Eagon P K, Chandar N, Epley M J, Elm M S, Brady E P, Rao K N
Veterans Affairs Medical Center, Pittsburgh, PA 15240.
Int J Cancer. 1994 Sep 1;58(5):736-43. doi: 10.1002/ijc.2910580519.
Exposure to a common phthalate, di(2-ethylhexyl)phthalate (DEHP), is associated with liver hyperplasia prior to the development of hepatocellular carcinoma in rodents. The exact mechanism of liver hyperplasia as well as tumorigenesis by this agent is not known. Since other lines of evidence point to estrogens as mediators of liver hyperplastic changes, we investigated whether DEHP exposure might alter hepatic estrogen metabolism and induce hyperplasia. Male Fischer 344 rats were fed either control or 1.2% DEHP-containing diets and sacrificed after 4, 8 and 16 weeks of exposure; activities of several sex hormone-responsive markers were measured. Rats fed DEHP had significantly increased serum estradiol levels, but hepatic activity of both cytosolic and nuclear estrogen receptor (ER) was significantly reduced. The serum content of ceruloplasmin, an estrogen-responsive protein synthesized by the liver, was also reduced, perhaps as a consequence of loss of ER activity. The rise in serum estradiol in DEHP-treated rats may be explained by the observation that these rats showed significant losses in hepatic activity of both a major male estrogen-metabolizing enzyme, estrogen 2-hydroxylase, and a male-specific estrogen-sequestering protein. In contrast to reductions in these activities, the expression of proliferating cell nuclear antigen and mRNAs for both ER and fos increased significantly as a result of exposure to DEHP. Our results suggest that changes in estrogen metabolism, receptor activity and activation of genes for cell proliferation are among the earliest metabolic alterations induced by DEHP. These changes together with the induced hyperplasia could play a crucial role in hepatocellular carcinoma development as a result of continuous exposure to DEHP.
在啮齿动物发生肝细胞癌之前，接触一种常见的邻苯二甲酸酯——邻苯二甲酸二（2-乙基己基）酯（DEHP）与肝脏增生有关。该物质导致肝脏增生以及肿瘤发生的确切机制尚不清楚。由于其他证据表明雌激素是肝脏增生性变化的介质，我们研究了接触DEHP是否可能改变肝脏雌激素代谢并诱导增生。给雄性Fischer 344大鼠喂食对照饮食或含1.2%DEHP的饮食，并在接触4、8和16周后处死；测量了几种性激素反应标志物的活性。喂食DEHP的大鼠血清雌二醇水平显著升高，但胞质和核雌激素受体（ER）的肝脏活性均显著降低。肝脏合成的雌激素反应蛋白铜蓝蛋白的血清含量也降低了，这可能是ER活性丧失的结果。DEHP处理的大鼠血清雌二醇升高可能是由于观察到这些大鼠肝脏中主要的雄性雌激素代谢酶雌激素2-羟化酶和雄性特异性雌激素结合蛋白的活性均显著降低。与这些活性的降低相反，接触DEHP后增殖细胞核抗原以及ER和fos的mRNA表达均显著增加。我们的结果表明，雌激素代谢、受体活性的变化以及细胞增殖基因的激活是DEHP诱导的最早的代谢改变之一。这些变化与诱导的增生一起，可能在持续接触DEHP导致肝细胞癌发展过程中起关键作用。
