Autoimmune diseases are a widespread human health problem. Preventing these incurable disorders is currently impossible due to our limited knowledge of autoimmune disease etiology. There is evidence that idiopathic autoimmune disease can be triggered by exposure to certain environmental pollutants such as the solvent trichloroethylene (TCE). We have shown that adult MRL+/+ mice exposed to low-level TCE developed autoimmune disease along with "heritable" alterations in CD4+ T cell function associated with DNA methylation. Although adult-only exposure to TCE triggered autoimmune disease, there is evidence that the developing immune system is even more sensitive than the adult immune system to chemical toxicity. Thus, developmental exposure to TCE is likely to augment the autoimmune-promoting effects of adult exposure. It is expected that this effect will be mediated by changes in the DNA methylation of specific effector genes in CD4+ T cells. If these predictions are confirmed it would support the concept that developmental exposure to chemicals at levels previously thought safe can promote autoimmune disease development in adults. These predictions and associated mechanism of action will be tested here in 3 Aims.
Aim 1. Determine impact of developmental TCE exposure on adult autoimmune disease. We will test whether autoimmune disease pathology and associated CD4+ T cell alterations are more robust if TCE exposure begins at gestation rather than as an adult.
Aim 2. Define TCE-induced epigenetic alterations in CD4+ T cells. Novel genome-scale DNA methylation profiles will identify time- and concentration-dependent gene alterations in CD4+ T cells from the TCE-treated mice.
Aim 3. Characterize autoreactivity of CD4+ T cells from TCE-treated mice. CD4+ T cells from TCE-treated MRL+/+ mice will be tested for their ability to generate autoimmune disease following adoptive transfer into lymphocyte-deficient (Rag knockout) MRL+/+ mice. This adoptive transfer experiment will compare the autoreactivity of CD4+ T cells generated from two windows of donor TCE exposure (developmental and adult- only).
This grant is focused on trichloroethylene (16th on the CERCLA Priority List), the most widely detected organic chemical at Superfund sites. Experiments will determine whether developmental exposure to this common water pollutant can trigger autoimmune disease, a significant human health problem of unknown etiology.
|Gilbert, Kathleen M; Reisfeld, Brad; Zurlinden, Todd J et al. (2014) Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis. Toxicol Appl Pharmacol 279:284-93|
|Gilbert, Kathleen M; Woodruff, William; Blossom, Sarah J (2014) Differential immunotoxicity induced by two different windows of developmental trichloroethylene exposure. Autoimmune Dis 2014:982073|