Immuno- and hepato-toxicity of dichloroacetic acid in MRL+/+ and B6C3F1 mice
Immuno- and hepato-toxicity of dichloroacetic acid in MRL+/+ and B6C3F1 mice
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DOI：
10.1080/15476910701337225
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发表时间：
2007-04-01
影响因子：
3.3
通讯作者：
Konig, Rolf
中科院分区：
文献类型：
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作者：
Cai, Ping;Boor, Paul J.;Konig, Rolf
二氯乙酸（DCA）是用氯消毒的饮用水中发生的氯化反应的副产品。三氯乙烯（TCE）的代谢也产生DCA。TCE暴露与自身免疫性疾病的发展有关，这可能是由TCE代谢物（如DCA）诱导的。因此，了解DCA的免疫毒性反应是很重要的。我们选择了2种小鼠模型，自身免疫易感性MRL+/+和正常B6C3F1小鼠。两种小鼠均暴露于DCA 12周。DCA处理后，两种小鼠的肝脏重量和肝体重比均显著高于各自的对照组。两种菌株血清丙氨酸和天冬氨酸转氨酶活性均无显著变化。MRL+/+小鼠血清IgG和IgM浓度显著升高，而B6C3F1小鼠仅血清IgG(3)升高。DCA治疗没有改变血清中炎症细胞因子的水平。然而，与治疗无关，MRL+/+小鼠血清中G-CSF浓度低于B6C3F1小鼠，而MRL+/+小鼠血清中IL-12水平较高。DCA处理降低了MRL+/+小鼠肝脏中IL-10和KC趋化因子的浓度，而DCA处理的B6C3F1小鼠肝脏中t辅助细胞因子（IL-4、IL-5、IL-10、IFN γ和GM-CSF）、促炎细胞因子（IL-6、IL-12和G-CSF）和KC趋化因子的浓度升高。用抗CD3和CD28的抗体刺激脾t淋巴细胞导致两株小鼠分泌的细胞因子有显著差异。淋巴细胞);与B6C3F1小鼠相比，MRL+/+小鼠分泌更多的IL-2、IL-4和IL-10，但分泌较少的IFN γ和GM-CSF。因此，血清和肝脏中的细胞因子水平以及受刺激的脾t淋巴细胞的细胞因子分泌模式表明，B6C3F1小鼠的炎症反应倾向高于MRL+/+小鼠。与MRL+/+小鼠相比，DCA治疗对B6C3F1小鼠肝脏脂质积累的影响更严重。因此，这些结果表明，DCA在B6C3F1小鼠中诱导的炎症反应更强，导致比MRL+/+小鼠更严重的肝毒性，后者的免疫反应更明显。
Dichloroacetic acid (DCA) is a by-product of chlorination that occurs in drinking water disinfected with chlorine. Metabolism of trichloroethene (TCE) also generates DCA. TCE exposure is associated with the development of autoimmune diseases, which may be induced by TCE metabolites, such as DCA. Thus, it is important to understand immunotoxic responses to DCA. We chose 2 murine models, autoimmune-prone MRL+/+ and normal B6C3F1 mice. Both strains of mice were exposed to DCA for 12 weeks. Following DCA treatment, liver weights and liver-to-body weight ratios were signiticantly increased in both strains of mice when compared to their respective controls. The serum activity of alanine and aspartate aminotransferases was not significantly altered in either strain. In MRL+/+ mice, the serum concentrations of IgG and IgM were significantly increased, whereas in B6C3F1 mice, only serum IgG(3) was increased. DCA treatment did not change the levels of inflammatory cytokines in the serum. However, independent of treatment, the concentrations of G-CSF in the serum were lower in MRL+/+ mice than in B6C3F1 mice, whereas IL-12 serum levels were higher in MRL+/+ mice. DCA treatment decreased IL-10 and KC chemokine concentrations in the livers of MRL+/+ mice, whereas T-helper cell cytokines (IL-4, IL-5, IL-10, IFN gamma, and GM-CSF), pro-inflammatory cytokines (IL-6, IL-12, and G-CSF), and KC chemokine were increased in the livers of DCA-treated B6C3F1 mice. Stimulation of splenic T-lymphocytes with antibodies against CD3 and CD28 resulted in a marked difference in the secreted cytokines between the two strains of mice. T-lymphocytes; from MRL+/+ mice secreted more IL-2, IL-4 and IL-10, but less IFN gamma and GM-CSF, than did T-lymphocytes from B6C3F1 mice. Thus, the cytokine levels in serum and liver, and the cytokine secretion patterns from stimulated splenic T-lymphocytes suggested a higher propensity of inflammatory responses in B6C3F1 than in MRL+/+ mice. Treatment with DCA also affected lipid accumulation in the liver more severely in B6C3F1 than in MRL+/+ mice. Thus, these results indicate that DCA induced stronger inflammatory responses leading to more severe hepatotoxicity in B6C3F1 mice than in MRL+/+ mice, and more pronounced immune responses in the latter.