Complex metal interaction networks and the mediating role of biological aging in dyslipidemia

Metal mixture exposure is a major risk factor for dyslipidemia. Numerous studies have shown an association between metal mixture exposure, biological aging, and dyslipidemia. However, the interactions between metals, their directions, and the potential mechanisms through which they influence dyslipidemia remain unclear. This study utilized data from a repeated-measures cohort collected between 2016 and 2021, including 403 participants (1612 observations). Levels of metals, including chromium (Cr), cadmium (Cd), lead (Pb), and manganese (Mn), were measured in urine, along with four dyslipidemia biomarkers and their extended indicators. Generalized Estimating Equations (GEE) and Bayesian Kernel Machine Regression (BKMR) were used to analyze the effects of single and combined metal exposures on dyslipidemia. BKMR and the Synergy Index were employed to explore binary metal interactions and their directions. Marginal effects analysis assessed the impact of multiple metal interactions on dyslipidemia, and mediation analysis was conducted to explore the role of KDM.Accel in mediating the relationship between metal exposure and dyslipidemia. The findings indicated that both individual and combined exposures to Cr, Cd, Pb, and Mn significantly affected dyslipidemia. Multiple binary metal interactions exhibited synergistic effects on lipid outcomes. Pb∗Cd∗Cr and Pb∗Cd∗Mn showed an antagonistic effect on non-high-density lipoprotein cholesterol (NHC), while Cd∗Cr∗Mn∗Pb demonstrated synergistic effects on NHC. Additionally, KDM.Accel was identified as a key mediator in the relationship between Pb exposure and dyslipidemia, influencing the associations between Pb and HDL-C, LDL-C, and AC abnormalities. Mixed heavy metal exposure and their interactions are associated with dyslipidemia outcomes, with KDM.Accel playing a mediating role in the relationship between metals and dyslipidemia. This study highlights the potential interactions between metals and the mechanisms by which KDM.Accel may influence dyslipidemia, offering new insights into the connection between metal mixtures and dyslipidemia.