Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel

Kwon,Jee  Young; Weon,Jong-Il; Koedrith,Preeyaporn; Park,Kang-Sik; Kim,Im  Soon; Seo,Young  Rok

doi:10.3892/or.2013.2587

Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel

Authors:
- Jee Young Kwon
- Jong-Il Weon
- Preeyaporn Koedrith
- Kang-Sik Park
- Im Soon Kim
- Young Rok Seo
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Affiliations: Department of Life Science, Institute of Environmental Medicine for Green Chemistry, Dongguk University, Seoul 100-715, Republic of Korea, Department of Safety Engineering, Institute of Environmental Medicine for Green Chemistry, Dongguk University, Gyeongju, Gyeongbuk 780-714, Republic of Korea, Faculty of Environment and Resource Studies, Mahidol University, Phuttamonthon District, NakhonPathom 73170, Thailand, Department of Physiology, and Biomedical Science Institute, Kyung Hee University School of Medicine, Seoul 130-701, Republic of Korea, Graduate School of Environmental Studies, Kwangwoon University, Seoul 139-701, Republic of Korea
Published online on: July 4, 2013 https://doi.org/10.3892/or.2013.2587
Pages: 1185-1194

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Abstract

Cadmium and nickel have been classified as carcinogenic to humans by the World Health Organization's International Agency for Research on Cancer. Given their prevalence in the environment, the fact that cadmium and nickel may cause diseases including cancer even at low doses is a cause for concern. However, the exact mechanisms underlying the toxicological effects induced by low-dose exposure to cadmium and nickel remain to be elucidated. Furthermore, it has recently been recognized that integrative analysis of DNA, mRNA and proteins is required to discover biomarkers and signaling networks relevant to human toxicant exposure. In the present study, we examined the deleterious effects of chronic low-dose exposure of either cadmium or nickel on global profiling of DNA copy number variation, mRNA and proteins. Array comparative genomic hybridization, gene expression microarray and functional proteomics were conducted, and a bioinformatics tool, which predicted signaling pathways, was applied to integrate data for each heavy metal separately and together. We found distinctive signaling networks associated with subchronic low-dose exposure to cadmium and nickel, and identified pathways common to both. ACTB, HSP90AA1, HSPA5 and HSPA8, which are key mediators of pathways related to apoptosis, proliferation and neoplastic processes, were key mediators of the same pathways in low-dose nickel and cadmium exposure in particular. CASP-associated signaling pathways involving CASP3, CASP7 and CASP9 were observed in cadmium-exposed cells. We found that HSP90AA1, one of the main modulators, interacted with HIF1A, AR and BCL2 in nickel-exposed cells. Interestingly, we found that HSP90AA1 was involved in the BCL2-associated apoptotic pathway in the nickel-only data, whereas this gene interacted with several genes functioning in CASP-associated apoptotic signaling in the cadmium-only data. Additionally, JUN and FASN were main modulators in nickel-responsive signaling pathways. Our results provide valuable biomarkers and distinctive signaling networks that responded to subchronic low-dose exposure to cadmium and nickel.

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