McMullan Ashleigh, Zwierzynski James B, Jain Nina, Haneline Laura S, Shou Weinian, Kua Kok Lim, Hota Swetansu K, Durbin Matthew D
Department of Pediatrics Herman B Wells Center for Pediatric Research, Indiana University School of Medicine Indianapolis IN USA.
Department of Biology Stanford University Stanford CA USA.
J Am Heart Assoc. 2025 May 6;14(9):e039684. doi: 10.1161/JAHA.124.039684. Epub 2025 May 2.
Congenital heart disease is a leading cause of death in newborns, yet many of its molecular mechanisms remain unknown. Both maternal obesity and diabetes increase the risk of congenital heart disease in offspring, with recent studies suggesting these conditions may have distinct teratogenic mechanisms. The global prevalence of obesity is rising, and while maternal obesity is a known risk factor for fetal congenital heart disease, the specific mechanisms are largely unexplored.
We used a murine model of diet-induced maternal obesity, without diabetes, to produce dams that were overweight but had normal blood glucose levels. Embryos were generated and their developing hearts analyzed. Transcriptome analysis was performed using single-nucleus and bulk RNA sequencing. Global and phospho-enriched proteome analysis was performed using tandem mass tag-mass spectroscopy. Immunobloting and histologic evaluation were also performed. Analysis revealed disrupted oxidative phosphorylation and reactive oxygen species formation, with reduced antioxidant capacity, evidenced by downregulation of genes and , and disrupted signaling. Evidence of oxidative stress, cell death signaling, and alteration in Rho GTPase and actin cytoskeleton signaling was also observed. Genes involved in cardiac morphogenesis, including , were downregulated, and fewer mature cardiomyocytes were present. Histologic analysis confirmed increased cardiac defects in embryos exposed to maternal obesity.
These findings demonstrate that maternal obesity alone can result in cardiac defects through mechanisms similar to those associated with maternal hyperglycemia. This study provides valuable insight into the role of maternal obesity, a growing and modifiable risk factor, in the development of the most common birth defect, congenital heart disease.
先天性心脏病是新生儿死亡的主要原因之一，但其许多分子机制仍不清楚。母亲肥胖和糖尿病都会增加后代患先天性心脏病的风险，最近的研究表明这些情况可能有不同的致畸机制。全球肥胖患病率正在上升，虽然母亲肥胖是胎儿先天性心脏病的已知风险因素，但其具体机制在很大程度上尚未得到探索。
我们使用饮食诱导的母亲肥胖小鼠模型（无糖尿病）来产生超重但血糖水平正常的母鼠。产生胚胎并分析其发育中的心脏。使用单核和大量RNA测序进行转录组分析。使用串联质量标签-质谱法进行全局和磷酸化富集蛋白质组分析。还进行了免疫印迹和组织学评估。分析显示氧化磷酸化和活性氧形成受到破坏，抗氧化能力降低，这通过基因和的下调以及信号通路的破坏得到证明。还观察到氧化应激、细胞死亡信号以及Rho GTP酶和肌动蛋白细胞骨架信号改变的证据。参与心脏形态发生的基因，包括，被下调，并且成熟心肌细胞数量减少。组织学分析证实暴露于母亲肥胖的胚胎中心脏缺陷增加。
这些发现表明，母亲单纯肥胖可通过与母亲高血糖相关的类似机制导致心脏缺陷。本研究为母亲肥胖这一日益增加且可改变的风险因素在最常见出生缺陷先天性心脏病发生中的作用提供了有价值的见解。
