Nanoparticles in the Human Placenta:Toxicokinetics

人胎盘中的纳米颗粒：毒代动力学

• 批准号: 7660838
• 负责人: Richard Kermit Miller
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660838
• 关键词: Affect; Albumins; Animals; Area; Biochemical; Blood; Blood Circulation; Breathing; Cadmium; Capsid Proteins; Catabolism; Cells; Characteristics; Charge; Data; Dependence; Development; Diffusion; Drug Formulations; Endocrine; Endocytosis; Endothelium; Exposure to; Fetus; Functional disorder; Future; Gold; Human; Immunoglobulin G; Immunoglobulins; In Vitro; Kinetics; Ligands; Lobule; Mediating; Metals; Modeling; Mothers; Nanotechnology; Newborn Infant; Occupational; Perfusion; Placenta; Pregnancy; Pregnant Women; Process; Proteins; Rattus; Research; Respiratory System; Respiratory tract structure; Serum Albumin; Serum Proteins; Signal Transduction; Solubility; Source; Staging; Stream; Surface; Syncytiotrophoblast; System; Tissues; Toxic effect; Toxicokinetics; Ultrafine; Work; abstracting; base; embryo/fetus; fetal; macrophage; nanomaterials; nanomedicine; nanoparticle; particle; placental transfer; pregnant; public health relevance; receptor; research study; surface coating

DESCRIPTION (provided by applicant): Ultrafine/nanoparticles (NPs) from many environmental sources, including those produced by the exploding field of nanotechnology, can occur in occupational and environmental settings and present humans with both exposures and toxicities. Even more of an issue is the expanding field of nanomedicine. Current research has not had the pregnant woman or fetus as a major focus. We plan to examine whether NPs can cross into the fetus through the human placenta in vitro. Because of their small size and large surface area per unit area, the propensity of NPs to interact biologically is high. Inhaled NPs exit the respiratory tract into circulation with distribution to extrapulmonary tissues. When NPs enter the blood stream they become coated with serum proteins, which may influence the manner in which they are recognized by these tissues. Two proteins in particular, IgG and albumin, are selectively recognized and either transported (IgG) or catabolized (albumin) by the placenta. HYPOTHESIS: In the human, NPs in maternal blood can cross the placenta and enter into fetal circulation, and this transfer of NPs is dependent on the protein surface coating and size of the NPs. SPECIFIC AIM 1: Determine the ability of NPs to accumulate and transfer into the fetal circuit by the perfused human placenta in vitro using 5 nm gold (Au) particles coated with human F105 IgG or serum albumin, SPECIFIC AIM 2: Determine if larger NPs transit from the maternal to fetal circuits under perfusion conditions using similarly coated 50 nm Au NPs. SPECIFIC AIM 3: Determine if exposure to NPs induces dysfunction in the human placenta using dynamic functional, morphologic, biochemical and endocrine assessments. These studies will establish whether the human placenta will a. accumulate Au NPs according to size and protein coating, b. transfer these Au NPs selectively from maternal to fetal circulation, and c. become acutely intoxicated due to interaction with any of these NPs formulations. A major objective of these experiments is to initiate development of a model that will help assess the developmental effects of nanomaterials in the maternal circulation. FUTURE DIRECTIONS: Using these model Au NPs, results from this project will be the basis for subsequent research objectives using other types of NPs, e.g., partially soluble and biodegradable NPs and NPs with varying surface charge and size to identify a) the mechanisms of placental transfer of NPs and the dependence not only on size and protein coating, but also on charge, solubility, and other physicochemical characteristics, and b) the fate, effects, and underlying mechanisms of NPs in the human placenta at different stages of gestation. This work will identify the potential for the embryo/fetus to be directly exposed to different environmental NPs, and for the placenta to be affected. PUBLIC HEALTH RELEVANCE: This study will determine if nanoparticles of different sizes and protein coatings will cross the placenta and enter into the fetal circulation utilizing a dually perfused human placenta lobule in vitro.

描述（由申请人提供）：来自许多环境来源的超细/纳米颗粒（NP），包括由纳米技术爆炸领域产生的纳米颗粒，可能发生在职业和环境中，并给人类带来暴露和毒性。更大的问题是纳米医学领域的不断扩大。目前的研究还没有将孕妇或胎儿作为主要焦点。我们计划在体外研究纳米颗粒是否可以通过人胎盘进入胎儿体内。由于它们的小尺寸和每单位面积的大表面积，NP生物相互作用的倾向是高的。吸入的NP离开呼吸道进入循环，分布到肺外组织。当纳米颗粒进入血流时，它们被血清蛋白包被，这可能影响它们被这些组织识别的方式。特别是两种蛋白质，IgG和白蛋白，被胎盘选择性识别并转运（IgG）或分解代谢（白蛋白）。假设：在人类中，母体血液中的纳米颗粒可以穿过胎盘并进入胎儿循环，纳米颗粒的这种转移取决于纳米颗粒的蛋白质表面涂层和尺寸。具体目标1：使用包被有人F105 IgG或血清白蛋白的5 nm金（Au）颗粒，测定NP通过体外灌注的人胎盘积聚并转移到胎儿回路中的能力。具体目的2：使用类似包被的50 nm Au NP，测定较大的NP是否在灌注条件下从母体回路转移到胎儿回路。具体目标3：使用动态功能、形态学、生物化学和内分泌评估确定暴露于NP是否诱导人胎盘功能障碍。这些研究将确定人类胎盘是否会发生变化。根据大小和蛋白质涂层积累Au NP，B.将这些Au NP选择性地从母体循环转移到胎儿循环，以及c.由于与任何这些NP制剂的相互作用而变得急性中毒。这些实验的一个主要目标是启动一个模型的开发，该模型将有助于评估纳米材料在母体循环中对发育的影响。未来发展方向：使用这些模型Au NPs，该项目的结果将成为使用其他类型NPs的后续研究目标的基础，例如，部分可溶性和生物可降解的NP和具有不同表面电荷和尺寸的NP，以鉴定a）NP的胎盘转移机制以及不仅对尺寸和蛋白质涂层的依赖性，而且对电荷、溶解度和其它物理化学特征的依赖性，和B）NP在妊娠的不同阶段在人胎盘中的命运、作用和潜在机制。这项工作将确定胚胎/胎儿直接暴露于不同环境NP以及胎盘受到影响的可能性。 公共卫生关系：本研究将确定不同大小和蛋白质涂层的纳米颗粒是否会穿过胎盘并利用体外双重灌注的人胎盘小叶进入胎儿循环。