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

Abstract

Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still 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 effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 microM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion 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 GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation.

Maternal Arsenic Exposure and Impaired Glucose Tolerance during Pregnancy

“…Environmental exposures may result in abnormal glucose metabolism, which in turn increases the risk of developing diabetes, through several plausible mechanisms (Longnecker and Daniels 2001). Arsenic is a known endocrine disruptor (Tseng 2004) and may disrupt the glucocorticoid receptor (Kaltreider et al 2001), which regulates a wide range of biological processes in humans, including insulin sensitivity. It is also possible that some aspect of having diabetes or prediabetes alters arsenic metabolism in such as way as to cause higher levels in the body.…”

Arsenic Disruption of Steroid Receptor Gene Activation: Complex Dose−Response Effects Are Shared by Several Steroid Receptors

“…H4IIE is a rat hepatoma cell line with 30,000-40,000 endogenous rGRs/cell. Culture of these lines was as described previously (10,16,18).…”

Immunosuppressive effects of arsenic in broiler chicks exposed to Newcastle disease virus

“…Likewise, phagocytic activity of macrophages and other immune responses have been reported to be significantly reduced in arsenic-treated broiler chickens (Vodela et al 1997). Generally, arsenic can disrupt glucocorticoid regulation of immune function (Kaltreider et al 2001) and arsenic-mediated apoptosis may lead to a reduced/diminished immune response in mice (Harrison & McCoy 2001), rats (Bustamante et al 1997 (T-lymphocyte macrophage-dependent response) in rats exposed to arsenic. Arsenic trioxide treatment of mice caused suppressed primary humoral responses to SRBC (Burchiel et al 2009).…”