Kiyosawa Naoki, Kwekel Joshua C, Burgoon Lyle D, Williams Kurt J, Tashiro Colleen, Chittim Brock, Zacharewski Timothy R
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.
Toxicol Sci. 2008 Feb;101(2):350-63. doi: 10.1093/toxsci/kfm275. Epub 2007 Nov 5.
Technical-grade dichlorodiphenyltrichloroethane (DDT) is an agricultural pesticide and malarial vector control agent that has been designated a potential human hepatocarcinogen. The o,p'-enantiomer exhibits estrogenic activity that has been associated with the carcinogenicity of DDT. The temporal and dose-dependent hepatic estrogenicity of o,p'-DDT was investigated using complementary DNA microarrays in immature ovariectomized Sprague-Dawley rats with complementary histopathology and tissue-level analysis. Animals were gavaged with 300 mg/kg o,p'-DDT either once or once daily for 3 consecutive days. Liver samples were examined 2, 4, 8, 12, 18, or 24 h after a single dose or following three daily doses. For dose-response studies, a single dose of 3, 10, 30, 100, or 300 mg/kg body weight o,p'-DTT was administered for 3 consecutive days. Genes associated with drug metabolism (Cyp2b2 and Cyp3a2), the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), cell proliferation (Ccnd1, Ccnb1, Ccnb2, and Stmn1), and oxidative stress (Gclm and Hmox1) were significantly induced. Cyp2b2 exhibited dose-dependent regulation and was significantly induced across all time points, while cell proliferation- and oxidative stress-related genes exhibited transient induction. The induction of Cyp2b2 and Cyp3a2 mRNA levels suggest PXR/CAR activation, consistent with expression of genes associated with oxidative stress. Few genes known to be estrogen receptor (ER) regulated were differentially expressed when compared to the hepatic gene expression profile elicited by ethynyl estradiol in immature ovariectomized C57BL/6 mice using the same study design and analysis methods. These data indicate that o,p'-DDT elicits PXR/CAR-, not ER-, mediated gene expression in the rat liver. Based on the species-specific differences in CAR regulation, the extrapolation of rodent DDT hepatocarcinogenicity to humans warrants further investigation.
工业级二氯二苯三氯乙烷（DDT）是一种农业杀虫剂和疟疾媒介控制剂，已被认定为潜在的人类肝癌致癌物。o,p'-对映体具有雌激素活性，这与DDT的致癌性有关。利用互补DNA微阵列，结合组织病理学和组织水平分析，研究了未成熟去卵巢的Sprague-Dawley大鼠中o,p'-DDT的时间和剂量依赖性肝脏雌激素活性。动物单次或连续3天每天灌胃300mg/kg的o,p'-DDT。单次给药或连续3天给药后2、4、8、12、18或24小时检查肝脏样本。对于剂量反应研究，连续3天给予单剂量3、10、30、100或300mg/kg体重的o,p'-DTT。与药物代谢相关的基因（Cyp2b2和Cyp3a2）、核受体组成型雄烷受体（CAR）和孕烷X受体（PXR）、细胞增殖（Ccnd1、Ccnb1、Ccnb2和Stmn1）以及氧化应激（Gclm和Hmox1）均被显著诱导。Cyp2b2表现出剂量依赖性调节，在所有时间点均被显著诱导，而与细胞增殖和氧化应激相关的基因表现出瞬时诱导。Cyp2b2和Cyp3a2 mRNA水平的诱导表明PXR/CAR被激活，这与氧化应激相关基因的表达一致。与使用相同研究设计和分析方法的未成熟去卵巢C57BL/6小鼠中乙炔雌二醇引起的肝脏基因表达谱相比，很少有已知受雌激素受体（ER）调节的基因差异表达。这些数据表明，o,p'-DDT在大鼠肝脏中引发的是PXR/CAR介导而非ER介导的基因表达。基于CAR调节的物种特异性差异，将啮齿动物DDT肝癌致癌性外推至人类需要进一步研究。
