Arsenic is a human bladder
carcinogen.
Arsenic is methylated to both monomethyl and dimethyl metabolites which have been detected in human urine. The trivalent methylated
arsenicals are more toxic than inorganic
arsenic. It is unknown if these trivalent methylated metabolites can directly cause malignant transformation in human cells. The goal of this study is determine if
monomethylarsonous acid (
MMA(III)) can induce malignant transformation in a human bladder urothelial cell line. To address this goal, a non-tumorigenic human urothelial cell line (UROtsa) was continuously exposed to 0.05 muM
MMA(III) for 52 weeks. Hyperproliferation was the first phenotypic change observed in exposed UROtsa (URO-MSC). After 12 weeks of exposure, doubling time had decreased from 42 h in unexposed control cells to 27 h in URO-MSC. Hyperproliferation continued to be a quality possessed by the URO-MSC cells after both 24 and 52 weeks of exposure to
MMA(III), which had a 40-50% reduction in doubling time. Throughout the 52-week exposure, URO-MSC cells retained an epithelial morphology with subtle morphological differences from control cells. 24 weeks of
MMA(III) exposure was required to induce anchorage-independent growth as detected by colony formation in soft
agar, a characteristic not found in UROtsa cells. To further substantiate that malignant transformation had occurred, URO-MSC cells were tested after 24 and 52 weeks of exposure to
MMA(III) for the ability to form
tumors in SCID mice. Enhanced tumorigenicity in SCID mouse xenografts was observed after 52 weeks of treatment with
MMA(III). These observations are the first demonstration of
MMA(III)-induced malignant transformation in a human bladder urothelial cell line and provide important evidence that
MMA(III) may be carcinogenic in human tissues.