The association between exposure to phthalates and cardiovascular disease: A comprehensive study utilizing NHANES data from 2005 to 2018 and network toxicology.

Phthalates are widely recognized endocrine-disrupting chemicals. This study investigates the association between phthalate exposure and cardiovascular disease (CVD), with a particular focus on elucidating the underlying molecular mechanisms. First, an epidemiological analysis was conducted using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005-2018 to assess the relationship between phthalate metabolites and CVD. Generalized linear models (GLM) and weighted quantile sum (WQS) regression were employed to evaluate the impact of phthalate exposure. Among 12,127 participants, 1301 were diagnosed with CVD. The results showed a significant positive association between phthalate mixtures and CVD prevalence. GLM analysis identified MECPP, MEHHP, MEOHP, and MBzP as independent predictors of CVD (P < 0.05). WQS regression further demonstrated that the phthalate metabolite mixture exposure index was associated with CVD (OR = 1.21, 95 % CI: 1.07-1.37, P = 0.002), highlighting MEOHP, MECPP, MBzP, and MnBP as key contributors. Subgroup analysis revealed that these associations were strongest among individuals aged ≥60 years, females, and during the 2013-2014 NHANES cycle. To further explore the potential molecular mechanisms, we conducted a network toxicology analysis. A protein-protein interaction (PPI) network was constructed using STRING and Cytoscape 3.9.1 to identify key molecular targets associated with phthalate-induced CVD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that phthalate-induced CVD is linked to neuroactive ligand-receptor interactions, GABAergic synapses, the PI3K-Akt and JAK-STAT signaling pathways, and calcium signaling. Among 29 identified CVD-related targets, seven core targets (GABRA3, GABRG2, GABRA5, GABRA2, BCL2, CCND2, and PIK3CA) were strongly implicated in phthalate-induced cardiovascular toxicity. Molecular docking analysis further confirmed strong binding affinities between phthalate metabolites and key targets, particularly GABRA5, PIK3CA, and BCL2. This study provided robust evidence linking phthalate exposure to CVD and suggests that phthalate-induced cardiovascular toxicity may involve neuroactive signaling, apoptosis, and inflammation-related mechanisms. These findings offered valuable insights for future research and potential therapeutic strategies in environmental health and CVD prevention.