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Indirect Response Model of Arsenic Exposure on Gene Expression

Meric A. Ovacik1, M.G. Ierapetritou2, P.G. Georgopoulos3, W. Welsh3, and I.P. Androulakis4. (1) Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, (2) Chemical & Biochemical Engineering Department, Rutgers University, the State University of New Jersey, 98 Brett Road, Piscataway, NJ 08854, (3) University of Medicine and Dentistry of New Jersey (UMDNJ)/Robert Wood Johnson Medical School (RWJMS), Piscataway, NJ 08854, (4) Biomedical Engineering, Rutgers University, Piscataway, NJ 08854

Arsenic is an environmental toxicant and the exposure to it is a worldwide public health issue. Arsenic is categorized as a human carcinogen based on epidemiological studies in human liver. Aside from cancer, arsenic exposure is associated with liver injury, developmental abnormalities and genotoxicity[1]. However, the mechanism of action to arsenic exposure, especially at the molecular level, is not fairly understood.

A simple conceptual model for arsenic metabolism in a cell includes incorporating components for influx, efflux of inorganic arsenic, its metabolites and molecular targets that refer to any intracellular molecule , which inorganic arsenic or its metabolites interact with[2]. Intracellular concentrations of arsenicals, which are responsible for the arsenic toxicity, depend on the uptake rate and the loss of the species from the cell. In this study, we used of gene expression data as molecular targets from zebrafish liver, which as a toxicological model has a potential to propose new perspectives into chemical toxicity, to construct an indirect response model of arsenic exposure. The experimental data was obtained from Gene Expression Omnibus (GEO). Adult zebrafish were treated with 15ppm As(V) for 96 hr and fish livers were sampled at 8, 24, 48 and 96 hours for the microarray study, where the histological studies confirmed liver injury[1]. For the arsenic metabolism, we employed gene expression of specific ABC transporters, MRP1 and MRP2, which are the critical factors in removal of arsenic metabolites from cells[3]. The expression profiles of these genes were used to characterize arsenic removal activity in the cells.

We employed a shape-based microclustering algorithm [4] to reveal important profiles of the gene expression over time and the overpopulated profiles. The functional categorizations of the extracted intrinsic responses of arsenic exposure were stress response, DNA damage, and increased metabolism due to stress response and cytoskeletal changes. Based on the adaptive response model of the zebrafish liver, we proposed an indirect response model of arsenic exposure on transcriptional regulation that can be used for understanding liver injury. Arsenic metabolism intermediates were known to directly apply oxidative stress damage to protein and DNA methylation[5]. Heat shock proteins and DNA repair protein could help to stabilize the arsenic effect on DNA and protein. Meanwhile, central liver metabolism was increased due to repair processes. The hypermetabolism and repair processes taken together required active transportation and many of the transport proteins are coupled with large movements within the cell. Therefore, genes coding for cytoskeletal changes were altered and suggesting large-scale reshaping and restructuring of cell that were the reasons of the histological changes in liver tissues.

The indirect response model, as it is, describes the liver injury of steady arsenic exposure in zebrafish for 96 hour. The intrinsic responses showed a constant decrease between 48 hour and 96 hour interval suggesting that the regulation of liver injury initiated in this time interval. The indirect response model aims to simulate and to analyze the responses where the liver injure can be interfered. Moreover, the indirect response model includes arsenic metabolism intermediates implicitly, which allows the model to be integrated in multiscale modeling of arsenic. Incorporation of available pharmacodynamic models of arsenic metabolism for several organisms, such as mouse and rats, would allow the indirect response model to analyze also different dose effects on liver injury. Additionally, since arsenic trioxide is a competent cancer medication, the model also can be used in drug administration complications such as over dose or understanding the side effects.

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