Toxic metals such as arsenic, cadmium and mercury induce the cellular stress response that, in part, results in increased expression and phosphorylation of the small heat-shock protein (sHSP) hsp27 as well as other sHSPs. The stress response protects , to some extent, individual cells against the harmful effects of toxicants. It has long been hypothesized that increased expression and/or phosphorylation of hsp27 may protect cells by stabilizing microfilaments. Recent results from others as well as our own laboratories also indicate that HSP27 and other sHSPs have a variety of activities in cells. While microfilament stabilization may be a mechanism by which the stress response protects cells from the effects of toxic metals, because microfilaments play key roles in many cellular functions that are required for coordinated tissue function and because sHSPs probably have other functions as well that are required for the coordinated function of cells in tissues, we simultaneously affecting coordination of cells required for tissue function in ways that may be harmful to, or that at the least alter, tissue function. To better understand the role of hsp27 and other sHSPs in cellular response to toxic metals, we believe that it would be useful to examine the effects of toxic metals in the tissue type which expresses the greatest amounts and most members of the sHSPs superfamily, namely muscle.
The specific aims of our proposed studies of muscle are: 1. To define temporal and spatial patterns of HSPO27, alphaB-crystallin, HSP20 and HSP22 expression and phosphorylation in control rodent embryos during development and in adult rodent tissues; 2. To determine the dose- response of the toxic metals arsenic cadmium and mercury, singly or in combinations, on induction of the stress response in rodent embryos as measured by increased expression and phosphorylation of sHSPs and changes in sHSPs cellular distributions; 3. To determine effects of toxic metals on muscle differentiation, structure and function in embryos; and 4. To study transgenic mice expressing altered amounts of HSP27, or mutant HSP27 that mimics phosphorylated or non-phosphorylated HSP27 (to duplicate specific effects of metal toxicants) and study the effect of altered HSP27 during embryo muscle development. These studies will provide novel information about sublethal effects of toxic metals in muscle development and should contribute to a better understanding of the mechanisms by which sublethal exposure to toxic metals affect the development and physiology of mammals.
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