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Int. J. Environ. Res. Public Health 2012, 9(2), 474-495; doi:10.3390/ijerph9020474
Article

Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo

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Received: 29 December 2011; in revised form: 29 January 2012 / Accepted: 30 January 2012 / Published: 1 February 2012
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Abstract: To understand mechanisms for arsenic toxicity in the lung, we examined effects of sodium m-arsenite (As3+) on microtubule (MT) assembly in vitro (0–40 µM), in cultured rat lung fibroblasts (RFL6, 0–20 µM for 24 h) and in the rat animal model (intratracheal instillation of 2.02 mg As/kg body weight, once a week for 5 weeks). As3+ induced a dose-dependent disassembly of cellular MTs and enhancement of the free tubulin pool, initiating an autoregulation of tubulin synthesis manifest as inhibition of steady-state mRNA levels of βI-tubulin in dosed lung cells and tissues. Spindle MT injuries by As3+ were concomitant with chromosomal disorientations. As3+ reduced the binding to tubulin of [3H]N-ethylmaleimide (NEM), an -SH group reagent, resulting in inhibition of MT polymerization in vitro with bovine brain tubulins which was abolished by addition of dithiothreitol (DTT) suggesting As3+ action upon tubulin through -SH groups. In response to As3+, cells elevated cellular thiols such as metallothionein. Taxol, a tubulin polymerization agent, antagonized both As3+ and NEM induced MT depolymerization. MT–associated proteins (MAPs) essential for the MT stability were markedly suppressed in As3+-treated cells. Thus, tubulin sulfhydryls and MAPs are major molecular targets for As3+ damage to the lung triggering MT disassembly cascades.
Keywords: trivalent arsenic (As3+); microtubules (MTs); tubulin; tubulin mRNA; tubulin sulfhydryl groups (-SH); microtubule-associated proteins (MAPs); chromosomal disorientations; metallothionein; taxol trivalent arsenic (As3+); microtubules (MTs); tubulin; tubulin mRNA; tubulin sulfhydryl groups (-SH); microtubule-associated proteins (MAPs); chromosomal disorientations; metallothionein; taxol
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Zhao, Y.; Toselli, P.; Li, W. Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo. Int. J. Environ. Res. Public Health 2012, 9, 474-495.

AMA Style

Zhao Y, Toselli P, Li W. Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo. International Journal of Environmental Research and Public Health. 2012; 9(2):474-495.

Chicago/Turabian Style

Zhao, Yinzhi; Toselli, Paul; Li, Wande. 2012. "Microtubules as a Critical Target for Arsenic Toxicity in Lung Cells in Vitro and in Vivo." Int. J. Environ. Res. Public Health 9, no. 2: 474-495.



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