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Abstract
Maternal body mass index (BMI) before pregnancy is known to affect both fetal growth and later-life health of the newborn, yet the implicated molecular mechanisms remain largely unknown. As the master regulator of the fetal environment, the placenta is a valuable resource for the investigation of processes involved in the developmental programming of metabolic health. We conducted a genome-wide placental transcriptome study aiming at the identification of functional pathways representing the molecular link between maternal BMI and fetal growth. We used RNA microarray (Agilent 8 × 60 K), medical records, and questionnaire data from 183 mother-newborn pairs from the ENVIRONAGE birth cohort study (Flanders, Belgium). Using a weighted gene co-expression network analysis, we identified 17 correlated gene modules. Three of these modules were associated with both maternal pre-pregnancy BMI and newborn birth weight. A gene cluster enriched for genes involved in immune response and myeloid cell differentiation was positively associated with maternal BMI and negatively with low birth weight. Two other gene modules, upregulated in association with maternal BMI as well as birth weight, were involved in processes related to organ and tissue development, with blood vessel morphogenesis and extracellular matrix structure as top Gene Ontology terms. In line with this, erythrocyte-, angiogenesis-, and extracellular matrix-related genes were among the identified hub genes. The association between maternal BMI and newborn weight was significantly mediated by gene expression for 5 of the hub genes (FZD4, COL15A1, GPR124, COL6A1, and COL1A1). As some of the identified hub genes have been linked to obesity in adults, our observation in placental tissue suggests that biological processes may be affected from prenatal life onwards, thereby identifying new molecular processes linking maternal BMI and fetal metabolic programming.
Highlights
MATERIALS AND METHODSIn 2016, 39% of the world’s adult population was overweight, and 13% was obese (Abarca-Gómez et al, 2017)
Using weighted gene co-expression network analysis (WGCNA), we identified placental co-expressed gene modules and hub genes associated with both maternal pre-pregnancy body mass index (BMI) and weight of the newborn and we investigated whether these modules and hub genes mediated the association between pre-pregnancy BMI and newborn weight
Using WGCNA as an alternative method to conventional differential gene expression analyses, we found interesting clusters of co-expressed genes and intramodular hub genes in placental tissue that were correlated with both maternal pre-pregnancy BMI and birth weight of the newborns
Summary
MATERIALS AND METHODSIn 2016, 39% of the world’s adult population was overweight, and 13% was obese (Abarca-Gómez et al, 2017). In the context of fetal programming, it is well-accepted that an obesogenic intrauterine environment has long-lasting effects on the fetus. A high maternal body mass index (BMI) is a risk factor for adverse birth outcomes and infant death (Aune et al, 2014; Marchi et al, 2015), and offspring of obese mothers have a higher risk of developing obesity, diabetes, and cardiovascular diseases in later life (Gaillard, 2015). The placenta can undergo major structural and functional adaptations in order to protect the fetus from environmental stressors. If the organ’s capacity for adaptation is exceeded or if placental function is impaired, the intrauterine environment might be perturbed and fetal development could be affected, with potential adverse consequences for later-life health
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