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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

Central Nervous System-Specific and Apoptosis-Related Gene Expression Values in Obese versus Lean Subjects.Each box encompasses the interquartile range (IQR) of log-normalized gene expression values for the gene of interest in all obese (shaded box) and all lean (white box) subjects. The dark horizontal lines represent the median gene expression value for the obese or lean subjects. The whiskers represent values within 1.5 times the interquartile range greater than or less than the upper or lower quartile, respectively. The open circles represent values greater than 1.5 times the interquartile range.
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pone-0088661-g002: Central Nervous System-Specific and Apoptosis-Related Gene Expression Values in Obese versus Lean Subjects.Each box encompasses the interquartile range (IQR) of log-normalized gene expression values for the gene of interest in all obese (shaded box) and all lean (white box) subjects. The dark horizontal lines represent the median gene expression value for the obese or lean subjects. The whiskers represent values within 1.5 times the interquartile range greater than or less than the upper or lower quartile, respectively. The open circles represent values greater than 1.5 times the interquartile range.

Mentions: Box-and-whisker plots were generated to examine the distribution of normalized gene expression data across samples (Figure S1), and to investigate the expression of genes of particular interest in obese versus lean study subjects (Figure 2). These plots demonstrate that the differences between groups are not driven by a single sample pair or by sample normalization, but indeed reflect differential expression between the obese and lean cohorts as a whole (Figure S1). Figure 2 depicts the distribution of log-normalized expression data for genes of interest, including genes tissue-specific for the central nervous system (APOD, CA11, PCLO), as well as those implicated in apoptotic pathways (BCL2, BCL2L11, BCL3, STK24). These boxplots provide further confirmation of the differences in gene expression in the obese and lean study populations for the CNS-specific genes, as well as for apoptosis-related genes, with clearly different median normalized gene expression values, no overlap in the interquartile ranges, and few outliers.


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)

Central Nervous System-Specific and Apoptosis-Related Gene Expression Values in Obese versus Lean Subjects.Each box encompasses the interquartile range (IQR) of log-normalized gene expression values for the gene of interest in all obese (shaded box) and all lean (white box) subjects. The dark horizontal lines represent the median gene expression value for the obese or lean subjects. The whiskers represent values within 1.5 times the interquartile range greater than or less than the upper or lower quartile, respectively. The open circles represent values greater than 1.5 times the interquartile range.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088661-g002: Central Nervous System-Specific and Apoptosis-Related Gene Expression Values in Obese versus Lean Subjects.Each box encompasses the interquartile range (IQR) of log-normalized gene expression values for the gene of interest in all obese (shaded box) and all lean (white box) subjects. The dark horizontal lines represent the median gene expression value for the obese or lean subjects. The whiskers represent values within 1.5 times the interquartile range greater than or less than the upper or lower quartile, respectively. The open circles represent values greater than 1.5 times the interquartile range.
Mentions: Box-and-whisker plots were generated to examine the distribution of normalized gene expression data across samples (Figure S1), and to investigate the expression of genes of particular interest in obese versus lean study subjects (Figure 2). These plots demonstrate that the differences between groups are not driven by a single sample pair or by sample normalization, but indeed reflect differential expression between the obese and lean cohorts as a whole (Figure S1). Figure 2 depicts the distribution of log-normalized expression data for genes of interest, including genes tissue-specific for the central nervous system (APOD, CA11, PCLO), as well as those implicated in apoptotic pathways (BCL2, BCL2L11, BCL3, STK24). These boxplots provide further confirmation of the differences in gene expression in the obese and lean study populations for the CNS-specific genes, as well as for apoptosis-related genes, with clearly different median normalized gene expression values, no overlap in the interquartile ranges, and few outliers.

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