母亲肥胖影响胎儿神经发育和代谢基因表达：一项试验研究
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Maternal Obesity Affects Fetal Neurodevelopmental and Metabolic Gene Expression: A Pilot Study
背景
在美国，每三个孕妇中就有一个是肥胖的。他们的后代患神经发育和代谢性疾病的风险增加。潜在的分子机制了解甚少。我们对肥胖与偏瘦的孕妇孕中期羊水中胎儿游离RNA进行了基因表达分析。
方 法
这项前瞻性研究包括临床表明可行孕中期羊膜腔穿刺的八名肥胖（BMI≥30）与八名偏瘦（BMI＜25）患者。用孕龄和胎儿性别将受试者匹配。异常核型或结构异常的染色体组型被排除在外。从羊水中提取胎儿游离RNA，并与全基因组表达阵列杂交。采用配对t检验分组并用Benjamini Hochberg校正（P< 0.05）。用IPA软件和基因表达图谱进行生物学分析。
结 果
肥胖孕妇胎儿中有205个基因差异显著。载脂蛋白D，大量表达于中枢神经系统的调节血脂的基因，是表达上调的。凋亡细胞显著下调，特别是在涉及大脑皮层的神经系统通路中。在肥胖妇女的胎儿中检测到转录调节雌激素受体蛋白、fos和STAT3的激活，表明了是促雌激素、促炎症的环境。
结 论
母亲肥胖早在孕中期就影响胎儿神经发育和代谢基因表达。这些发现可能对肥胖妇女后代中出现的后天神经发育和代谢异常有意义。
原始文献摘要
OBJECTIVE:
One in three pregnant women in the United States is obese. Their offspring are at increased risk for neurodevelopmentaland metabolic morbidity. Underlying molecular mechanisms are poorly understood. We performed a global gene expression analysis of mid-trimester amniotic fluid cell-free fetal RNA in obese versus lean pregnant women.
METHODS:
This prospective pilot study included eight obese (BMI≥30) and eight lean (BMI<25) women undergoing clinically indicated mid-trimester genetic amniocentesis. Subjects were matched for gestational age and fetal sex. Fetuses with abnormal karyotype or structural anomalies were excluded. Cell-free fetal RNA was extracted from amniotic fluid and hybridized to whole genome expressionarrays. Genes significantly differentially regulated in 8/8 obese-lean pairs were identified using paired t-tests with the Benjamini-Hochberg correction (false discovery rate of <0.05). Biological interpretation was performed with Ingenuity Pathway Analysis and the BioGPS gene expression atlas.
RESULTS:
In fetuses of obese pregnant women, 205 genes were significantly differentially regulated. Apolipoprotein D, a gene highly expressed in the central nervous system and integral to lipid regulation, was the most up-regulated gene (9-fold). Apoptotic cell death was significantly down-regulated, particularly within nervous system pathways involving the cerebral cortex. Activation of the transcriptional regulators estrogen receptor, FOS, and STAT3 was predicted in fetuses of obese women, suggesting a pro-estrogenic, pro-inflammatory milieu.
CONCLUSION:
Maternal obesity affects fetal neurodevelopmental and metabolic gene expression as early as the second trimester. These findings may have implications for postnatal neurodevelopmental and metabolic abnormalities described in the offspring of obese women.
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