DI(2-ethylhexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia

Abstract

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.

Effects of DEHP on endometrial receptivity and embryo implantation in pregnant mice

“…Ter Veld et al showed that food-associated estrogenic compounds such as DEHP could induce ER-mediated luciferase gene expression in transgenic male mice [44]. Eagon et al reported that DEHP induces the expression of ER in rat liver [45]. Our results also indicated elevated levels of ER␣ expression after DEHP exposure.…”

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

“…The experiments presented here indicate that the reactions catalyzed by P450 2C11, hydroxylations at the 2 and 16␣ positions of E 2 (summarized in Martucci and Fishman, 1993), would decrease in parallel with the down-regulation in P450 2C11. A decrease in the activity of 2␣-hydroxylation of E 2 and male E 2 binding protein has been observed after treatment with DEHP (Eagon et al, 1994). Elevation in the activity of aromatase observed in the male rat liver after treatment with ammonium perfluorooctanoate (Liu et al, 1996) could also contribute to increases in E 2 .…”

“…Increases in estradiol levels in male rats after exposure may be partly attributed to decreases in P450 2C11. In male rats, exposure to the PPC ammonium perfluorooctanoate, DEHP, clofibrate, and WY (Eagon et al, 1994;Hurtt et al, 1997, and references therein) have been shown to increase serum E 2 levels. These increases have been hypothesized to contribute to Leydig cell hyperplasia and subsequent Leydig cell adenomas after long term exposure to PPC (Liu et al, 1996).…”

Supportive Evidence for the Anticancerous Potential of Alternative Medicine against Hepatocarcinogenesis in Mice

“…Interestingly, in an analogous situation a decrease in testosterone level was observed in human male patients [41]. In a similar study, Eagon et al [42] showed an increased level of estradiol in females of a rat model of hyperplasia. Therefore, alterations in the levels of sex hormones could also reflect toxicity status and therefore be used in predictive risk factor assessments [41].…”