The developmental and reproductive toxicity of environmental contaminants by disrupting placental endocrine functions

在人类妊娠中，胎盘是类固醇激素的主要来源，类固醇激素对维持哺乳动物妊娠和胎儿发育的几个重要事件至关重要。考虑到胎盘的关键功能作用，疑似内分泌干扰物（EDCs）的环境污染物的发育和生殖毒性可能涉及胎盘。在这里，我们评估的影响，内分泌干扰物对类固醇激素在人胎盘使用人绒毛膜癌细胞。因此，我们发现一些有机锡化合物，如三丁基锡和三苯基锡，这是已知的导致雌性软体动物雄性化，是有效的刺激雌二醇（E2）的生物合成，以提高芳香酶，催化雄激素转化为雌激素，和17 β-羟基类固醇脱氢酶I型（17 ss-HSD I），其催化雌酮（E1）转化为E2，伴随着人胎盘中mRNA表达的增加。此外，这些有机锡化合物的功能 ...更多信息 离子作为维甲酸X受体（RXR）和过氧化物酶体增殖物激活受体γ的双重激动剂，通过RXR依赖的信号通路刺激人胎盘内分泌功能。这些结果表明，胎盘是这些化合物的潜在靶器官，其内分泌干扰作用可能是孕妇体内E2浓度局部变化的结果。尽管有机锡化合物在体外改变了人类胎盘细胞的E2生物合成，但仍不清楚内分泌干扰作用或畸形是否导致，至少部分是，从有机锡诱导的局部变化的E2浓度的胎盘在体内。此外，内分泌干扰物对人体胎盘的体内内分泌影响很难从动物研究中估计，特别是涉及啮齿动物的研究，因为人类妊娠期间的雌激素生物合成与啮齿动物有很大不同。在人类中，受精后卵巢功能逐渐下降，因为胎盘成为怀孕期间雌激素生物合成的主要场所。与人类的过程相反，卵巢（而不是胎盘）是啮齿动物怀孕期间雌激素的主要来源，因为啮齿动物的胎盘既不表达芳香化酶也不表达17 β-HSD I。因此，啮齿类动物不适合评价内分泌干扰物对人胎盘雌激素生物合成的影响。胎盘中雌激素生物合成的调节对人类胚胎非常重要，因为改变胎盘功能可对胚胎造成永久性影响。因此，迫切需要建立有效的工具来评估内分泌干扰作用和致畸性的内分泌干扰物，诱导局部雌激素浓度的变化，在体内胎盘。因此，我们尝试建立模型小鼠，其1）使用RGD纤维突变型腺病毒载体，或2）产生与小鼠胎盘特异性启动子组合的转基因小鼠，强制和限制人芳香化酶在胎盘中的表达。因此，我们建立了转基因小鼠，只表达人芳香化酶的滋养层巨细胞。少

In human pregnancy, the placenta is the main source of steroid hormones which are essential to several important events in maintenance of mammalian pregnancy and fetal development. Given the pivotal functional roles of the placenta, the developmental and reproductive toxicity of environmental contaminants suspected as endocrine-disrupting chemicals (EDCs) plausibly might involve them. Here, we assessed the effects of EDCs on steroidogenesis in human placenta by using human choriocarcinoma cells. As a result, we found some organotin compounds such as tributyltin and triphenyltin, which are known to cause masculinization in female mollusks, are potent stimulators of estradiol (E2) biosynthesis to enhance aromatase which catalyzes the conversion of androgens to estrogens, and 17ss-hydroxysteroid dehydrogenases type I (17ss-HSD I) which catalyzes the conversion estrone (E1) to E2, with a concomitant increase in mRNA expression in human placenta. In addition, these organotin compounds funct … More ion as dual agonists for retinoid X receptor (RXR) and peroxisome proliferator-activated receptor γ, and stimulate human placental endocrine function through RXR-dependent signaling pathway. These results suggest that the placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might be the result of local changes in E2 concentrations in pregnant women.Although organotin compounds alter E2 biosynthesis in human placental cells in vitro, it remains unclear whether endocrine-disrupting effects or malformations result, at least in part, from organotin-induced local changes in E2 concentrations of the placenta in vivo. Further, the in vivo endocrine effects of EDCs on the human placenta are difficult to estimate from animal studies, particularly those involving rodents, because estrogen biosynthesis during pregnancy in humans is much different from that in rodents. In humans, ovarian function gradually declines after fertilization, as the placenta becomes the primary site of estrogen biosynthesis during pregnancy. In contrast to the process in humans, the ovary (not the placenta) is the main source of estrogen during pregnancy in rodents, because the placenta of rodents expresses neither aromatase nor 17ss-HSD I. It has been suggested that rodents are therefore unsuitable for evaluating the effects of EDCs on estrogen biosynthesis in human placenta. The regulation of estrogen biosynthesis in placenta is very important for human embryo because altering placental function can cause permanent effects in the embryo. Consequently, there is an urgent need to establish effective tools to evaluate the endocrine-disrupting effects and teratogenicity of EDCs that induce changes in local estrogen concentrations of the placenta in vivo. Accordingly, we tried to establish model mice which force and restrict the expression of human aromatase to the placenta 1) using RGD fiber-mutant adenovirus vectors, or 2) producing transgenic mice, combined with the mouse placental specific promoter. As a result, we have established the transgenic mice which exclusively express human aromatase in trophoblast giant cells. Less