EFFECTS OF COCAINE ON PLACENTAL GROWTH FACTORS

在怀孕期间滥用可卡因的情况急剧增加。 有胎儿宫内发育迟缓、胎盘早剥和早产 送货。拟议研究的目的是调查 胎盘中的细胞和生化变化与 在怀孕期间接触可卡因。我们最近对人类的研究 和大鼠胎盘表明暴露在香烟烟雾中，并分离出来 香烟烟雾的成分，与选择性 生长因子受体的变化。拟议的研究将 使用相关方法研究可卡因对胎盘的影响 成长。第一个具体目标将调查是否 孕鼠给予可卡因具有剂量依赖性效应 胎盘重量。孤立迷路、基底带和蜕膜部 将称量胎盘的重量并进行组织学检查以寻找证据 出血和胎盘早剥。可卡因及其主要毒物的浓度 代谢物将在母体和胎儿血浆中进行测量。数据将 被分析以确定是否存在剂量依赖关系 在注射可卡因的量、母亲血浆可卡因水平之间， 和胎盘生长。 第二个具体目标将检查可卡因暴露是否会改变 母胎界面的生长因子受体。表皮生长因子与胰岛素 将描述受体结合和受体自动磷酸化的特征 胎盘组织的基底带和蜕膜部分 接触剂量的可卡因会导致胎盘发育迟缓。 在基底带组织中不存在胎儿血管成分的情况下， 这些研究应该提供仅与产妇有关的变化的证据。 血管供应。培养的大鼠滋养层细胞将用于检测 体外可卡因暴露是否对EGF和胰岛素有直接影响 感受器。拟议研究的第三个具体目标是 调查接触可卡因是否会改变胎盘肽激素 综合。大鼠胎盘催乳素II、大鼠催乳素样蛋白的合成 蛋白A和B，以及妊娠特异的β1糖蛋白 在服用可卡因的怀孕大鼠的基底区组织中进行了研究。 孕妇血清中这些胎盘蛋白的水平也将被测量。 这些实验将提供关于是否存在剂量的信息- 可卡因对胎盘蛋白质合成的相关影响，或可能是 母体血浆可卡因水平与循环的关系 胎盘蛋白。具体目标四将调查可卡因是否 改变母胎界面细胞因子的产生。这个 产生粒细胞-巨噬细胞集落刺激因子(GM-CSF)， 单核细胞集落刺激因子与转化生长因子 母体蜕膜和胎儿基底带组织中的转化生长因子-β 通过生物测定和免疫学程序进行定量。这些实验将会 提供关于可卡因是否具有潜在免疫功能的重要信息 抑制胎盘细胞因子的产生。如果可卡因做到了 抑制蜕膜产生GM-CSF和/或CSF-1，最终特异性 AIM将检查细胞因子治疗是否会逆转胎盘和/或 与可卡因联合给药对怀孕大鼠的胎儿毒性。在……里面 综上所述，拟议的研究将在体内和体外评估几个 可卡因在啮齿动物胎盘中的毒性模型。

Cocaine abuse during pregnancy has increased dramatically in association with intrauterine growth retardation, placental abruption and premature delivery. The objective of the proposed research is to investigate cellular and biochemical alterations in the placenta which are associated with exposure to cocaine during pregnancy. Our recent studies with human and rat placenta indicate that exposure to cigarette smoke, and isolated constituents of cigarette smoke, are associated with selective alterations in receptors for growth factors. The proposed research will use a related approach to investigate the effects of cocaine on placental growth. The first specific aim will investigate whether the administration of cocaine to pregnant rats has dose-dependent effects on placental weight. Isolated labyrinth, basal zone and decidua portions of the placenta will be weighed and examined histologically for evidence of hemorrhage and abruptions. Concentrations of cocaine and its major metabolites will be measured in maternal and fetal plasma. Data will be analyzed to determine if there are dose-dependent relationships between amount of cocaine administered, maternal plasma cocaine levels, and placental growth. The second specific aim will examine whether cocaine exposure alters growth factor receptors at the maternal-fetal interface. EGF and insulin receptor binding and receptor autophosphorylation will be characterized in basal zone and decidua portions of placental tissue following maternal exposure to doses of cocaine which produce placental growth retardation. Insofar as no fetal vascular elements are present in basal zone tissue, these studies should provide evidence of changes related only to maternal vascular supply. Cultured rat trophoblast cells will be used to examine whether cocaine exposure in vitro has direct effects on EGF and insulin receptors. The third specific aim of the proposed research will investigate whether cocaine exposure alters placental peptide hormone synthesis. The synthesis of rat placental lactogen II, rat prolactin-like proteins A and B, and pregnancy specific-beta1 glycoprotein will be studied in basal zone tissue from pregnant rats administered cocaine. Maternal serum levels of these placental proteins will also be measured. These experiments will provide information on whether there is a dose- related effect of cocaine on placental protein synthesis, or possibly a relationship between maternal plasma levels of cocaine and circulating placental proteins. Specific aim four wil investigate whether cocaine alters cytokine production at the maternal-fetal interface. The production of granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte colony-stimulating factor (CSF-1) and transforming growth factor beta (TGF-beta) by maternal decidua and fetal basal zone tissue wil be quantitated by bioassay and immunologic procedures. The experiments will provide important information on whether cocaine has potential immuno- suppressive effects on placental cytokine production. If cocaine does suppress decidual production of GM-CSF and/or CSF-1, the final specific aim will examine if cytokine therapy will reverse the placental and/or fetal toxicity when co-administered with cocaine to pregnant rats. In summary, the proposed research will evaluate several in vivo and in vitro models of toxicity of cocaine in the rodent placenta.