Placental Responses to Environmental Chemicals

胎盘对环境化学物质的反应

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要妊娠期间环境暴露会改变早期生长轨迹，并增加患有慢性疾病，包括糖尿病，高血压和肥胖症。最大的暴露关注的是镉，这是一种在电子行业广泛使用的金属。镉是高度优先级在成人和儿童中报告的具有不良临床作用的毒物。怀孕期间，镉积聚在诱导细胞应激，干扰骑马的生产的斑块中，并限制从母亲到孩子的营养素转移。这导致人类和动物出生时的后代大小较小型号。识别可以改变lopeta中镉毒性的细胞机制是至关重要的防止因镉引起的与胎儿生长限制相关的不良结果，这种化学物质将在可预见的未来，坚持在我们的环境中。一种减少占位物积累的机制环境化学物质是通过外排蛋白主动运输的。乳腺癌抗性蛋白（BCRP/ABCG2），一种高度表达在合成型成素细胞上的外排转运蛋白，在限制化学物质的位置积累。这项研究的总体假设是BCRP 是限制镉暴露的关键机制；当BCRP功能降低时，镉的功能毒性对骨a的有毒作用得到增强，从而导致胎儿生长限制。该假设将在使用创新和翻译的实验方法的三个特定目标。多学科研究团队包括生物化学毒理学家，生物医学工程师和流行病学家。研究能力 BCRP以防止镉诱导的占地毒性，培养模型的完成，包括一种新型将使用“芯片上的胎盘”以及健康妊娠的术语绒毛外浮体。测试体内 BCRP预防镉诱导的胎儿生长限制的能力，将治疗转基因怀孕小鼠与氯化镉一起评估，并评估了占地去的毒性和胎儿生长限制。上升队列的 310名健康的孕妇将检查产前接触金属的孕妇，包括镉和转运蛋白基因组学/蛋白质组学与3D斑点形态和婴儿生长结果有关。最终，这一研究将为科学界提供有关位置能力的信息转运蛋白保护胎儿免受环境化学诱导的发育毒性。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

A microphysiological model of human trophoblast invasion during implantation.

DOI：
10.1038/s41467-022-28663-4
发表时间：
2022-03-15
期刊：
Nature communications
影响因子：
16.6
作者：
Park JY;Mani S;Clair G;Olson HM;Paurus VL;Ansong CK;Blundell C;Young R;Kanter J;Gordon S;Yi AY;Mainigi M;Huh DD
通讯作者：
Huh DD