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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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Flow of Subjects Through the Study.Process by which the final subjects were selected for microarray analysis.
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pone-0088661-g001: Flow of Subjects Through the Study.Process by which the final subjects were selected for microarray analysis.

Mentions: This was a prospective pilot study of women with singleton fetuses without structural anomalies undergoing second trimester (14–24 weeks) genetic amniocentesis at Tufts Medical Center. Subjects signed informed consent for amniocentesis, which was performed for standard clinical indications (advanced maternal age, ultrasonographic soft markers of aneuploidy, abnormal serum screening results, or maternal request). Women with a BMI≥30 (obese, n = 14) or <25 (lean, n = 23) at the time of amniocentesis were enrolled. Per protocol, access to the medical record was limited to clinical information available at the time of amniocentesis (i.e. indications for the procedure, presence/absence of fetal anomalies, standard maternal demographic data), and cytogenetic results. Fetuses later found to have an abnormal karyotype, or those with RNA or cDNA of insufficient quality or quantity to hybridize to microarrays, were subsequently excluded. We aimed for a target of at least eight samples per group, based on the demonstration that near-maximal levels of statistical stability are obtained with between eight and 15 biological replicates in microarray studies [26]. Figure 1 depicts the flow of subjects through the study. Samples were matched for gestational age and fetal sex, both of which have been previously shown to influence fetal gene expression [13], [27]. The amniotic fluid samples were centrifuged at 165× g for 10 minutes at room temperature to separate amniocytes for subsequent diagnostic testing. The residual AFS was stored at −80°C until RNA extraction.


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)

Flow of Subjects Through the Study.Process by which the final subjects were selected for microarray analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0088661-g001: Flow of Subjects Through the Study.Process by which the final subjects were selected for microarray analysis.
Mentions: This was a prospective pilot study of women with singleton fetuses without structural anomalies undergoing second trimester (14–24 weeks) genetic amniocentesis at Tufts Medical Center. Subjects signed informed consent for amniocentesis, which was performed for standard clinical indications (advanced maternal age, ultrasonographic soft markers of aneuploidy, abnormal serum screening results, or maternal request). Women with a BMI≥30 (obese, n = 14) or <25 (lean, n = 23) at the time of amniocentesis were enrolled. Per protocol, access to the medical record was limited to clinical information available at the time of amniocentesis (i.e. indications for the procedure, presence/absence of fetal anomalies, standard maternal demographic data), and cytogenetic results. Fetuses later found to have an abnormal karyotype, or those with RNA or cDNA of insufficient quality or quantity to hybridize to microarrays, were subsequently excluded. We aimed for a target of at least eight samples per group, based on the demonstration that near-maximal levels of statistical stability are obtained with between eight and 15 biological replicates in microarray studies [26]. Figure 1 depicts the flow of subjects through the study. Samples were matched for gestational age and fetal sex, both of which have been previously shown to influence fetal gene expression [13], [27]. The amniotic fluid samples were centrifuged at 165× g for 10 minutes at room temperature to separate amniocytes for subsequent diagnostic testing. The residual AFS was stored at −80°C until RNA extraction.

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