Tetrachloroethylene (perchloroethylene;PCE) is a widely used dry-cleaning, fabric-finishing and metal degreasing agent. Large number of humans are exposed to this chemical either occupationally or through the environment. Besides its organ toxicity, PCE exposure has been implicated in inducing autoimmunity and/or autoimmune diseases (ADs), as evident from high levels of anti-nuclear antibodies, rashes, scleroderma and systemic lupus erythematosus (SLE)-like symptoms. The focus of this proposal is to establish that PCE exposure induces/exacerbates an autoimmune response and to elucidate the putative mechanism(s) of such response. We hypothesize that PCE can induce an autoimmune response through two possible mechanisms: 1) via PCE metabolism where metabolite-adducted proteins can act as neoantigens, and/or 2) via lipid peroxidation (LPO) where LPO-derived reactive aldehydes (LPDAs) such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA) can form LPDA-protein adducts and elicit an autoimmune response. Generation of neoantigen(s) via either of these mechanisms can elicit the production of antibodies against such neoantigen(s). These antibodies are expected to exhibit diverse specificities, particularly towards cellular macromolecule(s) to which PCE metabolites or LPDAs are bound and those macromolecules which share common epitopes. The binding of antibodies to these macromolecules would be detrimental to tissues and/or organs and eventually lead to ADs. Using female MRL +/+ and NZB/WF1 mice (autoimmune-prone) and B6C3F1 mice (non-autoimmune), the potential of PCE in inducing and/or exacerbating ADs will be evaluated by determining the markers of autoimmunity in the serum [anti-nuclear (ANA)-, anti-single stranded DNA (anti- ssDNA)-, anti-double stranded DNA (anti-dsDNA)-, anti-cardiolipin- and anti-Scl70-antibodies, and circulating immune complexes], and morphological assessment of tissues, especially kidneys (glomerulonephritis, vasculitis and deposition of immune complexes) and skin (perivascular infiltrates, thickening of the walls of dermal arterioles and capillaries). We will also evaluate te role of innate immune response in the progression to PCE-induced autoimmunity (Aim 1). Furthermore, to elucidate the mechanism(s) of PCE-induced autoimmunity and support our hypothesis, we will characterize trichloroacylated-protein adducts and LPDA- protein adducts using proteomic approaches in the tissues and/or serum of PCE-treated mice for quantitation and evaluation of their autoimmune potential. Antibodies to trichloroacylated-protein adducts and LPDA- protein adducts will also analyze for correlation with autoimmunity markers (Aim 2). These studies will establish that PCE induces and/or accelerates an autoimmune response and will also provide a link between PCE exposure, adducted proteins and autoimmunity. These studies will eventually help in designing strategies to prevent or reduce ADs resulting from exposure to PCE or related environmental/occupational agents.
Tetrachloroethylene (perchloroethylene;PCE) is a ubiquitous environmental contaminant with extensive use in the dry-cleaning industry. A sizable human population is continuously exposed to this chemical both environmentally and occupationally. The goal of this proposal is to establish that PCE exposure induces an autoimmune response/disease and also elucidate the mechanism(s) of such response so that better strategies can be designed for the management and prevention of such diseases.