Arsenic Exposure Perturbs Epithelial-Mesenchymal Cell Transition and Gene Expression In a Collagen Gel Assay

Abstract

Arsenic is a naturally occurring metalloid and environmental contaminant. Arsenic exposure in drinking water is reported to cause cancer of the liver, kidneys, lung, bladder, and skin as well as birth defects, including neural tube, facial, and vasculogenic defects. The early embryonic period most sensitive to arsenic includes a variety of cellular processes. One key cellular process is epithelial-mesenchymal transition (EMT) where epithelial sheets develop into three-dimensional structures. An embryonic prototype of EMT is found in the atrioventricular (AV) canal of the developing heart, where endothelia differentiate to form heart valves. Effects of arsenic on this cellular process were examined by collagen gel invasion assay (EMT assay) using explanted AV canals from chicken embryo hearts. AV canals treated with 12.5-500 ppb arsenic showed a loss of mesenchyme at 12.5 ppb, and mesenchyme formation was completely inhibited at 500 ppb. Altered gene expression in arsenic-treated explants was investigated by microarray analysis. Genes whose expression was altered consistently at exposure levels of 10, 25, and 100 ppb were identified, and results showed that 25 ppb in vitro was particularly effective. Three hundred and eighty two genes were significantly altered at this exposure level. Cytoscape analysis of the microarray data using the chicken interactome identified four clusters of altered genes based on published relationships and pathways. This analysis identified cytoskeleton and cell adhesion-related genes whose disruption is consistent with an altered ability to undergo EMT. These studies show that EMT is sensitive to arsenic and that an interactome-based approach can be useful in identifying targets.

Arsenite promotes intestinal tumor cell proliferation and invasion by stimulating epithelial-to-mesenchymal transition

“…12 Consistently, in the process of chronic AS exposure, we noted with great interest that AS treated HT-29 cells underwent a marked morphologic change, i.e., from epithelial to spindle-like mesenchymal morphology ( Fig. 4A-C).…”

P38/NF-κB/Snail Pathway Is Involved in Caffeic Acid-Induced Inhibition of Cancer Stem Cells-Like Properties and Migratory Capacity in Malignant Human Keratinocyte

“…Since EMT enables cell to move and invade [18], we then determined the effects of CaA on the EMT process in malignant HaCaT cells. As shown in Figure 2A, malignant HaCaT cells displayed a fibroblast-like mesenchymal appearance; however, after these cells were exposed to CaA for 48 h, they showed an epithelial-like morphology.…”

Endocardial cell epithelial-mesenchymal transformation requires Type III TGFβ receptor interaction with GIPC

“…We also confirmed that infection with adenovirus expressing GFP alone defined the basal distribution of cells as epithelial, activated, or transformed and the addition of vehicle or TGFβ2 do not alter this distribution (Fig 2C). Cell proliferation in explants is low and alterations in proliferation cannot explain the decreases in cell invasion noted in these assays ([26], and Fig 2D, E). …”