Quantification of heavy metal exposure in a British population cohort links total mercury levels in plasma with skin tissue-specific changes in mitochondrial-related gene expression

Heavy metals in our direct environment have profound effects on human health and while some are essential for life, others can be toxic. In vivo studies often focus on clinical features caused by overexposure to, or by deprivation of a heavy metal. However, to understand the cellular impact of heavy metals on health, studies in healthy volunteers before symptom onset are needed. Here, we explored the impact of mercury, lead and selenium in over 800 British female twins on multi-tissue gene expression levels as an intermediate phenotype. Total mercury, lead and selenium concentrations were determined in plasma as a proxy for heavy metal exposure. We identified significant associations between total mercury levels measured in plasma, that fall within normal ranges, and expression of 873 genes within skin tissue, including PUSL1, SAMD10, ERCC1, MRPL17, NDUFB8, SELENOH, SEC31A, and KAT7P1. Functional analysis of genes associated with total mercury levels in plasma show a strong link to the mitochondrial oxidative phosphorylation pathway (p-value = 3.02 × 10^-10). Analysis of mitochondrial-specific gene expression supported involvement of genes of oxidative phosphorylation complexes (MT-ND4L, and MT-ND5), which are encoded in mitochondrial DNA. These results suggest that mercury is likely detrimental to the energy metabolism of mitochondria. We also tested for associations between total mercury levels in plasma and gene expression in adipose and whole blood samples, but did not identify significant associations in these tissues, nor with lead or selenium in any tissue. Our results demonstrate that subtoxic mercury exposure leaves a clear molecular signature. It also underscores the necessity of conducting tissue-specific association studies to accurately capture the molecular impact of environmental exposures, as only relevant tissues will manifest a response to environmental exposures.