Ergaz Zivanit, Neeman-Azulay Meytal, Weinstein-Fudim Liza, Weksler-Zangen Sarah, Shoshani-Dror Dana, Szyf Moshe, Ornoy Asher
Laboratory of Teratology, Department of Medical Neurobiology, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Neonatology, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
Birth Defects Res B Dev Reprod Toxicol. 2016 Feb;107(1):21-31. doi: 10.1002/bdrb.21169. Epub 2016 Jan 7.
Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa-B and hypoxia inducing factor-1α. Both strains fed diabetogenic diet had increased immunostaining for Bcl-2-like protein and caspase 3 and decreased immunostaining for 5-methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet-induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults.
宫内高血糖环境会损害胎儿，使其更容易在出生后出现葡萄糖耐量异常。一种可能的机制是胎儿胰腺发育受损。我们之前发现，高蔗糖低铜致糖尿病饮食可诱导科恩糖尿病敏感大鼠患2型糖尿病，但对萨布拉对照大鼠则无此作用。然而，在糖尿病和非糖尿病对照大鼠的胎盘和足月胎儿肝脏中均观察到氧化应激。我们现在研究了这种饮食是否会影响胎儿胰腺，以及这些影响是由氧化应激、母体高血糖还是两者共同导致的。对足月胎儿胰腺进行了形态学、β细胞、氧化应激、细胞凋亡和DNA甲基化评估。两种品系胎儿胰腺的苏木精-伊红染色切片和β细胞免疫染色均无微观变化。喂食致糖尿病饮食的敏感品系胎儿超氧化物歧化酶和过氧化氢酶活性显著更高，低分子量抗氧化剂水平升高，核因子κB和缺氧诱导因子-1α的免疫染色更强。两种品系喂食致糖尿病饮食的胎儿胰岛和腺泡中Bcl-2样蛋白和半胱天冬酶3的免疫染色增加，5-甲基胞嘧啶的免疫染色减少。我们的数据表明，母体致糖尿病饮食会改变足月胎儿胰腺的凋亡率和表观遗传稳态，与母体糖尿病无关。母体高血糖会进一步增加胰腺氧化应激，加重胰腺损伤。饮食对胎儿胰腺的损害可能是代谢性宫内损伤后糖尿病易感性高的一个重要因素。
