Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

Abstract

Background: Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored.

Results: In this study, we examined the effects of in vitro exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis.

Conclusions: This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.

Figure 1

Molecular interactomes and sub-networks modulated in TK6 cells exposed to arsenic or cadmium. Two large interactomes were identified in TK6 cells exposed to (A) arsenic or (B) cadmium. The two most significant cancer-enriched sub-networks within the interactomes were identified for (C) arsenic and (D) cadmium. Networks are displayed with symbols representing encoded proteins corresponding to their RNA transcripts that were either directly up-regulated (red symbols), down-regulated (green symbols), or associated with the modified transcripts (while symbols). P-values representing network significance are shown.

Figure 2

Biological functions enriched in molecular networks altered in TK6 cells exposed to arsenic or cadmium. The five most significantly enriched biological functions within the (A) arsenic or (B) cadmium-induced molecular networks are illustrated.