Low level exposure to monomethyl arsonous acid-induced the over-production of inflammation-related cytokines and the activation of cell signals associated with tumor progression in a urothelial cell model.

Human bladder cancer has been associated with chronic exposure to arsenic. Chronic exposure of an immortalized non-tumorigenic urothelial cell line (UROtsa cells) to arsenicals has transformed these cells to a malignant phenotype, but the involved mechanisms are not fully understood. Chronic inflammation has been linked with cancer development mainly because many pro-inflammatory cytokines, growth factors as well as angiogenic chemokines have been found in tumors. In this study the chronology of inflammatory cytokines production was profiled in UROtsa cells chronically exposed to the toxic arsenic metabolite, monomethylarsonous acid [50 nM MMA(III)] to know the role of inflammation in cell transformation. Acute 50 nM MMA(III) exposure induced over-production of many pro-inflammatory cytokines as soon as 12 h after acute exposure. The same cytokines remain over-regulated after chronic exposure to 50 nM MMA(III), especially after 3 mo exposure. At 3 mo exposure the sustained production of cytokines like IL-1, IL-6, IL-8 and TNF is coincident with the appearance of characteristics associated with cell transformation seen in other arsenic-UROtsa studies. The sustained and increased activation of NFkappaB and c-Jun is also present along the transformation process and the phosphorylated proteins p38 MAPK and ERK 1/2 are increased also through the time line. Taken together these results support the notion that chronic inflammation is associated within MMA(III)-induced cell transformation and may act as a promoting factor in UROtsa cell transformation.

Interactive toxicity and stress protein expression by vinylidene chloride and monochloroacetate in precision-cut rat liver slices.

Vinylidene chloride (VDC) is a groundwater and drinking water contaminant. Monochloroacetic acid (MCA) is a chlorination by-product of drinking water. Because environmental or occupational exposure to chemicals takes place at low concentrations, a sensitive in vitro system of liver slices was used to examine the interactive toxicity of MCA and VDC. Liver slices from Sprague-Dawley rats were exposed to 100 microM MCA for 1 hr before exposure to 20 or 48 microM VDC and incubated for 1 to 8 hr. MCA + 48 microM VDC resulted in a significant leakage of K+ by 4 hr, while MCA+ 20 microM VDC did not. At 4 hr, MCA + 48 microM VDC resulted in centrilobular necrosis. MCA caused a significant depletion of slice glutathione (GSH) at 1 hr, which was maintained up to 3 hr. As reactive VDC metabolites are detoxified by conjugation with GSH, the increase in VDC toxicity by MCA is possibly due to GSH-depleting effects of MCA. Heat shock protein (HSP) 72 was increased 2.5-fold by MCA + 20 microM VDC as early as 2 hr, although K+ leakage was not increased. MCA + 48 microM VDC resulted in a 3-fold increase in HSP 72 by 2 hr, while there were modest increases in HSPs 60 and 32. Therefore, HSP 72 is an early sensitive indicator of interactive toxicity of nontoxic concentrations of MCA and VDC. This is the first time that micromolar concentrations of these drinking water contaminants were observed to affect cellular homeostasis in the liver.