Mitochondrial DNA copy number mediates PPD-Qs-induced lipid level alterations in humans

In recent years, human exposure to p-phenylenediamine-derived quinone (PPD-Qs) has attracted great attention due to their potential toxic effects on humans. While, their potential health risks to the lipid metabolism in humans remain inadequately elucidated. This cross-sectional study analyzed blood samples for six PPD-Qs, lipid profiles, and mitochondrial DNA copy number (mtDNAcn), and investigated the association between PPD-Q exposure and lipid levels in a population-based cohort comprising 255 healthy Chinese adults. Results showed that PPD-Qs in human serum was dominated by 6PPD-Q (mean 1.8 ng/mL), followed by 77PD-Q (0.73 ng/mL) and DTPD-Q (0.60 ng/mL). Multivariate analyses demonstrated significantly positive correlations between exposure to specific PPD-Qs (i.e., 6PPD-Q, CPPD-Q, DPPD-Q, and DTPD-Q) and elevated serum concentrations of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Weighted quantile sum regression showed that mixed PPD-Q exposure was positively correlated with TG levels (β = 0.050, 95% CI: 0.009 -0.16), with 6PPD-Q showing the highest weight for TC (weight 0.27), TG (0.31), low-density lipoprotein (0.28), apolipoprotein A1 (ApoA1; 0.52), and apolipoprotein B (ApoB; 0.33). Bayesian kernel machine regression analysis confirmed dose-dependently positive relationships between combined PPD-Q exposure and TC, TG, LDL-C, ApoA1, and ApoB. Mechanistically, mtDNAcn mediated 34 (95% CI: 9.3 -138%)-70% (95% CI: 12 -266%) of the total serum TG-elevating effects induced by PPD-Q exposure, revealing a novel pathway through which these PPD-Qs disrupt lipid homeostasis. Findings of this study address critical knowledge gaps regarding the toxicological impacts of these emerging environmental contaminants on human metabolic health.