161 - The Role of Maternal Obesity in Offspring Congenital Heart Defects

Publication Number: 161.6928

Ashleigh McMullan, Indiana University School of Medicine, Indianapolis, IN, United States; James Zwierzynski, Stanford University School of Medicine, Stanford, CA, United States; Kevin Carthy, Indiana University School of Medicine, Carmel, IN, United States; Nina J. Jain, University of California, Davis, Carmel, IN, United States; Laura Haneline, Riley Hospital for Children at Indiana University Health, Indianapolis, IN, United States; Caelan Rathke, Indiana University School of Medicine, Shelbyville, IN, United States; Ellen Trautman, Indiana University School of Medicine, Zionsville, IN, United States; Kok Lim Kua, Indiana University School of Medicine, Indianapolis, IN, United States; Swetansu Hota, Indiana University School of Medicine, Indianapolis, IN, United States; Matthew Durbin, Indiana University School of Medicine Riley Hospital for Children, Indianapolis, IN, United States

Background: Congenital heart disease (CHD) is the most common birth defect and the leading cause of birth defect-related death. However, many of the molecular mechanisms remain unknown. Maternal obesity and diabetes are linked to an increased risk of CHD in fetuses and are becoming more prevalent worldwide. Recent studies suggest that maternal obesity and diabetes have different risk profiles and may therefore involve distinct teratogenic mechanisms for CHD.

Objective: Maternal obesity is a known risk factor for fetal CHD, but the mechanism is mostly unexplored. We will interrogate the mechanism of fetal CHD due to maternal obesity.

Design/Methods: We employed a murine model of diet-induced maternal obesity, without diabetes, to produce dams that were overweight but had normal blood glucose levels. We then generated embryos and performed analysis on developing embryo hearts to interrogate the mechanism of CHD pathology due to maternal obesity. We performed a complementary analysis of the transcriptome, using both single-nuclei (snRNAseq) and bulk RNA sequencing (RNA-seq), as well as both global and phospho-enriched proteome analysis using tandem-mass tag mass spectroscopy (TMT-MS), as well as histologic evaluation.

Results: Analysis revealed mechanistic insight, including disrupted oxidative phosphorylation and reactive oxygen species formation. There was also reduced antioxidant capacity, with downregulated Sod1, Gp4x, and Hif1a signaling. Finally, results demonstrated upregulated oxidative stress signalling, cell death, and altered rho kinase and actin cytoskeleton signalling. Histologic analysis confirmed increased embryo cardiac defects due to maternal obesity.

Conclusion(s): These data provide valuable insight into the role of maternal obesity in offspring CHD. The findings highlight that maternal obesity results in cardiac defects with mechanisms mirroring the cardiac defects due to maternal hyperglycemia. These findings are important for understanding how the growing and modifiable risk factor, obesity, contributes to the most common birth defect, CHD.