Mixed Metals Exposure, Cardiac Autonomic Responses, Inflammation and DNA Methylation

Abstract

Background: welders are often exposed to various types of metals from the welding fumes and they also have high risks of cardiac autonomic dysfunction. Knowing the hazardous components within metals mixture as well as understanding the potential underlying mechanisms is essential for environmental and occupational regulations. Objective: to identify metal components which are associated with cardiac autonomic responses, as measured by two novel markers -acceleration capacity (AC) and deceleration capacity (DC); to examine whether inflammation mediates effects of metals exposure on AC/DC changes; to identify epigenetic variants which are associated with AC/DC changes. Methods: we collected urine, blood and electrocardiogram (ECG) samples from 75 welders over six sampling occasions between June 2003 and June 2012. Urinary concentrations of 16 types of metals were determined. Blood serum samples were analyzed for inflammatory cytokines levels including CRP, IL-2, IL4, IL6 and IL8. AC and DC values were quantified from ECG recordings. Firstly, we used linear mixed-effects models with Lasso to identify hazardous metals that were significantly associated with AC or DC changes. We fitted the co-pollutants model with “selected” metals in the linear mixed model to estimate the exposure-response relationship. Then, we conducted a mediation analysis to examine whether inflammatory cytokines mediated the effects of metals exposure on AC or DC changes. We report both direct and indirect effects in single pollutant model as well as co-pollutants models. Finally, we conducted the epigenome-wide association study (EWAS) to identify epigenetic variants that were associated with AC or DC changes. Results: we observed negative associations between urinary mercury and chromium concentrations with both DC and AC changes. Indirect effects of metals exposure on AC or DC through inflammation pathway were not significant. We identified GPR133 gene at which methylation level changes were associated with DC values. Conclusion: metals exposures are associated with impaired cardiac autonomic functions. Our study did not provide evidence that these effects were mediated through inflammation pathway. However, DNA methylation of specific genes may be a potential pathway linking environmental and occupational pollutants exposure and alterations in cardiac autonomic responses.