Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: kidney effects.
Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: kidney effects.
复制标题
DOI：
10.1080/15287394.2015.958418
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Rusyn I
中科院分区：
文献类型：
--
作者：
Yoo HS;Bradford BU;Kosyk O;Uehara T;Shymonyak S;Collins LB;Bodnar WM;Ball LM;Gold A;Rusyn I
三氯乙烯（TCE）是一种众所周知的环境和职业毒物，根据与肾细胞癌高风险相关的流行病学证据，被归类为人类致癌物。许多对评估TCE对人类健康风险至关重要的科学问题仍未得到解决，例如形成的肾毒性谷胱甘肽偶联代谢物的数量、物种间和个体间的差异以及肾致癌性的作用方式。我们假设肾脏中的TCE代谢物水平与肾脏特异性毒性有关。在亚急性（600 mg/kg/d， 5天，7个近交小鼠品系）和亚慢性（100或400 mg/kg/d， 1、2或4周，2个近交小鼠品系）设计中口服TCE。我们评估了细胞色素p450介导的氧化[三氯乙酸（TCA）、二氯乙酸（DCA）和三氯乙醇]和谷胱甘肽偶联物[S-（1,2-二氯酰）- l -半胱氨酸和S-（1,2-二氯酰）谷胱甘肽]中TCE代谢物形成的菌株、剂量和时间依赖性之间的定量关系，以及各种肾毒性表型。在亚急性研究中，我们观察到肾中TCE代谢物水平在品系间的差异。此外，我们发现在一些菌株中，TCE对肾脏的特异性影响包括诱导过氧化物酶体增殖物标记基因Cyp4a10和Acox1，增加细胞增殖和表达KIM-1（肾小管损伤和再生的标志）。在亚慢性研究中，NZW/LacJ小鼠的过氧化物酶体增殖物标记基因诱导和肾毒性减弱，而细胞增殖反应呈剂量依赖方式升高，而C57BL/6J小鼠则没有。总的来说，我们表明肾脏中TCE代谢物水平与肾脏特异性毒性有关，并且这些影响是菌株依赖性的。
Trichloroethylene (TCE) is a well-known environmental and occupational toxicant that is classified as carcinogenic to humans based on the epidemiological evidence of an association with higher risk of renal cell carcinoma. A number of scientific issues critical for assessing human health risks from TCE remain unresolved, such as the amount of kidney-toxic glutathione conjugation metabolites formed, inter-species and -individual differences, and the mode of action for kidney carcinogenicity. We hypothesized that TCE metabolite levels in the kidney are associated with kidney-specific toxicity. Oral dosing with TCE was conducted in sub-acute (600 mg/kg/d; 5 days; 7 inbred mouse strains) and sub-chronic (100 or 400 mg/kg/d; 1, 2, or 4 weeks; 2 inbred mouse strains) designs. We evaluated the quantitative relationship between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P450-mediated oxidation [trichloroacetic acid (TCA), dichloroacetic acid (DCA), and trichloroethanol] and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione], and various kidney toxicity phenotypes. In sub-acute study, we observed inter-strain differences in TCE metabolite levels in the kidney. In addition, we found that in several strains kidney-specific effects of TCE included induction of peroxisome proliferator-marker genes Cyp4a10 and Acox1, increased cell proliferation, and expression of KIM-1, a marker of tubular damage and regeneration. In sub-chronic study, peroxisome proliferator-marker gene induction and kidney toxicity diminished while cell proliferative response was elevated in a dose-dependent manner in NZW/LacJ, but not C57BL/6J mice. Overall, we show that TCE metabolite levels in the kidney are associated with kidney-specific toxicity and that these effects are strain-dependent.
登录
查看更多内容
影响因子：
5.3
作者：
Lash, Lawrence H.;Chiu, Weihsueh A.;Guyton, Kathryn Z.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
影响因子：
3.8
作者：
Harrill, Alison H.;DeSmet, Kristina D.;Watkins, Paul B.
通讯作者：
Watkins, Paul B.
影响因子：
10.4
作者：
Chiu, Weihsueh A.;Okino, Miles S.;Evans, Marina V.
通讯作者：
Evans, Marina V.
影响因子：
4.5
作者：
COJOCEL, C;BEUTER, W;MAYER, D
通讯作者：
MAYER, D
影响因子：
10.3
作者：
Brauch, H;Weirich, G;Brüning, T
通讯作者：
Brüning, T