责人: Lauren M Aleksunes
• 金额: $ 13.95万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360791
• 关键词: 3-Dimensional; ABCG2 gene; Active Biological Transport; Adult; Animal Model; Award; Biochemical; Biomedical Engineering; Birth; Cadmium; Cadmium chloride; Cellular Stress; Chemicals; Child; Chronic Disease; Communities; Complement; Diabetes Mellitus; Electronics; Environment; Environmental Exposure; Environmental Pollution; Epidemiologist; Exposure to; Fetal Growth Retardation; Fetus; Future; Genomics; Growth; Health; Hormones; Hypertension; Industry; Infant; Interdisciplinary Study; Joints; Metal exposure; Metals; Modeling; Mothers; Mus; National Institute of Environmental Health Sciences; Nutrient; Obesity; Outcome; Placenta; Placental Toxicity; Play; Postdoctoral Fellow; Pregnancy; Pregnant Women; Production; Proteins; Proteomics; Reporting; Research; Risk; Role; Syncytiotrophoblast; Testing; Toxic effect; Toxicology; Transgenic Organisms; Universities; Villous; Walkers; adverse outcome; clinical effect; cohort; developmental toxicity; environmental chemical; healthy pregnancy; human model; in vivo evaluation; innovation; macrophage; novel; offspring; parent grant; parent project; placental morphology; pregnant; prenatal exposure; prevent; programs; response; toxicant

PARENT PROJECT ABSTRACT Environmental exposures during gestation can alter early growth trajectories and increase the risk of developing chronic diseases including diabetes, hypertension, and obesity. Among the exposures of greatest concern is cadmium, a metal that is extensively used in the electronics industry. Cadmium is a high priority toxicant with adverse clinical effects reported in both adults and children. During pregnancy, cadmium accumulates in the placenta where it induces cellular stress, interferes with hormone production, and limits the transfer of nutrients from mother to child. This leads to smaller offspring size at birth in humans and animal models. Identifying cellular mechanisms that can modify cadmium’s toxicity in the placenta are key to preventing the adverse outcomes associated with fetal growth restriction due to cadmium, a chemical that will persist in our environment for the foreseeable future. One mechanism that reduces placental accumulation of environmental chemicals is active transport by efflux proteins. The breast cancer resistance protein (BCRP/ABCG2), an efflux transporter highly expressed on syncytiotrophoblasts, plays a critical role in restricting the placental accumulation of chemicals. The overarching hypothesis of this research is that BCRP is a critical mechanism limiting placental exposure to cadmium; when BCRP function is reduced, cadmium’s toxic effects on the placenta are enhanced, resulting in fetal growth restriction. This hypothesis will be tested in three specific aims using innovative and translational experimental approaches. The multidisciplinary research team includes a biochemical toxicologist, biomedical engineer, and an epidemiologist. To study the ability of BCRP to prevent cadmium-induced placental toxicity, a complement of culture models, including a novel ‘Placenta-on-a-Chip’ as well as term villous explants from healthy pregnancies will be used. To test the in vivo ability of BCRP to prevent cadmium-induced fetal growth restriction, transgenic pregnant mice will be treated with cadmium chloride and evaluated for placental toxicity and fetal growth restriction. The UPSIDE cohort of 310 healthy, pregnant women will be examined for prenatal exposure to metals, including cadmium, and transporter genomics/proteomics in relation to 3D placental morphology and infant growth outcomes. Ultimately, this line of research will inform the scientific community regarding the ability of placental transporters to protect the fetus from environmental chemical-induced developmental toxicities.

项目简介 妊娠期间的环境暴露可改变早期生长轨迹，并增加发展中国家的风险。 慢性疾病，包括糖尿病、高血压和肥胖症。最令人担忧的风险之一是 镉是一种广泛用于电子工业的金属。镉是一种高度优先的有毒物质， 在成人和儿童中均报告了不良临床效应。在怀孕期间，镉会积聚在 胎盘，在那里它诱导细胞应激，干扰激素的产生，并限制营养物质的转移 从母亲到孩子这导致在人类和动物模型中出生时后代尺寸较小。识别细胞 能够改变镉在胎盘中毒性的机制是预防不良后果的关键 与胎儿生长限制有关，由于镉，一种化学物质，将持续在我们的环境中， 可预见的未来一种机制，减少胎盘积累的环境化学物质是积极的 通过外排蛋白转运。乳腺癌耐药蛋白（BCRP/ABCG 2）是一种高度表达的外排转运蛋白， 在合体滋养层上表达，在限制胎盘化学物质积累方面起关键作用。 本研究的总体假设是，BCRP是限制胎盘暴露于 当BCRP功能降低时，镉对胎盘的毒性作用增强，导致 胎儿生长受限这一假设将在三个具体的目标进行测试，使用创新和翻译 实验方法。多学科研究团队包括生化毒理学家，生物医学 工程师和流行病学家为了研究BCRP预防镉诱导的胎盘毒性的能力， 培养模型的补充，包括一种新的“胎盘芯片”以及来自 将使用健康的妊娠。检测BCRP预防镉诱导胎儿生长的体内能力 限制，转基因妊娠小鼠将用氯化镉处理，并评估胎盘毒性 和胎儿生长受限由310名健康孕妇组成的UPSIDE队列将接受产前检查 接触金属，包括镉，以及与3D胎盘相关的转运蛋白基因组学/蛋白质组学 形态学和婴儿生长结果。最终，这一系列的研究将告知科学界 关于胎盘转运蛋白保护胎儿免受环境化学物质诱导的能力， 发育毒性。