Dimethylarsinic acid (DMA^V) changed the expressions of proliferative related factors and secretion of inflammatory cytokines in rat bladder

Abstract

Dimethylarsinic acid (DMA(V) ), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen and bladder tumor promoter in adult rats. Increased urothelial cellular proliferation has been considered as an earlier phenotype in DMA(V) -induced bladder carcinogenesis. The present study examined the ultrastructural changes of bladder epithelial cells and expressions of proliferation factors, as well as the secretion of inflammatory cytokines in rats exposed to DMA(V) for 10 weeks by transmission electron microscopy (TEM), qRT-PCR, immunohistochemical staining and ELISA methods. The results showed that DMA(V) administered in the drinking water produced urothelial cytotoxicity and ultrastructural changes in rats. PCNA, cyclin D1 and COX-2 mRNA expressions and immunoreactivities were elevated in bladder urothelium. In addition, 200 ppm DMA(V) treatment increased the transforming growth factor-beta 1 (TGF-β1) secretion and decreased tumor necrosis factor-alpha (TNF)-α level in the urine of rats. These data suggest that chronic inflammation, bladder epithelium lesions and proliferation might be the basic process of the chronic toxicity effects in DMA(V) -treated rats.

DMAV in Drinking Water Activated NF‐κB Signal Pathway and Increased TGF‐β and IL‐1β Expressions in Bladder Epithelial Cells of Rats

“…In our previous study, 200 ppm DMA V treated rats exhibited significantly increased inflammatory factor TGF- β 1 level in urine compared to the control rats [ 5 ]. In the present immunohistochemical localization analysis, TGF- β expression was elevated in 100 and 200 ppm DMA V treated rat bladder epithelium.…”

“…Our precious study found DMA elevated expressions of proliferation factors, such as PCNA, cyclin D1, and COX-2, in bladder epithelium [ 5 ]. The possible mechanism of DMA V on bladder epithelium in this study was speculated because DMA V activated NF- κ B signal pathway, which increased the secretion of TGF- β and IL-1 β in rats.…”

“…The mechanism of DMA V induced cancer may be related to proliferation, apoptosis, oxidative stress, and inflammatory reaction. Our previous study showed that DMA V increased the expressions of proliferation factors in bladder urothelium and elevated transforming growth factor-beta 1 (TGF- β 1) secretion and decreased tumor necrosis factor-alpha (TNF- α ) level in the urine of rats [ 5 ]. Our and other studies suggested that chronic inflammation, bladder epithelium lesions, and proliferation might be the basic process of the chronic toxicity effects of DMA V on rats.…”

Pesticides and Bladder Cancer: Mechanisms Leading to Anti-Cancer Drug Chemoresistance and New Chemosensitization Strategies

“…In the past, arsenical herbicides were extensively used in the US and elsewhere. Dimethylarsinic acid (DMA), the major urinary metabolite of inorganic arsenic, is a urinary bladder carcinogen that increased TGF-β secretion in rat urine [136]. A separate study found that DMA induced EMT through several mechanisms including upregulation of HER2 that is also known to increase TGF-β [137].…”