PLACENTAL TOXICOLOGY

胎盘可能是特定毒性作用的部位，损害 胚胎从出生到分娩的生长和存活，例如。 镉可导致啮齿动物胎盘坏死和胎儿死亡 人胎盘在灌流条件下的坏死。在过去 两年来，我们已经将人类胎盘的灌流时间延长到24小时 并开发了滋养层细胞和人类的三维培养 子宫内膜培养模式，从分离的细胞发展成腺体 间质被上皮所覆盖。利用灌流的人胎盘 都证明了锌可以保护人体免受 人体胎盘中的镉。此外，镉的初始作用 似乎是蛋白质合成而不是ATP，因为31P核磁共振/核磁共振 光谱分析显示HPL和hCG对ATP无明显影响 减少了。进一步的研究证实了对三磷酸腺苷的持续监测 证明人类胎盘有巨大的糖酵解 能力；然而，一旦耗尽-ATP水平确实会下降；然而，在 如果发生复氧，ATP的恢复是迅速和持久的。 在正常情况下，ATP水平在10小时内保持不变 灌流条件(研究的最长时间)。更多研究表明 证明人类胎盘(包括早期和晚期胎盘)可以代谢 类维甲酸，特别是异维甲酸(阿卡托品)为维甲酸。是这样的 人类胎盘的新陈代谢可能是该物种的部分原因 啮齿类动物与人类在致畸性方面的差异 这些特工。此外，还证明了肠道病毒不能穿透。 通过人类胎盘，即使在暴露15小时后，当病毒 在母体灌流液和胎盘样本中发现。具体目标 这一建议的主要内容是：1.确定镉(Cd)的关系 毒性及其修饰剂(锌、硒、钙) 已知胎盘功能和形态，2.确定早期 滋养层细胞及其与人子宫内膜的相互作用 (附着/侵入(“植入”)对镉和RU486有反应，3. 由于镉诱导金属硫蛋白(MT)，确定其调节 MT(I/II)的诱导及其与镉保护的关系 毒性，以及4.研究怀孕的不吸烟者和吸烟者的胎盘(&gt；30 香烟/天)，然后确定重度吸烟者是否 对体外急性胎盘毒性有保护作用。

The placenta can be a site for specific toxic action compromising the growth and survival of the conceptus from birth until delivery, e.g,. cadmium can produce placental necrosis and fetal death in rodents and necrosis under perfusion conditions in the human placenta. During the past two years, we have extended the perfusion of human placentae to 24 hours and developed a 3-dimensional culture of trophoblast and a human endometrial culture model, which develops from isolated cells into glands and stroma covered by epithelium. Utilizing the perfused human placenta we have documented that zinc can protect against acute toxic effects of cadmium in the human placenta. In addition, the initial actions of cadmium appear to be on protein synthesis rather than ATP, since 31p NMR/MRI spectroscopy demonstrated no effect on ATP while hPL and hCG were decreased. Further studies demonstrated continuous monitoring of ATP demonstrated that the human placenta has the tremendous glycolytic capacity; however, once exhausted - ATP levels do fall; however, at that point if reoxygenation occurs, recovery of ATP is rapid and persistent. ATP levels have been found constant for period of 10 hours under normal perfusion conditions (longest period studied). Additional studies have demonstrated that the human placenta (both early and term) can metabolize retinoids, in particular isotretinoin (Accutane) to tretinoin. Such metabolism by the human placenta may partially account for the species differences between rodents and human concerning the teratogenicity of these agents. Also it was demonstrated that enteroviruses do not penetrate through he human term placenta even after 15 hours of exposure, when virus is found in maternal perfusate and placental specimens. The specific aims of this proposal are: 1. Determine the relationship between cadmium (Cd) toxicity and modifiers of that toxicity (zinc, selenium and calcium) on known placental function and morphology, 2. Determine if the early trophoblast and its interaction with the human endometrium (Attachment/Invasion ("implantation") is responsive to Cd and Ru486, 3. Since Cd induces metallothionein (MT), determine the regulation of induction of MT(I/II) and its relationship to protection against Cd toxicity, and 4. Study placentae from pregnant nonsmokers and smokers (>30 cigarettes/day) using perfusion and then determine if heavy smokers are protected from the acute placental toxicity in vitro.