Urinary thymine dimer as a biomarker of exposure to ultraviolet radiation

Exposure to ultraviolet radiation (UVR) is associated with all three major forms of skin cancer; squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and cutaneous malignant melanoma (CMM). Different exposure patterns are suggested to influence the development; SCC and BCC have been linked to occupational (continuous) expo-sure and CMM, and to some extent BCC to intermittent exposure. UVR can be meas-ured by using different types of dosimeters or, alternatively, by estimations of the inten-sity and the time of exposure. However, such measurements do not consider skin type or dose-limiting factors like use of clothes or sunscreen. Biomarkers of exposure offer an alternative that confirms and quantifies the exposure on a biological level. The cy-clopyrimidine dimer (T=T) is the dominating photoproduct formed in the DNA of the skin after exposure to UVR of the sun. This adduct is after excision degraded and fi-nally excreted in the urine. A method for analysis of urinary T=T has been developed and validated in previous research, but the association between the amount formed in the target tissue (skin) and urine has not been examined.

The main aim of this thesis was to further validate T=T as a biomarker of UVR exposure, and to apply it in outdoor studies. The specific aims of paper I was to exam-ine the relationship between the target dose in the skin and the dose estimated from analysis of the urine including correction by creatinine level. In paper II the aim was to investigate the effects of single exposure in adults and children. Paper III concerned the consequence of continuous exposure of UVR as analyzed by T=T levels in the urine of outdoor workers.

The result of the investigations in paper I showed that urinary T=T was signifi-cantly correlated to the amounts of T=T formed in the skin, i.e. that creatinine corrected urine samples may be used as a surrogate for skin in the analysis of T=T. We also found a significant dose-response relationship after single exposure outdoors, and fur-thermore that children and adults form similar amounts of T=T per unit dose (paper II). In paper III it was found that the continuous exposure led to steady-state levels of T=T in the urine. This association could be described by utilizing a mixed statistical model, and it suggested that the T=T levels mainly reflected the UVR exposure of the last three days. We conclude that urinary T=T is a valid biomarker of exposure to UVR ready to be applied in human environmental studies of adults as well as of children. In this re-spect it may assist in primary prevention of human skin cancer.

List of scientific papers

I. Sandberg Liljendahl T, Harrison GI, Gulliver R, Douki T, Segerbäck D and Young AR. Thymine dimer levels in human skin and urine are correlated after a single whole-body sub-erythemal dose of broadband UVB. [Manuscript]

II. Sandberg Liljendahl T, Kotova N and Segerbäck D. Quantification of ultraviolet radiation-induced DNA damage in the urine of Swedish adults and children following exposure to sunlight. Biomarkers. 2012; 17(7): 634-41.
https://doi.org/10.3109/1354750X.2012.709881

III. Sandberg Liljendahl T, Blomqvist A, Andersson EM, Barregard L and Segerbäck D. Urinary levels of thymine dimers as a biomarker of exposure to ultraviolet radiation in humans during outdoor activities in the summer. Mutagenesis. [Accepted]
https://doi.org/10.1093/mutage/ges077