Abstract
BACKGROUND: Environmental exposure to toxic and trace metals has been implicated in colorectal carcinogenesis through oxidative DNA damage and epigenetic dysregulation. However, human evidence linking tissue-level metal accumulation with epigenetic and genotoxic biomarkers remains limited, particularly in studies using paired tumor and adjacent non-cancerous colon tissues. OBJECTIVES: This study aimed to (i) characterize concentrations of selected toxic and trace metals in paired cancerous and non-cancerous colon tissues, (ii) examine associations between tissue metal concentrations and global DNA methylation in colon tissue, and (iii) evaluate relationships between tissue metal burden and circulating biomarkers of oxidative DNA damage and global DNA methylation in peripheral blood. METHODS: Fifty adult patients with newly diagnosed primary colon cancer undergoing surgical resection were included. Concentrations of lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), chromium (Cr), and titanium (Ti) were measured in paired colon tissue samples using ICP-MS. Global DNA methylation was assessed in colon tissue and peripheral blood using ELISA-based quantification of 5-methylcytosine, while oxidative DNA damage in peripheral blood lymphocytes was measured using the comet assay (tail moment). Paired comparisons were conducted using the Wilcoxon signed-rank test. Multivariable linear regression models adjusted for age, sex, body mass index, education, and tumor location were used to evaluate associations between metals, a composite Metal Burden Index, DNA methylation, and oxidative DNA damage. RESULTS: Cadmium concentrations were significantly lower in cancerous compared with non-cancerous colon tissue (median 0.011 vs. 0.019 μg/g wet weight; p = 0.005), while no significant differences were observed for Pb, Hg, As, Cr, or Ti. No statistically significant associations were found between individual tissue metals or the Metal Burden Index and global DNA methylation in either colon tissue type. Tissue metal concentrations were generally not associated with blood global DNA methylation. An inverse association was observed between Hg concentration in cancerous tissue and blood comet assay tail moment (β = -0.582; 95% CI: -1.004 to -0.160; p = 0.008), which should be interpreted cautiously. Correlations between tissue and blood-based epigenetic and genotoxic biomarkers were weak. CONCLUSIONS: In this cross-sectional study, metal accumulation in colon tissue was not consistently associated with global DNA methylation in tissue or blood. The limited concordance between tissue-based metal concentrations and circulating epigenetic or genotoxic biomarkers highlights the complexity of exposure-biomarker relationships in established colon cancer and suggests that blood-based markers may inadequately reflect localized tissue-level processes, with implications for environmental exposure assessment and public health biomonitoring.