Ability of Trichloroethylene Metabolite to Promote Immune Pathology is Strain-Specific

Abstract

Chronic low-level exposure to the environmental pollutant trichloroethylene has been shown to promote autoimmune disease in association with CD4 + T-lymphocyte activation in lupus-prone MRL +/+ mice. One of the primary metabolites of trichloroethylene, trichloroacetaldehyde hydrate (TCAH), was similarly shown to increase the percentage of IFNγ-producing CD4 + T-lymphocytes when added to the drinking water of MRL +/+ mice. In addition, TCAH-treated MRL +/+ mice developed skin inflammation and alopecia. In the present study TCAH was tested for its ability to accelerate the development of alopecia in C3H/HeJ mice which tend to develop the disorder spontaneously late in life. In contrast to MRL +/+ mice, C3H/HeJ mice treated with TCAH did not develop alopecia at an increased rate. In addition, TCAH did not promote the expansion of activated IFNγ-producing CD4 + Tlymphocytes in C3H/HeJ mice. CD4 + T-lymphocytes from TCAHtreated C3H/HeJ mice, unlike their MRL +/+ counterparts, did not become resistant to activation-induced apoptosis following in vivo exposure to TCAH. Taken together, it appears that the ability of TCAH to promote immune-mediated pathology is strain-specific and may require an autoimmune-prone genetic background.

Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus

“…TCAH is a highly reactive aldehyde that has been proposed to spontaneously condense with the biogenic amine tryptamine to produce an alkaloid-type neurotoxin (Bringmann et al ., 1990). Our lab has studied the ability of TCAH extensively to form adducts with T cells and promote their activation in vitro and in vivo (Blossom et al, 2004; Blossom et al, 2006a; Blossom et al, 2006b; Blossom et al, 2007b; Gilbert et al, 2004) The ability of reactive aldehydes (i.e., from ethanol metabolism) to inhibit methionine synthase activity and subsequently lower glutathione has been documented (Waly et al ., 2011; Waly et al ., 2004). Decreased methionine synthase activity would therefore result in an accumulation of SAH and inhibition of SAM, and a depletion of GSH similar to what is observed in our model.…”

Trichloroethylene Alters Th1/Th2/Th17/Treg Paradigm in Mice: A Novel Mechanism for Chemically Induced Autoimmunity

“…13 However, the immune mechanisms, especially the role of T-cell subtypes, remain unclear. [14][15][16] Based on the surface phenotype and functional characteristics, the primary CD4 þ T cells can be classified into T helper 1 (Th1), Th2, Th17, and Treg subsets. 17 T helper 1 cells mainly secrete interferon-g (IFN-g), while Th2 cells produce interleukin-4 (IL-4) and IL-5, forming the major proand anti-inflammatory pair.…”

Metabolic changes and DNA hypomethylation in cerebellum are associated with behavioral alterations in mice exposed to trichloroethylene postnatally

“…The MRL+/+ strain of mice were used based on this strain’s sensitivity to TCE toxicity as described (Blossom et al ., 2006;Blossom et al ., 2007;Blossom et al ., 2008 Blossom et al, 2008). MRL +/+ mice are by all accounts normal and are often used as the control strain for studies using MRL/lpr mice.…”