The role of reactive oxygen species in arsenite and monomethylarsonous acid-induced signal transduction in human bladder cells: Acute studies

Abstract

Arsenicals are known to induce ROS, which can lead to DNA damage, oxidative stress, and carcinogenesis. A human urothelial cell line, UROtsa, was used to study the effects of arsenicals on the human bladder. Arsenite [As(III)] and monomethylarsonous acid [MMA(III)] induce oxidative stress in UROtsa cells after exposure to concentrations as low as 1 microM and 50 nM, respectively. Previous research has implicated ROS as signaling molecules in the MAPK signaling pathway. As(III) and MMA(III) have been shown to increase phosphorylation of key proteins in the MAPK signaling cascade downstream of ErbB2. Both Src phosphorylation (p-Src) and cyclooxygenase-2 (COX-2) are induced after exposure to 50 nM MMA(III) and 1 microM As(III). These data suggest that ROS production is a plausible mechanism for the signaling alterations seen in UROtsa cells after acute arsenical exposure. To determine importance of ROS in the MAPK cascade and its downstream induction of p-Src and COX-2, specific ROS antioxidants (both enzymatic and non-enzymatic) were used concomitantly with arsenicals. COX-2 protein and mRNA was shown to be much more influenced by altering the levels of ROS in cells, particularly after MMA(III) treatment. The antioxidant enzyme superoxide dismutase (SOD) effectively blocked both As(III)-and MMA(III)- associated COX-2 induction. The generation of ROS and subsequent altered signaling did lead to changes in protein levels of SOD, which were detected after treatment with either 1 microM As(III) or 50 nM MMA(III). These data suggest that the generation of ROS by arsenicals may be a mechanism leading to the altered cellular signaling seen after low-level arsenical exposure.

Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

“…However, Wnek et al (2010) were able to observe these changes as early as 12 weeks of exposure, and this acquired phenotype was sustained even after withdrawal of MMA(III). Therefore, the documented biochemical effects from MMA(III) exposure in UROtsa, such as the induction of ROS, DNA damage, production of pro-inflammatory cytokines, activation of mitogenic signals, and the increase in proliferation rate, exemplifies the utility of the model in the study of arsenic carcinogenesis and the unique effects of MMA(III) on the biology of the urothelium (Eblin et al, 2008b; Wnek et al, 2009; Escudero-Lourdes et al, 2010). Unlike previous studies, the research herein associates transcriptional changes with the malignant transformation of a human urothelial cell line, allowing for a more comprehensive understanding of the biological changes associated with chronic MMA(III) exposure.…”

Pro-Inflammatory and Pro-Fibrogenic Effects of Ionic and Particulate Arsenide and Indium-Containing Semiconductor Materials in the Murine Lung

“…EMMPRIN and MIF production requires transcriptional activation of the respective genes by the NF-κB cascade. 45, 46 In this regard, it is known that arsenic-induced toxicity involves NF-κB activity in vitro , 47–49 as well as in arsenic-exposed human subjects. 50 Thus, As release from III-V arsenides (Figure S6) could induce EMMPRIN and MIF production through the activation of the NF-κB cascade.…”

Solid surface photochemistry of montmorillonite: mechanisms for the arsenite oxidation under UV-A irradiation

“…•− (reaction (14)) and generating more H 2 O 2 through reactions (8) and (9) (Eblin et al 2008). Fe(II) then reacts with H 2 O 2 and produces HO • in the Fenton system (Ou et al 2008), which readily promotes the oxidation of As(III) to As(V).…”