Multiple metals exposure and blood mitochondrial DNA copy number: A cross-sectional study from the Dongfeng-Tongji cohort

Mitochondria are essential organelles that execute fundamental biological processes, while mitochondrial DNA is vulnerable to environmental insults. The aim of this study was to investigate the individual and mixture effect of plasma metals on blood mitochondria DNA copy number (mtDNAcn).This study involved 1399 randomly selected subcohort participants from the Dongfeng-Tongji cohort. The blood mtDNAcn and plasma levels of 23 metals were determined by using quantitative real-time polymerase chain reaction (qPCR) and inductively coupled plasma mass spectrometer (ICP-MS), respectively. The multiple linear regression was used to explore the association between each metal and mtDNAcn, and the LASSO penalized regression was performed to select the most significant metals. We also used the quantile g-computation analysis to assess the mixture effect of multiple metals.Based on multiple linear regression models, each 1% increase in plasma concentration of copper (Cu), rubidium (Rb), and titanium (Ti) was associated with a separate 0.16% [β(95% CI) = 0.158 (0.066, 0.249), P = 0.001], 0.20% [β(95% CI) = 0.196 (0.073, 0.318), P = 0.002], and 0.25% [β(95% CI) = 0.245 (0.081, 0.409), P = 0.003] increase in blood mtDNAcn. The LASSO regression also confirmed Cu, Rb, and Ti as significant predictors for mtDNAcn. There was a significant mixture effect of multiple metals on increasing mtDNAcn among the elder participants (aged ≥65), with an approximately 11% increase in mtDNAcn for each quartile increase in all metal concentrations [β(95% CI) = 0.146 (0.048, 0.243), P = 0.004].Our results show that plasma Cu, Rb and Ti were associated with increased blood mtDNA, and we further revealed a significant mixture effect of all metals on mtDNAcn among elder population. These findings may provide a novel perspective on the effect of metals on mitochondrial dysfunction.