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In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components
Verma, R.; Xu, X.; Jaiswal, M.K.; Olsen, C.; Mears, D.; Caretti, G.; Galdzicki, Z. (2011). In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components. Toxicol. Appl. Pharmacol. 253(3): 178-187. https://dx.doi.org/10.1016/j.taap.2011.04.002
In: Toxicology and applied pharmacology. Elsevier: San Diego etc.. ISSN 0041-008X; e-ISSN 1096-0333
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| Trefwoorden |
Chemical elements > Metals > Transition elements > Heavy metals > Cobalt
Chemical elements > Metals > Transition elements > Heavy metals > Nickel
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| Author keywords |
Tungsten-alloy; H3-histone modifications; Cytotoxicity; Epigenetics; Calcium channel blockers; Calcium chelators 2-photon calcium imaging |
| Auteurs | | Top |
- Verma, R.
- Xu, X.
- Jaiswal, M.K.
- Olsen, C.
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- Mears, D.
- Caretti, G.
- Galdzicki, Z.
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|
| Abstract |
Tungsten-alloy has carcinogenic potential as demonstrated by cancer development in rats with intramuscular implanted tungsten-alloy pellets. This suggests a potential involvement of epigenetic events previously implicated as environmental triggers of cancer. Here, we tested metal induced cytotoxicity and epigenetic modifications including H3 acetylation, H3-Ser10 phosphorylation and H3-K4 trimethylation. We exposed human embryonic kidney (HEK293), human neuroepithelioma (SKNMC), and mouse myoblast (C2C12) cultures for 1-day and hippocampal primary neuronal cultures for 1-week to 50–200 μg/ml of tungsten-alloy (91% tungsten/6% nickel/3% cobalt), tungsten, nickel, and cobalt. We also examined the potential role of intracellular calcium in metal mediated histone modifications by addition of calcium channel blockers/chelators to the metal solutions. Tungsten and its alloy showed cytotoxicity at concentrations > 50 μg/ml, while we found significant toxicity with cobalt and nickel for most tested concentrations. Diverse cell-specific toxic effects were observed, with C2C12 being relatively resistant to tungsten-alloy mediated toxic impact. Tungsten-alloy, but not tungsten, caused almost complete dephosphorylation of H3-Ser10 in C2C12 and hippocampal primary neuronal cultures with H3-hypoacetylation in C2C12. Dramatic H3-Ser10 dephosphorylation was found in all cobalt treated cultures with a decrease in H3 pan-acetylation in C2C12, SKNMC and HEK293. Trimethylation of H3-K4 was not affected. Both tungsten-alloy and cobalt mediated H3-Ser10 dephosphorylation were reversed with BAPTA-AM, highlighting the role of intracellular calcium, confirmed with 2-photon calcium imaging. In summary, our results for the first time reveal epigenetic modifications triggered by tungsten-alloy exposure in C2C12 and hippocampal primary neuronal cultures suggesting the underlying synergistic effects of tungsten, nickel and cobalt mediated by changes in intracellular calcium homeostasis and buffering. |
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