| Co-Investigator(Kenkyū-buntansha) |
NAKANISHI Tsuyoshi Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究科, 助手 (50303988)
ITOH Norio Osaka University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 講師 (60176352)
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| Research Abstract |
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
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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
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