Abstract
Arsenic, a known human carcinogen, is widely distributed around the world and found in particularly high concentrations in certain regions including Southwestern US, Eastern Europe, India, China, Taiwan and Mexico. Chronic arsenic poisoning affects millions of people worldwide and is associated with increased risk of many diseases including arthrosclerosis, diabetes and cancer. In this study, we explored genome level global responses to high and low levels of arsenic exposure in Caenorhabditis elegans using Affymetrix expression microarrays. This experimental design allows us to do microarray analysis of dose-response relationships of global gene expression patterns. High dose (0.03%) exposure caused stronger global gene expression changes in comparison with low dose (0.003%) exposure, suggesting a positive dose-response correlation. Biological processes such as oxidative stress, and iron metabolism, which were previously reported to be involved in arsenic toxicity studies using cultured cells, experimental animals, and humans, were found to be affected in C. elegans. We performed genome-wide gene expression comparisons between our microarray data and publicly available C. elegans microarray datasets of cadmium, and sediment exposure samples of German rivers Rhine and Elbe. Bioinformatics analysis of arsenic-responsive regulatory networks were done using FastMEDUSA program. FastMEDUSA analysis identified cancer-related genes, particularly genes associated with leukemia, such as dnj-11, which encodes a protein orthologous to the mammalian ZRF1/MIDA1/MPP11/DNAJC2 family of ribosome-associated molecular chaperones. We analyzed the protective functions of several of the identified genes using RNAi. Our study indicates that C. elegans could be a substitute model to study the mechanism of metal toxicity using high-throughput expression data and bioinformatics tools such as FastMEDUSA.
Highlights
Arsenic is a metalloid, which is distributed throughout the Earth crust in diverse complex forms with pyrites
We found that sixty seven percent of the C. elegans gst genes are differentially expressed upon arsenic exposure (Table 2)
We found that ferritin encoding genes of C. elegans, ftn1, and ftn-2 are upregulated upon sodium arsenite exposure
Summary
Arsenic is a metalloid, which is distributed throughout the Earth crust in diverse complex forms with pyrites. In this study we used C. elegans whole genome expression microarrays to examine global changes in the nematode transcription profile upon arsenic exposure. FastMEDUSA analysis We used FastMEDUSA [43] to elucidate transcription factors (TFs) that putatively regulate the genome-level responses to high and low levels of arsenic exposure in C. elegans.
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