Urothelial genotoxicity of environmental chemicals detected in the urine of healthy dogs and their owners

Introduction: Major risk factors for urothelial cell carcinoma (UCC) in people are smoking and occupational exposures. However, up to 30% of human UCC risk is still unexplained. Pet dogs develop UCC that models the clinical behavior of muscle-invasive human UCC. Dogs may therefore provide a useful model for non-tobacco, nonoccupational UCC risk. We previously found that nonsmoking human subjects and their pet dogs share exposures to the urothelial carcinogens acrolein and arsenic. We hypothesized that these urinary exposures would reach genotoxic concentrations in some individuals.

Methods: We exposed immortal and primary human and canine urothelial cells in vitro to acrolein and inorganic arsenic and used the γ-H2AX and comet assays to measure DNA damage.

Results: For acrolein, we found a genotoxic threshold of 1.1-4.4 μM in human cells and a threshold of 20.0-55.6 μM in canine cells. These findings are consistent with potentially genotoxic urinary acrolein exposures in 51% of healthy human subjects and 17% of pet dogs previously surveyed. For inorganic arsenic, we found a genotoxic threshold of ≥10 μM in canine and human cell lines. No healthy human or canine subject reached these urinary inorganic arsenic exposures when assayed at a single time point.

Conclusions: Non-tobacco, nonoccupational acrolein exposures could increase the risk of early urothelial DNA damage in both people and pet dogs. Ongoing studies will assess these chemical exposures in the setting of UCC in both human and canine patients.