Gilbert Kathleen M, Przybyla Beata, Pumford Neil R, Han Tao, Fuscoe James, Schnackenberg Laura K, Holland Ricky D, Doss Jason C, Macmillan-Crow Lee Ann, Blossom Sarah J
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA.
Chem Res Toxicol. 2009 Apr;22(4):626-32. doi: 10.1021/tx800409r.
Exposure to the environmental pollutant trichloroethylene (TCE) has been linked to autoimmune disease development in humans. Chronic (32-week) low-level exposure to TCE has been shown to promote autoimmune hepatitis in association with CD4(+) T cell activation in autoimmune-prone MRL+/+ mice. MRL+/+ mice are usually thought of as a model of systemic lupus rather than an organ-specific disease such as autoimmune hepatitis. Consequently, the present study examined gene expression and metabolites to delineate the liver events that skewed the autoimmune response toward that organ in TCE-treated mice. Female MRL+/+ mice were treated with 0.5 mg/mL TCE in their drinking water. The results showed that TCE-induced autoimmune hepatitis could be detected in as little as 26 weeks. TCE exposure also generated a time-dependent increase in the number of antibodies specific for liver proteins. The gene expression correlated with the metabolite analysis to show that TCE upregulated the methionine/homocysteine pathway in the liver after 26 weeks of exposure. The results also showed that TCE exposure altered the expression of selective hepatic genes associated with immunity and inflammation. On the basis of these results, future mechanistic studies will focus on how alterations in genes associated with immunity and inflammation, in conjunction with protein alterations in the liver, promote liver immunogenicity in TCE-treated MRL+/+ mice.
接触环境污染物三氯乙烯（TCE）与人类自身免疫性疾病的发展有关。在自身免疫易感的MRL+/+小鼠中，慢性（32周）低水平接触TCE已被证明会促进自身免疫性肝炎，并伴有CD4(+) T细胞活化。MRL+/+小鼠通常被认为是系统性红斑狼疮的模型，而非诸如自身免疫性肝炎之类的器官特异性疾病模型。因此，本研究检测了基因表达和代谢产物，以描绘在TCE处理的小鼠中使自身免疫反应偏向该器官的肝脏事件。雌性MRL+/+小鼠饮用含0.5 mg/mL TCE的水。结果显示，在短短26周内即可检测到TCE诱导的自身免疫性肝炎。TCE暴露还使肝脏蛋白特异性抗体数量随时间增加。基因表达与代谢产物分析相关，表明在暴露26周后，TCE上调了肝脏中的蛋氨酸/同型半胱氨酸途径。结果还显示，TCE暴露改变了与免疫和炎症相关的选择性肝脏基因的表达。基于这些结果，未来的机制研究将聚焦于与免疫和炎症相关的基因改变，以及肝脏中的蛋白质改变如何共同促进TCE处理的MRL+/+小鼠的肝脏免疫原性。
