Epigenetic Profiling in the Saliva of Obese Pregnant Women

Abstract

Maternal obesity is associated with inflammation and oxidative stress, strongly impacting the intrauterine environment with detrimental consequences for both mother and offspring. The saliva is a non-invasive biofluid reflecting both local and systemic health status. This observational study aimed to profile the epigenetic signature in the saliva of Obese (OB) and Normal-Weight (NW) pregnant women. Sixteen NW and sixteen OB Caucasian women with singleton spontaneous pregnancies were enrolled. microRNAs were quantified by the OpenArray Platform. The promoter region methylation of Suppressor of Cytokine Signaling 3 (SOCS3) and Transforming Growth Factor Beta 1 (TGF-Beta1) was assessed by pyrosequencing. There were 754 microRNAs evaluated: 20 microRNAs resulted in being differentially expressed between OB and NW. microRNA pathway enrichment analysis showed a significant association with the TGF-Beta signaling pathway (miTALOS) and with fatty acids biosynthesis/metabolism, lysine degradation, and ECM–receptor interaction pathways (DIANA–miRPath). Both SOCS3 and TGF-Beta1 were significantly down-methylated in OB vs. NW. These results help to clarify impaired mechanisms involved in obesity and pave the way for the understanding of specific damaged pathways. The characterization of the epigenetic profile in saliva of pregnant women can represent a promising tool for the identification of obesity-related altered mechanisms and of possible biomarkers for early diagnosis and treatment of pregnancy-adverse conditions.

Characterization of Maternal Circulating MicroRNAs in Obese Pregnancies and Gestational Diabetes Mellitus

“…This is in accordance with data recently reported by our group, which showed a significant association between these pathways and salivary miRNAs of obese pregnant women in the third trimester of pregnancy [25]. These findings may be suggestive of a disarranged fatty acid metabolism, as well as an excessive lysine catabolism in obese pregnancies with or without GDM, which were mediated by miRNA epigenetic alterations.…”

“…Indeed, elevated TGF-Beta1 levels were associated with glucose intolerance and increased adiposity in women with a prior history of GDM [50,51]. The same pathway emerged from our previous miTALOS analysis of third trimester saliva of obese pregnant women [25]. Significantly decreased TGF-Beta1 gene methylation levels were also reported, supporting TGF-Beta1 upregulation.…”

“…For each of the three comparisons, miRNAs showing differential expression with a Fold Regulation >2 or <−2 and statistical significance (p-value < 0.05) were further investigated to better understand their biological role. Pathways prediction analyses were performed using two of the most updated and literature-accepted online bioinformatics tools: miTALOS and DIANA-miRPath, as previously described by our group [25].…”

Dilemma of Epigenetic Changes Causing or Reducing Metabolic Disorders in Offsprings of Obese Mothers

“…Among these, hsa-miR-505 and hsa-miR-616 were downregulated while hsa-miR-618, hsa-miR-206, hsa-miR-376a, hsa-miR-517c, hsa-miR-133a, hsa-miR-1285, hsa-miR-635, hsa-miR-551b, hsa-miR-548b-5p, hsa-miR-1256, hsa-miR-302c, hsa-miR-184, and hsa-miR-548c-5p were upregulated in obese pregnant women. These miRNAs were found to be associated with the TGF-β signalling pathway, fatty acids biosynthesis/metabolism, lysine degradation, and ECM-receptor interaction pathways through miRNA pathway enrichment analysis indicating the susceptibility of offspring towards metabolic disorder [87]. Zhao et al observed 23 circulatory miRNAs including miR-15b, MiR-31, miR-122, miR-125b, miR-142, miR-130b, and miR-519d that were associated with obesity and weight gain [88].…”

Maternal and Placental DNA Methylation Changes Associated with the Pathogenesis of Gestational Diabetes Mellitus

“…In addition, the mRNA expression of SOCS3 in visceral fat of GDM women increased, and there was no significant difference in promoter methylation [ 53 ]. The methylation level of the SOCS3 promoter region in saliva of obese pregnant women was lower than that of the control group [ 54 ]. The increase of SOCS3 expression leads to the down-regulation of JAK2 pathway and the impairment of STAT3 signal, leading to leptin resistance, obesity and abnormal glucose metabolism [ 41 ] ( Figure 3 ).…”