PLACENTAL TOXICOLOGY

胎盘毒理学

• 批准号: 3250070
• 负责人: Richard Kermit Miller
• 金额: $ 20.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-12-02 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250070
• 关键词: aminoacid transport; atomic absorption spectrometry; binding proteins; biological models; blood pressure; blood volume; cadmium; calcium; carbon dioxide tension; electron microscopy; embryo /fetus toxicology; environmental adaptation; environmental contamination; environmental toxicology; estrogens; gestational age; high performance liquid chromatography; histology; hormone biosynthesis; human pregnant subject; human tissue; laboratory rat; membrane permeability; metal metabolism; metal poisoning; metallothionein; model design /development; organ culture; oxygen consumption; oxygen tension; perfusion; physiology; placenta; placental transfer; pregnancy circulation; progesterone; psychobiology; radioimmunoassay; respiratory gas analyzer; respiratory gas level; respiratory gas transport; selenium; tobacco abuse; toxicant interaction; toxin metabolism; trophoblast; zinc

The placenta can be a site for specific toxic action compromising the growth and survival of the conceptus, e.g., cadmium can produce placental necrosis and fetal death in rats. During the past three years, studies were undertaken to determine if the human placenta can be selectively affected by environmental agents at levels detected in animals or humans. An in vitro dual perfused, recirculating human placental preparation was developed to study the normal physiology and toxic response to cadmium without mother or baby being involved. The human placental perfusion system can maintain the placenta morphologically (ultrastructurally), physiologically and biochemically for periods in excess of 12 hours. When Cd is introduced into the maternal perfusate at such (Cd) noted in rat plasma for a placental toxic dose, there is a rapid accumulation of cd in the placental with little passage to the fetal circuit. Within twelve hours following the administration of Cd, there is a dose related (10, 20, or 100nmoles/ml initial dose) increase in necrosis, subsynctiotrophoblastic vesiculation, stromal edema, fetal volume loss (leakiness), (within 12 hours) and decrease in human chorionic gonadotropin synthesis and release (within 4 hours). The objectives of this proposal are four-fold: 1. to establish an in vitro human placental perfusion model for periods of 24-36 hours for determining the toxic interactions and distribution of environmental agents at circulating blood levels noted in animals and humans, and for comparing this in vitro model with other animal and human studies. The proposed studies would involve understanding the normal physiological functioning of the placenta (hormone secretion, transport processes, especially receptor-mediated endocytosis for vitamin magnetic induction12 and other nutrients, and energy metabolism); 2. to determine the mechanisms by which acute exposure to cadmium produces placental toxicity in the human and rodent and whether protection can be provided by other metals (Zn, Se) and under other conditions (induction of metallothionein); 3. to compare the acute effects of Cd and to find a no effect dose in placentae from normal mothers and from smoking mothers in relationship to metallothionein content and induction, toxic response, and potential protection of chronic low Cd exposure to acute Cd exposure and 4. to utilize this in vitro human placental perfusion model to investigate the potential for other suspected placental toxins in animals, e.g., Pb and chloroform, to be directly placental toxic in the human under well-controlled conditions.

胎盘可以是一个特定的毒性作用的网站， 孕体的生长和存活，例如，镉会 导致大鼠胎盘坏死和胎儿死亡。 期间 过去三年，进行了研究，以确定 人类胎盘可以选择性地受到环境影响， 在动物或人类中检测到的水平。 一种体外双重 灌注的，再循环的人胎盘制剂， 是为了研究正常的生理学和对 没有母亲或婴儿的参与。 人类 胎盘灌注系统可以维持胎盘 形态学（超微结构）、生理学和 在生物化学上持续超过12小时。 当Cd 在大鼠中观察到的（Cd）水平下引入母体灌注液 血浆中的胎盘毒性剂量，有一个快速积累 胎盘中的cd几乎不通过胎儿回路。 内 在给予Cd后12小时， 相关（10、20或100 nmol/ml初始剂量）坏死增加， 亚合体滋养层泡状形成，间质水肿，胎儿体积 人绒毛膜细胞丢失（渗漏）（12小时内）和减少 促性腺激素合成和释放（4小时内）。 的 这项建议有四个目标：1.建立一种 24-36小时的体外人胎盘灌注模型 用于确定毒性相互作用和分布 在动物中观察到的循环血液水平的环境因子 和人类，并将该体外模型与其他 动物和人类研究。 拟议的研究将涉及 了解正常的生理功能， 胎盘（激素分泌，运输过程，特别是 维生素磁诱导受体介导的内吞作用12 和其他营养素，以及能量代谢）; 2.确定 急性接触镉产生 对人类和啮齿类动物的胎盘毒性以及是否具有保护作用 可以由其它金属（Zn、Se）提供，并且在其它金属（Zn、Se）下， 条件（金属硫蛋白的诱导）; 3.比较急性 镉的影响，并找到一个没有影响的剂量在胎盘， 正常母亲和吸烟母亲的关系， 金属硫蛋白含量和诱导，毒性反应， 慢性低镉暴露对急性镉的潜在保护作用 曝光，4。利用这种体外人类胎盘灌注 模型，以研究其他疑似胎盘 动物中的毒素，例如，铅和氯仿，直接被胎盘 在良好控制的条件下对人体有毒。