Involvement of Lipid Peroxidation-Derived Aldehyde–protein Adducts in Autoimmunity Mediated by Trichloroethene

Abstract

Lipid peroxidation, a major contributor to cellular damage, is also implicated in the pathogenesis of autoimmune diseases (AD). The focus of this study was to elucidate the role of lipid peroxidation-derived aldehydes in autoimmunity induced and/or exacerbated by chemical exposure. Previous studies showed that trichloroethene (TCE) is capable of inducing/accelerating autoimmunity. To test whether TCE-induced lipid peroxidation might be involved in the induction/exacerbation of autoimmune responses, groups of autoimmune-prone female MRL +/+ mice were treated with TCE (10 mmol/kg, i.p., every 4th day) for 6 or 12 wk. Significant increases of the formation of malondialdehyde (MDA)- and 4-hydroxynonenal (HNE)–protein adducts were found in the livers of TCE-treated mice at both 6 and 12 wk, but the response was greater at 12 wk. Further characterization of these adducts in liver microsomes showed increased formation of MDA–protein adducts with molecular masses of 86, 65, 56, 44, and 32 kD, and of HNE–protein adducts with molecular masses of 87, 79, 46, and 17 kD in TCE-treated mice. In addition, significant induction of anti-MDA– and anti-HNE–protein adduct-specific antibodies was observed in the sera of TCE-treated mice, and showed a pattern similar to MDA– or HNE–protein adducts. The increases in anti-MDA– and anti-HNE–protein adduct antibodies were associated with significant elevation in serum anti-nuclear-, anti-ssDNA- and anti-dsDNA-antibodies at 6 wk and, to a greater extent, at 12 wk. These studies suggest that TCE-induced lipid peroxidation is associated with induction/exacerbation of autoimmune response in MRL+/+ mice, and thus may play an important role in disease pathogenesis. Further interventional studies are needed to establish a causal relationship between lipid peroxidation and TCE-induced autoimmune response.