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展的风险 包括糖尿病，高血压和肥胖症在内的慢性疾病。最关心的暴露是 镉，一种在电子行业广泛使用的金属。镉是高优先级有毒物质的 成人和儿童报告的不良临床影响。在怀孕期间，镉在 lopeta诱导细胞应力，干扰骑马的产生并限制营养的转移 从母亲到孩子。这导致人类和动物模型出生时的后代大小较小。识别细胞 可以修改镉在子宫结构中的毒性的机制是防止不良结果的关键 与镉引起的胎儿生长限制有关，这种化学物质将在我们的环境中持续存在 可预见的未来。一种减少环境化学物质积聚的机制是活跃的 通过外排蛋白运输。乳腺癌耐药性蛋白（BCRP/ABCG2），一种外排转运蛋白 在合成细胞细胞上表达，在限制化学物质的斑点积累中起着至关重要的作用。 这项研究的总体假设是，BCRP是限制占地暴露于的关键机制 镉;当降低BCRP功能时，镉对斑点的毒性影响会增强，从而导致 胎儿生长限制。该假设将使用创新和翻译的三个特定目标进行检验 实验方法。多学科研究团队包括生物医学的生化毒理学学家 工程师和流行病学家。研究BCRP预防镉诱导的斑点毒性的能力， 文化模型的补充，包括新颖的“胎盘片”以及术语 健康怀孕将被使用。测试BCRP预防镉诱导胎儿生长的体内能力 限制，转基因怀孕小鼠将用氯化镉治疗，并评估占地去的毒性 和胎儿生长限制。将检查310名健康孕妇的上升队列是否需要检查产前 接触金属，包括镉和转运蛋白基因组/蛋白质组学，相对于3D斑点 形态学和婴儿成长结果。最终，这一研究将为科学界提供信息 涉及胎盘转运蛋白保护胎儿免受环境化学诱导的能力 发育毒性。