Kiyosawa Naoki, Kwekel Joshua C, Burgoon Lyle D, Dere Edward, Williams Kurt J, Tashiro Colleen, Chittim Brock, Zacharewski Timothy R
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
BMC Genomics. 2008 Oct 16;9:487. doi: 10.1186/1471-2164-9-487.
Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data.
Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT.
Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.
滴滴涕（DDT）是一种持久性雌激素类有机氯农药，是啮齿动物肝脏肿瘤促进剂，对人类的致癌性尚无定论。我们之前报道过，邻，对'-滴滴涕主要引发孕烷X受体（PXR）/组成型雄烷受体（CAR）介导的活性，而非雌激素受体（ER）介导的肝脏反应，并表明与ER介导的效应相反，CAR介导的效应在大鼠肝脏肿瘤促进中可能更重要。为了进一步表征物种特异性肝脏反应，我们在用300mg/kg邻，对'-滴滴涕处理的未成熟、去卵巢的C57BL/6小鼠中进行了基因表达分析，并结合了组织病理学和组织水平分析，并与斯普拉格-道利大鼠的数据进行了比较。
大鼠和小鼠在邻，对'-滴滴涕快速代谢的情况下，组织病理学变化可忽略不计。基因表达谱也相似，表现出PXR/CAR调节以及Cyp2b10和Cyp3a11的特征性诱导。然而，与小鼠中的CAR特异性基因相比，PXR特异性靶基因如Apoa4或Insig2表现出更明显的诱导。此外，小鼠的Car mRNA水平下降，这可能有助于小鼠PXR的优先激活。ER调节的基因Cyp17a1和Cyp7b1也被诱导，表明邻，对'-滴滴涕也在小鼠中引发ER介导的基因表达，而在大鼠中ER介导的效应可忽略不计，这可能是由于CAR对ER活性的抑制作用。此外，邻，对'-滴滴涕诱导了Gadd45a、Gadd45b和Cdkn1，表明DNA损伤可能是另一个风险因素。此外，小鼠在处理后12小时血液中脱氢表雄酮硫酸盐（DHEA-S）水平升高也可能导致邻，对'-滴滴涕的内分泌相关效应。
尽管已知滴滴涕会导致啮齿动物肝脏肿瘤，但PXR/CAR结构、表达模式和配体偏好的显著物种差异以及类固醇生成，尤其是CYP17A1表达和活性的显著物种特异性差异，使得这些结果难以外推至人类。然而，确定潜在的作用模式以及物种特异性反应可能有助于选择和进一步开发更合适的模型，以评估滴滴涕对人类和野生动物的毒性。
