(55) Investigating Maternal Obesity's Role in Congenital Heart Defects Using Multi-Omics Analysis of a Murine Model

Background: Congenital heart disease (CHD) is the most common birth defect and is the leading cause of birth defect-related death; Despite its prevalence, its pathogenesis is mostly unknown. There is an increased risk of fetal CHD associated with maternal obesity. Obesity is a major public health concern, with rates rising globally, impacting a substantial proportion of women of reproductive age. Though maternal obesity during pregnancy is associated with an increased risk of CHD in offspring, the mechanism is unknown.

Objectives: Determine the mechanism of congenital heart defects due to maternal obesity.

Design/Methods: We employed a diet-induced maternal obesity murine model and performed analysis on developing embryo hearts to elucidate 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) and histologic analysis.

Results: The disrupted cardiac transcriptome and proteome demonstrated substantial overlap in cardiac disease-related signaling pathways. Analysis revealed mechanistic insight, including altered oxidative phosphorylation and reactive oxygen species formation, reduced antioxidant capacity, with downregulated Sod1, Gp4x, and Hif1a signaling, resulting in oxidative stress, cell death, and altered rho kinase and actin cytoskeleton signaling. Histologic analysis confirmed these alterations results in murine embryo cardiac defects.

Conclusion: These data offer insight into the mechanisms by which maternal obesity disrupts embryonic cardiac development.