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Metal-binding Proteins as Novel Urothelial Biomarkers of Cadmium Exposure


RHIANNON MCNEILL1, James Catto2, Jennifer Southgate1

1Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York YO10 5DD
2Department of Oncology, University of Sheffield, The Medical School, Beech Hill Road, Sheffield S10 2RX

Elevated incidence rates of aggressive bladder cancer (BC) have been observed in Yorkshire for a number of years, with recent epidemiological evidence strongly correlating this trend with occupational exposure to heavy metals such as cadmium. The metallothionein (MT) superfamily consists of 11 genes whose proteins bind to and sequester metals within the cell. Although the presence of so many isoforms raises the possibility of differing metal specificities and functions, they are rarely discriminated between in the literature. Our aim was to determine whether specific MT isoforms expressed by bladder epithelium (‘urothelium’) could be used as discriminatory biomarkers of cadmium exposure. We used specialised techniques previously developed by the lab for the cell, tissue and organ culture of normal human urothelium, obtained ethically from patients undergoing elective urological procedures. These cultures were exposed to relevant concentrations of cadmium and analysed using isoform-specific primers and antibodies to define MT transcript and protein expression. The work resulted in the identification of two MT-1 isoforms whose protein induction was highly specific to cadmium exposure, with exposure to other metals (both essential and carcinogenic) failing to induce expression. Although MT transcript induction appeared transient, the protein expression of one of these isoforms appeared to persist at least 6 weeks post exposure, consistent with a metal sequestration role. Further investigation using spectroscopic techniques showed directly that cadmium was able to penetrate the protective urothelial barrier and enter urothelial cells, where it may be sequestered by MT within the long-lived cells, thus serving as a long-term source for chronic exposure. Overall our results suggest that MT-1 isoforms may prove useful as urothelial biomarkers of cadmium exposure, potentially allowing the identification of individuals ‘at risk’ of developing aggressive BC and additionally, stratifying a subset of cadmium-induced BC. Ongoing work aims to determine whether increased expression of these biomarkers can be detected in BC tissue and urine from patients thought to have been occupationally exposed to cadmium in their lifetime.
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