DNA methylation profile of the mother-child binomial in maternal obesity, fetal and neonatal adiposity

Author(s)

Perla Pizzi Argentato

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Saúde Pública (FSP/CIR)
• Defense date: 2022-07-28

Examining board members

Patricia Helen de Carvalho Rondó; Regina Mara Fisberg; Carla Barbosa Nonino; Fábio da Veiga Ued

• Advisor: Patricia Helen de Carvalho Rondó

Abstract

Introduction: An epigenetic mechanism by which the adverse effects of the intrauterine environment are transferred to offspring is DNA methylation. Objective: Evaluate the relationship between maternal obesity, gestational weight gain and DNA methylation alteration on fetal and neonatal development. Methodology: Subpopulation of pregnant women from the prospective epidemiological study \"Cohorte Araraquara\" were followed during the three trimesters of pregnancy, delivery and postpartum and were allocated into 2 groups: A. adequate weight (N=25) and B. overweight/obesity (N=39 pregnant women). Fetal biometry and adiposity were evaluated by ultrasound and the neonate\'s body composition by plethysmography, with the PEA POD (Cosmed®, Concord, CA, USA). Maternal diet in the end of pregnancy was investigated using 24-hour recalls and analyzed using the Nutrition Data System for Research software (NDSR, Minnesota, USA). DNA maternal and umbilical cord blood, and placental villus and decidua were extracted using proteinase K by the santing-out method. The hypo and hypermethylated regions were analyzed by the Methylation Sensitive Enzymatic Digestion technique associated with quantitative PCR (qPCR) and gene expression by qPCR. To analyze the influence of gestational weight gain (GWG), maternal blood DNA from pregnant women with adequate AGWG (N=8) versus excessive EGWG (N=8) was hybridized on the Human Methylation 850K Bead Chip (Illumina, CA). For statistical analysis, the t test, chi-square (X2) test, repeated measures ANOVA and multiple linear regression models were applied, and the significance level adopted was p≤0.05. Results: The pre-gestational weight, pre-gestational BMI and BMI during pregnancy were higher in group B. In this same group, higher values of fasting insulin, us-CRP and lipid consumption were found in relation to group A. subcutaneous abdominal fat thickness (SCFT) and subcutaneous fat of the fetal arm was also higher in group B compared to group A. Regarding the body composition of neonates, the amount of fat mass was higher in group B. The H19DMR gene was less methylated in maternal blood from group B. No statistical difference was found in the values of IGF2 and H19 gene expression between the groups. There were associations between methylation of the H19DMR gene in umbilical cord blood with fetal biparietal diameter (BPD) and SCFT and neonatal head circumference (HC); in the decidua with occipito frontal diameter (OFD), fetal length and HC; in the villi with DOF, HC and SCFT and neonatal HC. Excessive gestational weight gain altered 46 CpG sites, 11 differentially methylated regions (DMRs) located in 13 genes, namely: EMILIN1, HOXA5, CPT1B, CLDN9, ZFP57, BRCA1, POU5F1, ANKRD33, HLA-B, RANBP17, ZMYND11, DIP2C, TMEM232. These DMRs were enriched in 142 biological processes, 21 molecular functions, 17 cellular components and 9 human phenotypes. In addition, 3 differentially methylated gene modules were identified to the phenotype of interest. Conclusion: DNA methylation was altered by maternal nutritional status and was associated with fetal adiposity and growth. Excessive GPG altered maternal methylome and was associated with the phenotype of metabolic diseases such as diabetes mellitus. (AU)

• FAPESP's process: 18/17824-0 - DNA metilation profile of mother-concept binomy in the context of Maternal Obesity and fetal and neonatal adiposity
• Grantee: Perla Pizzi Argentato
• Support Opportunities: Scholarships in Brazil - Doctorate