Int. J. Environ. Res. Public Health 2012, 9 491 functions, loss of MTs/tubulins, a cell structural protein, may be a critical basis for As-induced lung pathology such as bronchiectasis, bronchitis, COPD, etc. Synthesis of tubulin is subjected to a novel feedback autoregulation, i.e., the level of the free tubulin pool directly controls the level of tubulin expression [52]. Thus, As3+ disrupts MTs increasing the free tubulin pool, as a result, inhibiting new tubulin synthesis. Our studies have shown As3+ downregulation of tubulin synthesis occuring at the mRNA level, i.e., marked reduction of steady-state I-tubulin expression in in vitro and in vivo models [Figures 3(B) and 4(B)]. As reported, the binding of tubulin subunits to the nascent N-terminal tetrapeptide (Met-Arg-Glu-Ile) of -tubulin triggers the adjacent ribosome to activate an RNase that degrades the polysome bound tubulin mRNA, inducing its destabilization [53]. In addition to its effects on tubulin mRNA stability, As3+ may also reduce tubulin mRNA initiation (synthesis) leading to low levels of steady-state tubulin mRNAs in lung cells and tissues. MTs play a fundamental role in regulation of cell division. Mitosis requires precise execution of a number of MT-based processes such as reduplication and splitting of the centrosome, assembly of a bipolar spindle, attachment of spindle MTs to chromosomes through kinetochores, tension generation on kinetochores by the dynamics of bipolar spindle MTs, and finally pulling each chromatid to one of the spindle poles [54]. An error in any step of such interdependent subcellular processes could perturb chromosomal organization, resulting in failure of mitosis. In this study we have observed cell division aberrations in the forms of chromosome lagging, scattering and clustering associated with spindle MT injury in the cell model following As3+ exposure (Figure 2). These characteristic chromosomal disorientations are also evident in cells treated with colchicine, an MT disassembly reagent [55]. Disassembly of all spindle MTs by As3+ may induce chromosomal scattering and clustering at metaphase while partial injure of spindle MT (such as disconnection of a few spindle fibers with chromosomes and/or monopole or multipoles, etc.) may lead to chromosomal lagging at anaphase/telophase. The latter appears to result from escaping the mitotic block (i.e., passing through metaphase) as seen [Figure 2(i)]. Importantly, lagging chromosomes are believed to induce aneuploidy [56], which is in turn closely related to tumorigenesis [57]. Oxidation and methylation status of As displayed various effects on the mitotic apparatus [58]. As3+-resulted in production of aneuploid cells was associated with disruption of both the MT assembly and the spindle formation [59]. Thus, As3+-induced disassembly of spindle MTs and aberrations in the cell division have a critical biological significance for human tumor pathogenesis. 5. Conclusions Briefly, present studies demonstrate two molecular targets of MTs for As3+ insult, i.e., tubulin -SH groups and MAPs. As3+ binding to tubulin -SH groups and inhibition of MAPs enhanced MT instability leading to its disassembly. Increase in the free tubulin pool by As3+ as a result of MT disassembly triggered an autoregulation mechanism inducing inhibition of tubulin synthesis at protein and mRNA levels and thus further aggravating lung MT injury, which was accompanied by activation of cellular metallothionein and -GCS, a critical thiol defense mechanism. As3+ damage to MTs was antagonized by taxol. Cytoskeletal MT injury by As3+ may be a critical basis for pulmonary pathology. These findings are expected to provide a piece of information for preventing As3+ cellular toxicity in the lung.