Sex-specific associations between phthalate exposure and stroke risk: a cross-sectional study integrating molecular mechanisms of vascular dysfunction

Background: Stroke is a significant global health issue, resulting in substantial mortality and morbidity. Environmental exposures are increasingly recognized as essential contributors to cerebrovascular risk profiles. Phthalates are ubiquitous synthetic plasticizers with well-established endocrine-disrupting properties and have been associated with various vascular and metabolic disturbances. However, their specific contribution to stroke pathogenesis, particularly concerning potential sex-specific vulnerability patterns, remains poorly understood. Methods: A cross-sectional analysis was conducted on 8,184 participants (4,140 women and 4,044 men) from the National Health and Nutrition Examination Survey (NHANES) to evaluate the associations between urinary phthalate metabolite concentrations and stroke prevalence. The weighted quantile sum (WQS) regression methodology assessed the effects of cumulative exposure to the phthalate mixture. An integrative approach was used, incorporating network toxicology, protein-protein interaction mapping, and the Friends algorithm, to identify molecular targets related to stroke that may be affected by phthalate exposure. Molecular docking analyses were performed to characterise binding affinities between key phthalate metabolites and identified protein targets. We analyzed single-cell RNA sequencing data to determine cell-type-specific expression patterns of implicated molecular targets. Results: Sex-stratified analyses revealed that phthalate exposure was positively associated with stroke risk in women but not in men. Specifically, higher urinary concentrations of Mono(carboxynonyl) phthalate (MCNP) were significantly associated with self-reported stroke in women. WQS regression confirmed cumulative effects, with MCNP identified as the primary contributor. Network and docking analyses revealed strong interactions between MCNP and vascular proteins KDR, AKT1, and MAPK8, which were predominantly expressed in endothelial cells. These findings suggest that phthalate exposure may increase stroke risk in a sex-specific manner through disruption of an endothelial-specific KDR–AKT1–MAPK8 signaling pathway. Conclusion: This work highlights a novel mechanism of environmentally mediated cerebrovascular risk and provides potential targets for therapeutic intervention, particularly in women.