Effect of Gestational Diabetes and Maternal Obesity on Fetal Programming—Are miRNAs Key Epigenetic Modifiers or Biomarkers of an Altered Intrauterine Milieu?

Abstract

Background: Pregnancies complicated by gestational diabetes (GDM) or maternal obesity (MOB) induce abnormal fetal development that can lead to diabetes and obesity later in life with sex specific manifestations. Alterations in miRNA expression in GDM and MOB exposed offspring and effects on development have not been fully described. Hypothesis: Exposure to an aberrant intrauterine milieu complicated by GDM and MOB leads to changes in miRNA and target gene expression in human fetal liver. Methods: Candidate miRNA expression was measured in second trimester AF from women diagnosed with GDM via multiplex miRNA assay (Firefly Bioworks, Abcam). Gene targets of differentially expressed miRNAs were determined from TargetScan and pathway enrichment determined via Ingenuity Pathway Analysis (IPA). MiRNA and target gene expression (mRNA and protein) were measured in a separate cohort of 2nd trimester primary human fetal hepatocytes (PHFH) exposed to MOB via QPCR and western blot. All studies were approved by UPENN and TEMPLE University IRBs. Results: GDM exposed AF had significant increases in miRNAs 199a-3p, 503-5p, and 1268a (p<0.05) and sex specific analysis showed enrichment in miRNAs 378a-3p, 885-5p, and 7-1-3p in female offspring samples (p<0.05). IPA with gene targets of enriched miRNAs centered hepatic pathways. GDM exposed AF miRNA enrichment was confirmed in PHFH exposed to MOB for miRNAs 885-5p, 199-3p, 503-5p, and 7-1-3p (p<0.05). Female PHFH exposed to MOB were enriched for miRNAs 885-5p, 199-3p, 503-5p, and 7-1-3p (p<0.05) and corresponded to decreased expression of target genes ABCA1, PAK4. In male PHFHs, no miRNA expression changes were measured but there was increased expression of ABCA1 and PAK4 (p<0.05). Conclusion: Our data suggest sex specific changes in miRNA and target gene expression in PHFH may be one mechanism responsible for sex specific metabolic changes in offspring exposed to GDM and obesity in utero. Disclosure A. Joshi: None. L. Goetzl: None. S.E. Pinney: None.