Placental Responses to Environmental Chemicals

胎盘对环境化学物质的反应

• 批准号: 9914832
• 负责人: Lauren M Aleksunes
• 金额: $ 70.65万
• 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/9914832
• 关键词: 3-Dimensional; ABCG2 gene; Active Biological Transport; Adult; Affect; Age-Months; Animal Model; Attenuated; Biochemical; Biomedical Engineering; Birth; Body Composition; Cadmium; Cadmium chloride; Cellular Stress; Chemicals; Child; Chronic Disease; Communities; Complement; Data; Diabetes Mellitus; Electronics; Endothelial Cells; Environment; Environmental Exposure; Epidemiologist; Exposure to; Fetal Growth Retardation; Fetus; Food; Future; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Growth; Health; Histopathology; Hormones; Human; Hypertension; Impairment; Industry; Infant; Infant Health; Interdisciplinary Study; Knowledge; Life; Low Birth Weight Infant; Measurable; Measures; Metal exposure; Metals; Microfluidics; Modeling; Morphology; Mothers; Mus; Nutrient; Obesity; Orthologous Gene; Outcome; Pathway interactions; Pharmacology; Placenta; Placental Toxicity; Plasma; Play; Pregnancy; Pregnant Women; Production; Proteins; Proteomics; Public Health; Reporting; Research; Resistance; Risk; Role; Source; Syncytiotrophoblast; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Umbilical Cord Blood; Urine; Variant; Villous; Woman; adverse outcome; cardiometabolism; clinical effect; cohort; developmental toxicity; disorder risk; environmental chemical; exposed human population; fetal; genetic variant; healthy pregnancy; human model; in vivo Model; in vivo evaluation; innovation; loss of function; novel; offspring; overexpression; placental morphology; pregnant; prenatal; prenatal exposure; prevent; protein expression; response; toxicant; transcriptomics; translational approach; trophoblast

PROJECT SUMMARY 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.

项目摘要 妊娠期间的环境暴露可改变早期生长轨迹，并增加妊娠风险。 患上慢性疾病，包括糖尿病、高血压和肥胖症。其中最大的曝光 令人担忧的是镉，一种广泛用于电子工业的金属。镉是一个高优先级 有毒物质，对成人和儿童均有不良临床影响。怀孕期间，镉 在胎盘中积累，在那里它诱导细胞应激，干扰激素的产生，并限制 将营养从母亲传给孩子。这导致人类和动物出生时后代尺寸较小 模型确定可以改变镉在胎盘中毒性的细胞机制是关键， 防止与镉引起的胎儿生长受限相关的不良后果，镉是一种化学物质， 在可预见的未来会持续存在于我们的环境中。一种机制是减少胎盘中 环境化学物质是主动运输的外排蛋白。乳腺癌耐药蛋白 (BCRP/ABCG 2），一种在合体滋养层细胞上高度表达的外排转运蛋白，在 限制胎盘中化学物质的积累。这项研究的首要假设是，BCRP 是限制胎盘暴露于镉的关键机制;当BCRP功能降低时， 对胎盘的毒性作用增强，导致胎儿生长受限。这一假设将在 使用创新和转化实验方法的三个具体目标。多学科研究 研究小组包括一名生化毒理学家、一名生物医学工程师和一名流行病学家。研究的能力 BCRP预防镉诱导的胎盘毒性，是培养模型的补充，包括一种新的 将使用“胎盘芯片”以及来自健康妊娠的足月绒毛外植体。为了测试体内 BCRP预防镉诱导的胎儿生长受限的能力，将对转基因妊娠小鼠进行治疗 并评估胎盘毒性和胎儿生长受限。UPSIDE队列 将对310名健康孕妇进行产前金属暴露检查，包括镉， 转运蛋白基因组学/蛋白质组学与3D胎盘形态学和婴儿生长结果的关系。 最终，这一系列的研究将告知科学界关于胎盘的能力， 保护胎儿免受环境化学品诱导的发育毒性。