PLACENTAL TOXICOLOGY

这项建议的目标是开发一种体外人类啮齿动物 建立胎盘模型，建立正常功能，并测定 环境制剂的药代动力学和毒性，例如重金属， 对母亲和胎儿都没有风险。具体来说，目标是(1) 建立具有生理和形态功能的灌流系统 用于评估正常母亲和接触过艾滋病的人的胎盘 环境毒素，如吸烟的母亲；(2)发育成人-啮齿动物 用胎盘模型直接检测阿昔洛韦的药代动力学和毒性 以镉为原型的环境制剂；(3)将镉关联起来 人胎盘滋养层结构和功能的暴露 并确定(A)镉引起其变化的机制和 (B)锌和硒在改变镉的影响方面的作用； 研究镉结合的滋养细胞蛋白的类型和 胎盘金属硫蛋白的诱导特性 金属硫蛋白的其他潜在来源。三个一般工艺将是 用于这些研究：a)体外人胎盘小叶灌流 激素的合成和释放.氨基酸的双向运输 转移；膜完整性-菊粉转移；母体/胎儿pO2，pCO2， PH、血糖、血压和流速；血流分布 (微球)、线粒体Ca++水平、Cd和Cd的药代动力学 形态学)；b)体外切片技术(与特定试剂孵育 测定在相同条件下的摄取和结合/代谢 啮齿动物和人类；c)体内Wistar大鼠毒性研究(一般毒性 分析，激素状态(雌激素，黄体酮)，器官血流 (微球)、药代动力学、线粒体钙水平和 形态学。本研究的目的是为了更好地适应环境的变化。 滋养层细胞对环境的暴露，无论是在人还是在动物中 反映在这些形态、生化和生理上 回应。然而，同样重要的是继续发展 生理、生化、形态和内分泌标准 现在7个小时。但正在朝着18-24小时的方向发展。灌流。有了这样一个 人-啮齿动物胎盘模型的潜力确定正常 对人胎盘的功能、药代动力学和妥协可能是 接受调查，不会对母亲或婴儿造成风险。

The objectives of this proposal are to develop an in vitro human-rodent placental model to establish normal function, and to determine the pharmacokinetics and toxicity of environmental agents, e.g., heavy metals, without risk to either mother or fetus. Specifically, the aims are (1) to establish a physiologically and morphologically functional perfusion system for evaluating human placentae from normal mothers and those exposed to environmental toxins, e.g., smoking mothers; (2) to develop a human-rodent placental model for directly examining the pharmacokinetics and toxicity of environmental agents using cadmium as a prototype; (3) to correlate cadmium exposure with trophoblastic structure and function in the human placenta and determine (a) the mechanisms by which cadmium induces its change and (b) the role of zinc and selenium in modifying the effects of Cd; (4) to study the types of trophoblastic proteins to which cadmium binds and the induction characteristics for placental metallothionein, when there is no other potential source for metallothionein. Three general technics will be utilized for these studies: A) in vitro human placental lobule perfusion (hormone synthesis and release; amino acid transport-bidirectional transfer; membrane integrity-inulin transfer; maternal/fetal pO2, pCO2, pH, glucose, blood pressure and flow rate; blood flow distribution (microspheres), mitochondrial Ca++ levels, pharmacokinetics of Cd and morphology); B) in vitro slice technic (incubation with specific agents to determine uptake and binding/metabolism under identical conditions for rodent and human; C) in vivo Wistar rat toxicity studies (general toxicity analysis, hormonal status (estrogens, progesterones), organ blood flow (microspheres), pharmacokinetics, mitochondrial calcium levels, and morphology. This research is targeted at the adaptability of the trophoblast to environmental exposure whether in man or in animal as reflected in these morphological, biochemical, and physiological responses. However, equally important is the continuing development of physiological, biochemical, morphological and endocrinological standards now for 7 hrs. but progressing toward an 18-24 hr. perfusion. With such a human-rodent placental model, the potential for determining normal function, pharmacokinetics and compromise to the human placenta may be investigated without risk to either mother or baby.