Placental Responses to Environmental Chemicals

项目总结 妊娠期的环境暴露会改变早期的生长轨迹，增加罹患 发展慢性疾病，包括糖尿病、高血压和肥胖症。在最大的曝光中 令人担忧的是镉，这是一种在电子行业广泛使用的金属。镉是最优先考虑的 对成人和儿童都有不良临床影响的毒物。在怀孕期间，镉 在胎盘中积聚，在那里它诱导细胞压力，干扰激素的产生，并限制 从母亲到孩子的营养转移。这导致人类和动物出生时后代尺寸较小 模特们。确定可以改变镉在胎盘中的毒性的细胞机制是 预防由镉引起的胎儿生长受限的不良后果，镉是一种化学物质，它将 在可预见的未来坚持我们的环境。一种减少胎盘堆积的机制 环境化学物质是通过外排蛋白质进行主动运输的。乳腺癌耐药蛋白 (BCRP/ABCG2)是合体滋养层细胞高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。这一假设将在#年进行检验。 使用创新和转化性实验方法的三个具体目标。多学科研究 该团队包括一名生化毒物学家、生物医学工程师和一名流行病学家。研究……的能力 为预防镉诱导的胎盘毒性，补充了培养模型，包括一种新的 将使用“芯片上的植入物”以及来自健康孕妇的长期绒毛外植体。为了测试体内的 BCRP预防镉致胎儿生长受限的能力，转基因孕鼠将得到治疗 并对胎盘毒性和胎儿生长受限进行评估。上行的一群人 310名健康的孕妇将接受产前金属暴露检查，包括镉，以及 转运蛋白基因组学/蛋白质组学与三维胎盘形态和婴儿生长结果的关系。 最终，这一系列研究将告知科学界有关胎盘能力的信息。 转运体，以保护胎儿免受环境化学诱导的发育毒性。

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.