Anti-angiogenic effects of p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) in the human microvasculature

p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is a primary and persistent metabolite of the pesticide dichlorodiphenyltrichloroethane. p,p'-DDE bioaccumulates in humans and has been associated with adverse health effects including endocrine disruption and cancer. Epidemiological studies also suggest associations with cardiovascular disease, but mechanisms are unknown. Here, we sought to investigate the effects of p,p'-DDE on human angiogenic microvascular function. Blood plasma samples (2006-2021, n = 80) and subcutaneous adipose tissues specimens (2024-2025, n = 18) were collected from adult human subjects undergoing elective bariatric surgery. Plasma samples were analyzed for p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and its primary metabolites p,p'-dichlorodiphenyldichloroethane (p,p'-DDD) and p,p'-DDE by GC-MS. In a separate cohort of bariatric subjects, we examined the effect of p,p'-DDE on angiogenic capacity in fat pad specimens ex vivo. Cultured human aortic endothelial cells (HAECs) were used to study p,p'-DDE-mediated transcriptional changes in endothelial cells. p,p'-DDE was detected in the blood of all subjects and at higher concentrations than p,p'-DDD or p,p'-DDT. Ex vivo p,p'-DDE exposure significantly impaired microvascular angiogenic capacity (P < 0.05 vs. control) in adipose tissue and downregulated fibroblast growth factor 2 (FGF2) gene expression in HAECs in a dose-dependent manner. Moreover, we observed that p,p'-DDE-induced angiogenic impairment was fully reversed by exogenous recombinant FGF2 supplementation. We provide evidence that p,p'-DDE may interfere with human microvascular angiogenic processes via downregulation of FGF2 expression. Our results provide a novel mechanism by which environmental pollutants such as p,p'-DDE could negatively impact cardiovascular health.