Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium
Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium
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DOI：
10.1002/tox.20693
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发表时间：
2013-01-01
影响因子：
4.5
通讯作者：
Shimoi, K.
中科院分区：
文献类型：
--
作者：
Kido, T.;Sakakibara, H.;Shimoi, K.
氯化苯并[a]蒽（Cl-BaA）是一种卤代芳香族化合物（以二恶英为代表），在环境中以相对较高的浓度存在。Fischer 344大鼠连续14天灌胃给予Cl-BaA或其母体化合物苯并[a]蒽（BaA）0、1或10 mg/kg体重。两种化学品在10 mg/kg/天剂量下均抑制体重增加，从而抑制相对肝脏重量增加。与对照组相比，BaA（10 mg/kg/天）给药显著刺激了细胞色素P450（CYP）1A 1、1A 2和1B 1的肝脏基因表达。Cl-BaA给药后，即使在较低剂量下，也只有CYP 1A 2基因被显著诱导;与对照组相比，Cl-BaA治疗组大鼠的CYP 1A 1和1B 1 mRNA水平保持不变。为了阐明这种Cl-BaA暴露和诱导CYP在毒性发作时的作用，我们使用鼠伤寒沙门氏菌TA 98和TA 100研究了BaA和Cl-BaA的致突变性。在存在大鼠S-9的情况下，10 μ g/平板的BaA和Cl-BaA在两种菌株中均产生阳性结果。Cl-BaA与重组大鼠CYP 1A 2孵育在TA 98和TA 100中产生的回复突变菌落数显著高于对照组，但未观察到BaA的此类变化。总之，BaA通过氯化改变其自身的生理和毒理学作用;（1）每日暴露于Cl-BaA选择性诱导大鼠肝脏CYP 1A 2;（2）Cl-BaA在CYP 1A 2存在的情况下诱导移码突变，尽管BaA不具有致突变性。这表明CYP 1A 2可能将Cl-BaA代谢为活性形式。(c)2011 Wiley Periodicals，Inc.环境毒理学，2013年。
Chlorinated benz[a]anthracenes (Cl-BaA) are halogenated aromatic compounds (typified by dioxins) found in the environment at relatively high concentrations. Fischer 344 rats were intragastrically administered 0, 1, or 10 mg of Cl-BaA or its parent compound benz[a]anthracene (BaA) per kg of body weight for 14 consecutive days. Both chemicals at 10 mg/kg/day inhibited the gain in body weight, and consequent increase in relative liver weight. Hepatic gene expression of cytochrome P450 (CYP) 1A1, 1A2, and 1B1 was significantly stimulated by administration of BaA (10 mg/kg/day) compared with the control. After administration of Cl-BaA, only the CYP1A2 gene was significantly induced, even at the lower dosage; CYP1A1 and 1B1 mRNA levels remained unchanged in Cl-BaA-treated rats compared with controls. To elucidate the role of such Cl-BaA exposure and induced CYPs at toxicity onset, we investigated the mutagenicity of BaA and Cl-BaA using Salmonella typhimurium TA98 and TA100. BaA and Cl-BaA at 10 mu g/plate produced positive results in both strains in the presence of rat S-9. Incubation of Cl-BaA with recombinant rat CYP1A2 produced a significantly higher number of revertant colonies in TA98 and TA100 than in controls, but no such change was observed for BaA. In conclusion, BaA changes its own physiological and toxicological actions by its chlorination; (1) daily exposure to Cl-BaA selectively induces hepatic CYP1A2 in rats and (2) Cl-BaA induces frameshift mutations in the presence of CYP1A2, although BaA does not exert mutagenicity. This indicates that CYP1A2 may metabolize Cl-BaA to active forms. (c) 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.