Placental Responses to Environmental Chemicals

胎盘对环境化学物质的反应

• 批准号: 10614236
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614236
• 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; Cardiometabolic Disease; 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; 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.

项目概要 妊娠期间的环境暴露会改变早期生长轨迹并增加以下风险： 罹患慢性疾病，包括糖尿病、高血压和肥胖症。 值得关注的是镉，一种主要用于电子工业的金属，镉是重中之重。 镉是一种对成人和儿童都有不良临床影响的有毒物质。 积聚在胎盘中，引起细胞应激，干扰激素产生，并限制 营养物质从母亲转移到孩子身上，这导致人类和动物出生时体型较小。 确定可以改变胎盘中镉毒性的细胞机制是关键。 预防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，会 在可预见的未来，这种机制会持续存在于我们的环境中，从而减少胎盘积累。 环境化学物质是通过外排蛋白主动转运的，乳腺癌抗性蛋白。 (BCRP/ABCG2) 是一种在合体滋养细胞上高度表达的外排转运蛋白，在 限制化学物质的胎盘积累 本研究的总体假设是 BCRP。 是限制胎盘接触镉的关键机制；当 BCRP 功能降低时，镉的 对胎盘的毒性作用增强，导致胎儿生长受限。 使用创新和转化实验方法的三个具体目标。 团队包括生化毒理学家、生物医学工程师和流行病学家。 BCRP 可预防镉引起的胎盘毒性，是培养模型的补充，包括一种新型 将使用“胎盘芯片”以及来自健康妊娠的足月绒毛外植体来测试体内。 BCRP能够预防镉引起的胎儿生长受限，转基因怀孕小鼠将得到治疗 氯化镉并评估胎盘毒性和胎儿生长受限。 310 名健康孕妇将接受产前金属暴露情况检查，包括镉和 与 3D 胎盘形态和婴儿生长结果相关的转运蛋白基因组学/蛋白质组学。 最终，这一系列研究将向科学界通报胎盘的能力 转运蛋白以保护胎儿免受环境化学物质引起的发育毒性的影响。

项目成果

A microphysiological model of human trophoblast invasion during implantation.

植入过程中人滋养层侵袭的微生理学模型。

• 发表时间: 2022-03-15
• 影响因子: 16.6
• 作者: Park, Ju Young;Mani, Sneha;Clair, Geremy;Olson, Heather M;Paurus, Vanessa L;Ansong, Charles K;Blundell, Cassidy;Young, Rachel;Kanter, Jessica;Gordon, Scott;Yi, Alex Y;Mainigi, Monica;Huh, Dan Dongeun
• 通讯作者: Huh, Dan Dongeun

Organ-on-a-chip technology for the study of the female reproductive system.

用于研究女性生殖系统的器官芯片技术。

• DOI: 10.1016/j.addr.2021.03.010
• 发表时间: 2021-06
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Young RE;Huh DD
• 通讯作者: Huh DD