Edlow Andrea G, Vora Neeta L, Hui Lisa, Wick Heather C, Cowan Janet M, Bianchi Diana W
Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.
Department of Computer Science, Tufts University, Medford, Massachusetts, United States of America.
PLoS One. 2014 Feb 18;9(2):e88661. doi: 10.1371/journal.pone.0088661. eCollection 2014.
One in three pregnant women in the United States is obese. Their offspring are at increased risk for neurodevelopmental and 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.
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 expression arrays. 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.
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.
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.
在美国，三分之一的孕妇肥胖。她们的后代患神经发育和代谢疾病的风险增加。其潜在的分子机制尚不清楚。我们对肥胖与体重正常的孕妇孕中期羊水游离胎儿RNA进行了全基因组表达分析。
这项前瞻性试点研究纳入了8名肥胖（BMI≥30）和8名体重正常（BMI<25）且正在接受临床指征的孕中期遗传羊膜腔穿刺术的女性。受试者在孕周和胎儿性别方面进行了匹配。排除染色体核型异常或结构异常的胎儿。从羊水中提取游离胎儿RNA，并与全基因组表达阵列杂交。使用经Benjamini-Hochberg校正的配对t检验（错误发现率<0.05）来识别在8/8对肥胖与体重正常的样本中显著差异调节的基因。使用Ingenuity Pathway Analysis和BioGPS基因表达图谱进行生物学解释。
在肥胖孕妇的胎儿中，有205个基因受到显著差异调节。载脂蛋白D是在中枢神经系统中高度表达且对脂质调节至关重要的基因，是上调最明显的基因（9倍）。凋亡性细胞死亡显著下调，尤其是在涉及大脑皮质的神经系统通路中。预测肥胖女性胎儿中的转录调节因子雌激素受体、FOS和STAT3被激活，提示存在促雌激素、促炎环境。
孕妇肥胖早在孕中期就会影响胎儿神经发育和代谢基因的表达。这些发现可能对肥胖女性后代中描述的产后神经发育和代谢异常具有启示意义。
