Prenatal e-cigarette exposure reprograms the cardiac proteome and increases ischemia susceptibility in a...

Prenatal electronic cigarette exposure has been associated with adverse cardiovascular outcomes in offspring, yet the underlying molecular mechanisms remain poorly understood. Using a rat model of gestational electronic cigarette aerosol exposure combined with quantitative liquid chromatography-tandem mass spectrometry proteomics and integrated Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, protein-protein interaction, and Evolutionary Genealogy of Genes: Non-Supervised Orthologous Groups analyses, we identified profound and sexually dimorphic alterations in the neonatal cardiac proteome. There was extensive mitochondrial and metabolic dysregulation in the developing heart following prenatal electronic cigarette exposure. In male offspring, enriched pathways included oxidative phosphorylation, tricarboxylic acid cycle activity, and respiratory chain assembly, indicating disruption of mitochondrial energy metabolism. In contrast, female offspring exhibited prominent dysregulation of mitochondrial chaperones (Hspa9 and Hspa4) and ribosomal proteins (Rps11, Rpl11, and Rps3), suggesting impaired proteostasis and translational capacity. Protein-protein interaction and Kyoto Encyclopedia of Genes and Genomes analyses further revealed sex-dependent perturbations of signaling and structural protein networks critical for cardiac contractility, cardiomyopathy progression, and myocardial stress resilience. Males primarily showed alterations in sarcomeric, structural, and metabolic proteins, whereas females exhibited widespread disruption of G protein-coupled receptor/cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-mediated regulatory pathways. These early-life proteomic alterations translated into functional deficits in adulthood, with males displaying impaired baseline cardiac function and exacerbated ischemia/reperfusion injury, while females showed preserved baseline function but heightened susceptibility to ischemia/reperfusion stress. Collectively, these findings demonstrate that prenatal electronic cigarette exposure programs long-lasting, sex-specific cardiac vulnerability through early-life proteomic reorganization, providing mechanistic insight into developmental cardiotoxicity and informing risk assessment during pregnancy.