Arsenic alters the function of the glucocorticoid receptor as a transcription factor

Chronic human exposure to nonovertly toxic doses of arsenic is associated w ith an increased risk of cancer. Although its carcinogenic mechanism is sti ll unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effec ts of low-dose arsenic (III) (arsenite) on expression of the hormone-regula ted phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We ther efore examined specifically the effects of arsenite on the biochemical func tion of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncy totoxic arsenite treatments (0.3-3.3 muM) significantly decreased dexametha sone-induced expression of transiently transfectcd luciferase constructs co ntaining either an intact hormone-responsive promoter from the mammalian PE PCK gene or two tandem glucocorticoid response elements (CRE). Western blot ting and confocal microscopy of a green fluorescent protein-tagged-GR fusio n protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with CR complexes and sel ectively inhibit GR-mediated transcription, which is associated with altere d nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.