LAUSR

ABSTRACT Iron promotes formation of hydroxyl radicals by the Fenton reaction, subsequently leading to potential oxidatively generated damage of nucleic acids. Oxidatively generated damage to RNA, measured as 8‐oxo‐7,8‐dihydroguanosine (8‐oxoGuo) in urine, is increased in patients with genetic iron overload, which have led us to test the hypothesis that high iron status, assessed by iron biomarkers and genetic disposition, increases urinary excretion of 8‐oxoGuo. In a general Danish population study we used a Mendelian randomization design with HFE genotypes as a proxy for iron status and supplemented with ex vivo experiments in mice muscle tissue exposed to iron(II) sulfate to attempt to clarify this hypothesis. The biomarkers ferritin, transferrin, and transferrin saturation (TS) were associated with 8‐oxoGuo (in linear univariable and multivariable regression analyses: P < 0.001). Mendelian randomization indicated a causal pathway between genetically elevated iron biomarkers (assessed by ferritin and TS) and high levels of 8‐oxoGuo. The ex vivo experiments showed a monotonically increase in 8‐oxoGuo with increased iron concentration (ANOVA: P = 0.0008) that was prevented with iron chelation (P = 0.01). Our results indicate a causal relationship between iron biomarkers and 8‐oxoGuo. Furthermore, the ex vivo experiment shows a mechanistic link between iron and 8‐oxoGuo formation. Both iron overload and the biomarker 8‐oxoGuo have been linked to e.g. diabetes, which merits future studies to investigate if iron induced 8‐oxoGuo is involved in disease development. Graphical abstract Figure. No caption available. HighlightsIron biomarkers are associated with urinary excretion of 8‐oxoGuo.Blood donor status and menopause status (in women) are associated with 8‐oxoGuo.There is an indication of causal relationship between iron biomarkers and 8‐oxoGuo population.Mouse muscle tissue exposed to iron results in increased 8‐oxoGuo.