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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

过量葡萄糖激活二酰基甘油蛋白激酶C （DAG-PKC）级联与糖尿病血管并发症有关。它与糖尿病胚胎病的关系尚未确定。我们检测了链脲霉素（STZ）糖尿病小鼠或短暂性高血糖小鼠在神经管形成过程中胚胎和蜕膜中DAG的产生和PKC的活性。第9.5天，STZ糖尿病显著提高蜕膜和胚胎的DAG和总PKC活性。膜相关PKC α， β i， δ和zeta在蜕膜中增加了1.25- 2.8倍。在第7.5天，即神经管形成开始的前一天，葡萄糖注射引起的母体高血糖也增加了第9.5天胚胎中DAG、PKC活性和PKC异构体。这些数据表明，器官发生前的高血糖激活了DAG-PKC级联，并与先天性缺陷相关。与正常胎盘相比，糖尿病小鼠胎盘中过氧化物酶体增殖物活化受体γ(ppp, ARγ)和VEGF的表达增加。在体外研究中，高糖条件增强PPARγ表达和hCG生成，但抑制细胞增殖。PPARγ配体的加入降低了高糖条件下的影响。虽然高糖条件不影响VEGF的产生，但PPARγ配体在正常和高糖条件下增强了VEGF的产生。这些数据表明PPARγ及其靶基因VEGF在胎盘发生中发挥作用，特别是在糖尿病妊娠期间。PPARγ配体可以消除高糖诱导的胎盘发育损伤，VEGF可能参与了这一途径。我们提出的证据表明，内分泌干扰化学物质（EDCs）双酚A和邻苯二甲酸酯通过与TRAP220相互作用激活雌激素受体（ER）介导的转录。此外，与邻苯二甲酸盐和雌二醇相比，双酚A对子宫组织中er - β和TRAP220的相互作用以及er - β和TRAP220的表达有积极的影响。这些数据提示，一些EDCs可能通过改变子宫组织中受体和辅激活因子的水平，以及通过对er与辅激活因子TRAP220相互作用的不同影响来改变内分泌功能。我们研究了晚期糖基化终产物（AGEs）及其受体（RAGE）在人滋养细胞中的作用。RAGE定位于滋养细胞。AGEs显著刺激滋养细胞分泌MIP-1 α和MIP-1 β，并呈时间和剂量依赖性。AGEs显著诱导细胞凋亡，减少hCG分泌。一氧化氮合酶（NOS）或甲磺酸那莫他酯抑制剂可显著抑制AGEs分泌的MIP-1 α和MIP-1 β。这些药物还抑制了AGEs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导致着床和胎盘受损。观察链脲佐菌素诱导的糖尿病妊娠大鼠血液流变学变化。糖尿病妊娠高血压大鼠红细胞压积升高，全血模型毛细血管瞬时时间100μl，全血黏度升高。他们的胎儿生长受限较少