Project description: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.

Project description:Folate deficiency, arsenic exposure, and gamma-IR are known developmental toxicants and have carcinogenic effects. The mechanism by which IR is known, but the effect of arsenic or folate deficiency remains unclear. Their effect may be mediated by epigenetic alterations, leading to miRNA expression changes, and this experiment examined this hypothesis We used microarrays to detail the miRNA expression profiles of TK6 cells treated with 2 uM sodium arsenite for 6 days, folate-deficient media for 6 days, or 2.5 Gy IR exposure either acutely at 4 hours post exposure or long-term at 6 days post exposure, as well as requiste controls, all in biological triplicate. Keywords: exposure differences TK6, were cultured in standard RPMI 1640 (Invitrogen Inc., Gaithersburg, MD) or folate-deficient RPMI 1640 (Invitrogen). Growth media was supplemented with 10% fetal bovine serum (Invitrogen) and 1% penicillin-streptomycin; dialyzed fetal bovine serum (Invitrogen) was added to the folate-deficient medium in order to eliminate folic acid in the serum. For controls, folate-deficiency, arsenic exposure, and 6-day ?-IR exposure groups, 106 cells were diluted into 50ml of appropriate growth media. For the 4-hour post-?-IR exposure group, 107 cells were diluted into 50ml of growth media. For the arsenic exposed group, sodium arsenite was added to the media to a concentration of 2 ?M. For the ?-IR exposure groups, cells were diluted and allowed to incubate for 4 hours prior to irradiation treatment, and were exposed at a dose rate of 86.76 rad/min to a final dose of 2.5 Gy using a Philips MGC-40 X-ray source. Following exposure, cells were returned to the incubator. After fours hours, the short-term post-??-IR exposure group was collected for RNA isolation, as well as a mock (control) group. All experimental and control conditions were performed in triplicate. For all other groups, cells were cultured for 6 days, with the media changed and renewed, with the appropriate treatment, on day 3.

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