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Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast

ABSTRACT: Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast The model implements arsenite (AsIII) transport regulation, its distribution within main cellular AsIII pools and detoxification. The intracellular As pools considered are free AsIII (AsIIIin), protein-bound AsIII (AsIIIprot), glutathione conjugated AsIII (AsGS3) and vacuolar sequestered AsIII (vAsGS3). This model is described in the article: Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast. Talemi SR, Jacobson T, Garla V, Navarrete C, Wagner A, Tamás MJ, Schaber J. Mol. Microbiol. 2014 Jun; 92(6): 1343-1356 Abstract: Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed experimentally by dedicated experiments. Specifically, our analyses suggest that: (i) arsenic is mainly protein-bound during short-term (acute) exposure, whereas glutathione-conjugated arsenic dominates during long-term (chronic) exposure, (ii) arsenic is not stably retained, but can leave the vacuole via an export mechanism, and (iii) Fps1 is controlled by Hog1-dependent and Hog1-independent mechanisms during arsenite stress. Our results challenge glutathione depletion as a key mechanism for arsenic toxicity and instead suggest that (iv) increased glutathione biosynthesis protects the proteome against the damaging effects of arsenic and that (v) widespread protein inactivation contributes to the toxicity of this metalloid. Our work in yeast may prove useful to elucidate similar mechanisms in higher eukaryotes and have implications for the use of arsenic in medical therapy. This model is hosted on BioModels Database and identified by: BIOMD0000000547. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Soheil Rastgou Talemi

PROVIDER: BIOMD0000000547 | BioModels | 2014-09-04

REPOSITORIES: BioModels

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Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast.

Talemi Soheil Rastgou SR Jacobson Therese T Garla Vijay V Navarrete Clara C Wagner Annemarie A Tamás Markus J MJ Schaber Jörg J

Molecular microbiology 20140523 6

Arsenic has a dual role as causative and curative agent of human disease. Therefore, there is considerable interest in elucidating arsenic toxicity and detoxification mechanisms. By an ensemble modelling approach, we identified a best parsimonious mathematical model which recapitulates and predicts intracellular arsenic dynamics for different conditions and mutants, thereby providing novel insights into arsenic toxicity and detoxification mechanisms in yeast, which could partly be confirmed expe ...[more]

PMID: 24798644

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Project description:Patancheru, near Hyderabad, India, is a major production site for the global bulk drug market. About 90 manufacturers send their wastewater to a common treatment plant in Patancheru. Extraordinary high levels of a wide range of pharmaceuticals have recently been demonstrated in the treated effluent. As little as 0.2% of this effluent can strongly reduce the growth rate of tadpoles, but the underlying mechanisms of toxicity are not known. To begin addressing how the effluent affects aquatic vertebrates, rainbow trout (Oncorhynchus mykiss) were exposed to 0.2% effluent for five days. Several physiological endpoints, together with effects on global hepatic gene expression patterns, were analyzed. The exposed fish showed both an induction of hepatic cytochrome P450 1A (CYP1A) gene expression, as well as EROD activity. Clinical blood chemistry analyses revealed an increase in plasma phosphate levels, which in humans indicates impaired kidney function. Several oxidative stress-related genes were induced in the livers, however, no significant changes in antioxidant enzyme activities or in the hepatic glutathione levels were found. Furthermore, estrogen-regulated genes were slightly up-regulated following exposure, and moderate levels of estriol were detected in the effluent. This study identifies changes in gene expression triggered by exposure to a high dilution of the effluent, supporting the hypothesis that these fish are responding to chemical exposure. The pattern of regulated genes may contribute to the identification of mechanisms of sub-lethal toxicity, as well as illuminate possible causative agents. Two exposure experiments were conducted with control fish and fish exposed to 0.2% effluent. 19 pools of RNA, each containing three fish, were hybrdizied to in situ synthesized custom-made oligonucleotide microarrays. In total, four exposed and four control pools from exposure experiment I and five exposed and six control pools from exposure experiment II were analyzed.

Dataset Information

Talemi2014 - Arsenic toxicity and detoxification mechanisms in yeast

Publications

Mathematical modelling of arsenic transport, distribution and detoxification processes in yeast.

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