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Maternal obesity affects fetal neurodevelopmental and metabolic gene expression: a pilot study.

Edlow AG, Vora NL, Hui L, Wick HC, Cowan JM, Bianchi DW - PLoS ONE (2014)

Bottom Line: 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).Apoptotic cell death was significantly down-regulated, particularly within nervous system pathways involving the cerebral cortex.Maternal obesity affects fetal neurodevelopmental and metabolic gene expression as early as the second trimester.

View Article: PubMed Central - PubMed

Affiliation: Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.

ABSTRACT

Objective: 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.

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 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.

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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Related in: MedlinePlus

Principal Component Analysis of Genes Implicated in Central Nervous System Apoptosis.Figure demonstrates the results of the principal component analysis. Obese subjects are represented by red spheres and lean subjects are represented by black spheres. The results suggest that gene expression segregates on the basis of maternal BMI. On the x-axis is principal component (PC) 1, maternal body mass index (BMI), which accounts for the greatest proportion of variance in the gene expression data (21%). On the y-axis is PC 2, which accounts for the second greatest proportion of variance (14%).
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pone-0088661-g003: Principal Component Analysis of Genes Implicated in Central Nervous System Apoptosis.Figure demonstrates the results of the principal component analysis. Obese subjects are represented by red spheres and lean subjects are represented by black spheres. The results suggest that gene expression segregates on the basis of maternal BMI. On the x-axis is principal component (PC) 1, maternal body mass index (BMI), which accounts for the greatest proportion of variance in the gene expression data (21%). On the y-axis is PC 2, which accounts for the second greatest proportion of variance (14%).

Mentions: Within the IPA category of “Cell Death,” many functional annotations associated with the central nervous system (CNS) were significantly dysregulated in fetuses of obese women. Apoptosis of cerebral cortex cells, sympathetic neurons, cortical neurons, and neuroblastoma cell lines, cell viability of dendritic cells and hippocampal neurons, and cell death of hippocampal cells were all significantly dysregulated. To investigate the association between maternal BMI and CNS apoptosis, a post hoc principal component analysis (PCA) was performed utilizing all the genes annotated by IPA to CNS apoptosis (BCL2, BCL2L1, BCL2L11, CASP9, P4HB, REST, HMGA1, XBP1). The PCA demonstrated that within our dataset, genes implicated in CNS apoptosis segregated primarily by maternal BMI (Figure 3).


Maternal obesity affects fetal neurodevelopmental and metabolic gene expression: a pilot study.

Edlow AG, Vora NL, Hui L, Wick HC, Cowan JM, Bianchi DW - PLoS ONE (2014)

Principal Component Analysis of Genes Implicated in Central Nervous System Apoptosis.Figure demonstrates the results of the principal component analysis. Obese subjects are represented by red spheres and lean subjects are represented by black spheres. The results suggest that gene expression segregates on the basis of maternal BMI. On the x-axis is principal component (PC) 1, maternal body mass index (BMI), which accounts for the greatest proportion of variance in the gene expression data (21%). On the y-axis is PC 2, which accounts for the second greatest proportion of variance (14%).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928248&req=5

pone-0088661-g003: Principal Component Analysis of Genes Implicated in Central Nervous System Apoptosis.Figure demonstrates the results of the principal component analysis. Obese subjects are represented by red spheres and lean subjects are represented by black spheres. The results suggest that gene expression segregates on the basis of maternal BMI. On the x-axis is principal component (PC) 1, maternal body mass index (BMI), which accounts for the greatest proportion of variance in the gene expression data (21%). On the y-axis is PC 2, which accounts for the second greatest proportion of variance (14%).
Mentions: Within the IPA category of “Cell Death,” many functional annotations associated with the central nervous system (CNS) were significantly dysregulated in fetuses of obese women. Apoptosis of cerebral cortex cells, sympathetic neurons, cortical neurons, and neuroblastoma cell lines, cell viability of dendritic cells and hippocampal neurons, and cell death of hippocampal cells were all significantly dysregulated. To investigate the association between maternal BMI and CNS apoptosis, a post hoc principal component analysis (PCA) was performed utilizing all the genes annotated by IPA to CNS apoptosis (BCL2, BCL2L1, BCL2L11, CASP9, P4HB, REST, HMGA1, XBP1). The PCA demonstrated that within our dataset, genes implicated in CNS apoptosis segregated primarily by maternal BMI (Figure 3).

Bottom Line: 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).Apoptotic cell death was significantly down-regulated, particularly within nervous system pathways involving the cerebral cortex.Maternal obesity affects fetal neurodevelopmental and metabolic gene expression as early as the second trimester.

View Article: PubMed Central - PubMed

Affiliation: Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America.

ABSTRACT

Objective: 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.

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 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.

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.

Show MeSH
Related in: MedlinePlus