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.

父项目摘要 妊娠期间的环境暴露会改变早期生长轨迹并增加发育风险 慢性疾病包括糖尿病、高血压和肥胖症。 镉是一种主要用于电子工业的金属，镉是一种高度优先的有毒物质。 据报道，在成人和儿童中，镉会在怀孕期间积聚在体内，产生不良临床影响。 胎盘会引起细胞应激、干扰激素产生并限制营养物质的转移 从母亲到孩子，这会导致人类和动物模型中的后代出生时体型较小。 改变胎盘中镉毒性的机制是预防不良后果的关键 与镉引起的胎儿生长受限有关，镉是一种化学物质，会持续存在于我们的环境中 在可预见的未来，一种减少胎盘环境化学物质积累的机制正在发挥作用。 乳腺癌抗性蛋白 (BCRP/ABCG2) 是一种高度外排转运蛋白。 在合体滋养细胞上表达，在限制化学物质的胎盘积累中起着关键作用。 本研究的总体假设是 BCRP 是限制胎盘暴露的关键机制 镉；当BCRP功能降低时，镉对胎盘的毒性作用增强，导致 该假设将通过创新和转化在三个特定目标上进行测试。 多学科研究团队包括生化毒理学家、生物医学家。 工程师和流行病学家研究 BCRP 预防镉引起的胎盘毒性的能力， 培养模型的补充，包括新颖的“胎盘芯片”以及来自 将使用健康妊娠来测试 BCRP 预防镉引起的胎儿生长的体内能力。 限制，转基因怀孕小鼠将接受氯化镉治疗并评估胎盘毒性 UPSIDE 队列中的 310 名健康孕妇将接受产前检查。 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 最终，这一系列研究将为科学界提供信息。 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。