2003 Fiscal Year Final Research Report Summary
Investigation for congenital anomaly. Relationship with diabetes mellitus and endocrine-disrupting chemical
| Project/Area Number |
14571563
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
HIRAMATSU Yuji Okayama University, Graduate School of Medicine & Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (80218817)
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| Co-Investigator(Kenkyū-buntansha) |
MASUYAMA Hisashi Okayama University, Hospital, Assistant, 医学部・歯学部附属病院, 助手 (30314678)
MIZUTANI Yasushi Okayama University, Hospital, Associate Professor, 医学部・歯学部附属病院, 講師 (20294465)
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| Project Period (FY) |
2002 – 2003
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| Keywords | diabetes mellitus / congenital anomaly / diacylglyiceroly / protein kinase C / PPARγ / endocrine-disrupting chemical / advanced glycation end products / hemorheology |
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| Research Abstract |
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
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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
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Research Products
(18 results)
