Investigation for congenital anomaly. Relationship with diabetes mellitus and endocrine-disrupting chemical

先天性异常的调查。

基本信息

批准号：
14571563
负责人：
HIRAMATSU Yuji
金额：
$ 2.24万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571563/
关键词：
diabetes mellitus congenital anomaly diacylglyiceroly protein kinase C PPARγ endocrine-disrupting chemical advanced glycation end products hemorheology diabetic embryopaty diabetes pregnancy diacylglycerol hemodilution feteus a

项目摘要

Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade by excess glucose has been implicated in vascular complications of diabetes. Its involvement in diabetic embryopathy has not been established. We examined DAG production and PKC activities in embryos and decidua of streptozotocin (STZ)-diabetic or transiently hyperglycemic mice during neural tube formation. STZ diabetes significantly increased DAG and total PKC activity in decidua and embryos on day 9.5. Membrane-associated PKC alpha, betaII, delta, and zeta were increased in decidua by 1.25- to 2.8-fold. Maternal hyperglycemia induced by glucose injection on day 7.5, the day before the onset of neural tube formation, also increased DAG, PKC activity, and PKC isoforms in the embryo on day 9.5. These data indicate that hyperglycemia just before organogenesis activates the DAG-PKC cascade and is correlated with congenital defects.In diabetic mouse placenta, the expression of peroxisome proliferator-activated receptorγ(PP … More ARγ) and VEGF increased compared with that in normal placenta. In an in vitro study, the high glucose condition enhanced the PPARγ expression and hCG production, but suppressed cell proliferation. The addition of PPARγ ligands diminished the effects under the high glucose condition. Although the high glucose condition didn't affect VEGF production, the PPARγ ligands enhanced it under normal and high glucose conditions. These data suggest PPARγ and its target gene, VEGF, play a role in placentogenesis, especially during diabetic pregnancy. PPARγ ligands can eliminate the impairment of placental development induced by high glucose conditions, and VEGF might be involved in this pathway.We present evidence that the endocrine-disrupting chemical (EDCs) bisphenol A and phthalate activate estrogen receptor (ER) -mediated transcription through interaction with TRAP220. Moreover, bisphenol A had positive effects on the interaction between ER-beta and TRAP220 and on the expression of ER-beta and TRAP220 compared with phthalate and estradiol in uterine tissue. These data suggested that some EDCs might alter endocrine function through the change of the receptor and coactivator levels in uterine tIssue and through the different effect on the interaction between ERs and coactivator TRAP220.We studied the effects of advanced glycation end products (AGEs) and its receptor (RAGE) in human trophoblasts. RAGE was localized in trophoblasts. AGEs significantly stimulated secretion of both MIP-1 alpha and MIP-1 beta from trophoblasts in a time- and dose-dependent manner. AGEs significantly induced apoptosis and reduced secretion of hCG. Increased secretions of MIP-1 alpha and MIP-1 beta by AGEs were significantly suppressed by inhibitors of nitric oxide synthase (NOS) or nafamostat mesilate. These agents also suppressed the effects of AGEs on hCG secretion and trophoblastic apoptosis. These AGE-mediated changes in trophoblasts may lead to impairment of implantation and placentation.Blood rheological changes in streptozotocin-induced diabetic pregnant rats were examined. Diabetic pregnant rats with hypertentsion showed increased hematocrit, model capillary transient time of 100μl of whole blood and whole blood viscosity. Their fetuses were growth restricted Less

糖尿病的血管并发症中隐含了多种葡萄糖的二酰基甘油蛋白激酶C（DAG-PKC）级联反应的激活。尚未确定其参与糖尿病性胚胎病。我们在神经管形成期间检查了链蛋白酶（STZ） - 糖尿病或瞬时高血糖小鼠的胚胎和Decidua中的DAG产生和PKC活性。在第9.5天，DECIDUA和胚胎中的STZ糖尿病显着增加了DAG和PKC的总PKC活性。膜相关的PKC Alpha，Betaii，Delta和Zeta在DECIDUA中增加了1.25- 2.8倍。在第7.5天（神经管形成发作的前一天），葡萄糖注射诱导的母体高血糖诱导，在第9.5天，胚胎中的DAG，PKC活性和PKC同工型也会增加。这些数据表明，在器官发生之前高血糖激活了DAG-PKC级联反应，并与先天性缺陷相关。在糖尿病小鼠胎盘中，过氧化物体增殖物激活受体γ（PP…更多的ARγ）的表达与正常胎盘相比增加。在一项体外研究中，高葡萄糖疾病增强了PPARγ的表达和HCG的产生，但抑制了细胞增殖。 PPARγ配体的添加减少了高葡萄糖条件下的影响。尽管高葡萄糖条件不影响VEGF的产生，但在正常和高葡萄糖条件下，PPARγ配体增强了它。这些数据表明PPARγ及其靶基因VEGF在置换症中起作用，尤其是在糖尿病妊娠期间。 PPARγ配体可以消除高葡萄糖条件引起的lopenal发育的损害，而VEGF可能与该途径有关。我们提供证据表明，内分泌干扰化学（EDCS）双酚A和邻苯二甲酸酯激活了通过与Trap220相互作用的转录。此外，与子宫组织中的邻苯二甲酸盐和雌二醇相比，双球醇A对ER-BETA和TRAP220之间的相互作用以及ER-BETA和TRAP220的表达具有积极影响。这些数据表明，某些EDC可能会通过子宫组织中受体和共激活剂水平的变化以及对ERS与共激活器TRAP220之间的相互作用的不同影响来改变内分泌功能。我们研究了先进的糖化终端产物（AGES）及其在人滋养细胞中的效果。愤怒定位于滋养细胞中。年龄以时间和剂量依赖性方式显着刺激了从滋养细胞中从滋养细胞中分泌的MIP-1α和MIP-1β。年龄显着诱导凋亡和HCG分泌减少。一氧化氮合酶（NOS）或Nafamostat中酸盐抑制剂可显着抑制MIP-1α和MIP-1β的分泌物分泌物。这些药物还抑制了年龄对HCG分泌和滋养细胞凋亡的影响。这些年龄介导的滋养细胞变化可能会导致植入和放置的损害。检查了链蛋糕素诱导的糖尿病孕妇孕妇的流变学变化。糖尿病怀孕大鼠的高血压显示血细胞比容增加，模型毛细血管瞬态时间为100μl全血和全血粘度。他们的胎儿越来越限制