Microtubules as a critical target for arsenic toxicity in lung cells in vitro and in vivo

Int J Environ Res Public Health. 2012 Feb;9(2):474-95. doi: 10.3390/ijerph9020474. Epub 2012 Feb 1.


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: chromosomal disorientations; metallothionein; microtubule-associated proteins (MAPs); microtubules (MTs); taxol; trivalent arsenic (As3+); tubulin; tubulin mRNA; tubulinsulfhydryl groups (-SH).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenic / toxicity*
  • Blotting, Western
  • Cell Line
  • Immunohistochemistry
  • In Vitro Techniques
  • Lung / drug effects*
  • Microscopy, Fluorescence
  • Microtubules / drug effects*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction


  • Arsenic