Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, College of Medicine, Arkansas, USA.
Toxicol Sci. 2011 Feb;119(2):281-92. doi: 10.1093/toxsci/kfq345. Epub 2010 Nov 17.
We have shown previously that chronic (32 weeks) exposure to occupationally relevant concentrations of the environmental pollutant trichloroethylene (TCE) induced autoimmune hepatitis (AIH) in autoimmune-prone MRL+/+ mice. In real-life, individuals are never exposed to only one chemical such as TCE. However, very little is known about the effects of chemical mixtures on the immune system. The current study examined whether coexposure to another known immunotoxicant, mercuric chloride (HgCl(2)), altered TCE-induced AIH. Female MRL+/+ mice were treated for only 8 weeks with TCE (9.9 or 186.9 mg/kg/day in drinking water) and/or HgCl(2) (260 μg/kg/day, sc). Unlike mice exposed to either TCE or HgCl(2) alone, mice exposed to both toxicants for 8 weeks developed significant liver pathology commensurate with early stages of AIH. Disease development in the coexposed mice was accompanied by a unique pattern of anti-liver and anti-brain antibodies that recognized, among others, a protein of approximately 90 kDa. Subsequent immunoblotting showed that sera from the coexposed mice contained antibodies specific for heat shock proteins, a chaperone protein targeted by antibodies in patients with AIH. Thus, although TCE can promote autoimmune disease following chronic exposure, a shorter exposure to a binary mixture of TCE and HgCl(2) accelerated disease development. Coexposure to TCE and HgCl(2) also generated a unique liver-specific antibody response not found in mice exposed to a single toxicant. This finding stresses the importance of including mixtures in assessments of chemical immunotoxicity.
我们之前已经表明，长期（32 周）接触环境污染物三氯乙烯（TCE）会导致自身免疫性肝炎（AIH）在自身免疫倾向的 MRL + / + 小鼠中。在现实生活中，个体从未接触过 TCE 等单一化学物质。然而，人们对化学混合物对免疫系统的影响知之甚少。目前的研究检查了另一种已知的免疫毒素氯化汞（HgCl 2 ）是否会改变 TCE 诱导的 AIH。仅用 TCE（饮用水中 9.9 或 186.9 mg/kg/天）和/或 HgCl 2 （260 μg/kg/天，sc）处理雌性 MRL + / + 小鼠 8 周。与单独接触 TCE 或 HgCl 2 的小鼠不同，接触两种毒物 8 周的小鼠会出现明显的肝病理变化，与 AIH 的早期阶段相当。在共同暴露的小鼠中，疾病的发展伴随着一种独特的抗肝和抗脑抗体模式，这些抗体除其他外，还识别约 90 kDa 的蛋白质。随后的免疫印迹显示，来自共同暴露的小鼠的血清含有针对热休克蛋白的抗体，这些抗体是 AIH 患者抗体的靶标，热休克蛋白是一种伴侣蛋白。因此，尽管 TCE 可以在长期接触后促进自身免疫性疾病，但较短时间暴露于 TCE 和 HgCl 2 的二元混合物会加速疾病的发展。TCE 和 HgCl 2 的共同暴露也产生了一种独特的肝脏特异性抗体反应，在暴露于单一毒物的小鼠中未发现。这一发现强调了在评估化学免疫毒性时包括混合物的重要性。
