PFAS and adipokines: Decoding their roles in the risk of breast nodules and breast cancer

Per- and polyfluoroalkyl substances (PFAS), recognized as endocrine-disrupting chemicals (EDCs), have been implicated in breast cancer development. However, the specific PFAS compounds link to both benign breast nodules and breast cancer development remain unclear. The roles of adipokines in these relationships warrant further investigation. This case-control study included 127 patients with benign breast nodules, 278 patients with breast cancer, and 166 healthy controls. Serum concentrations of 10 PFASs, three adipokines (adiponectin, leptin, and resistin), and leptin to adiponectin ratio (LAR) were measured. Quantile-based g-computation (QGcomp) was employed to identify key PFASs associated with both benign breast nodules and breast cancer, and the interactions and mediating effects involving adipokines were explored. PFAS mixture exposure was associated with an increased risks of breast cancer [OR (95% CI) = 1.13 (1.05, 1.22)], whereas no significant association was observed for benign breast nodules [OR (95% CI) = 1.02 (0.86, 1.21)]. Five PFASs (PFOA, PFECHS, 6:2Cl-PFESA, PFOS, and PFUnDA) were implicated as risk factors for benign breast nodules, whereas six (PFHpA, 8:2Cl-PFESA, PFUnDA, PFECHS, PFNA, and PFHxS) were identified as risk factors for breast cancer. Notably, PFUnDA and PFECHS were identified as potential shared risk factors for both conditions, exhibiting positive associations with leptin and LAR, and negative associations with adiponectin. The association between PFUnDA and breast cancer risk was significantly amplified with increased leptin levels and LAR (P_interaction = 0.029 and 0.028, respectively). However, no significant interaction or mediation effects involving adipokines were otherwise detected (P > 0.05). These preliminary findings suggest a link between PFAS exposure and benign breast nodules, and identify PFUnDA and PFECHS as potential risk factors shared by both benign and malignant breast lesions. Adipokines appear to contribute to the PFAS-breast cancer associations. Further confirmation through large prospective studies is required to substantiate these initial observations.