Sequential Appearance and Ultrastructure of Amphophilic Cell Foci, Adenomas, and Carcinomas in the Liver of Male and Female Rats Treated with Dehydroepiandrosterone

Abstract

Dehydroepiandrosterone (DHEA), a hormone of the adrenal cortex, acts as a peroxisome proliferator and hepatocarcinogen in rats upon long-term treatment with high doses in the diet. The aim of the present study was to identify the site of origin of hepatocellular neoplasms and the sequence of preneoplastic lesions. Twenty-five female and 25 male rats were given 0.6% DHEA in the diet; 25 animals of each sex were controls. Groups of 5 treated and untreated animals were sacrificed after 4, 20, 32, 70, and 84 wk. Amphophilic cell foci were detected after 32 wk of treatment; they developed from the liver parenchyma almost exclusively in the vicinity of portal tracts. Adenomas of the amphophilic or amphophilic/tigroid cell phenotype were observed at 70 wk of treatment. Highly differentiated hepatocellular carcinomas presenting a similar cellular phenotype occurred after 70-84 wk. The incidence of hepatocellular carcinomas was 44% in female and 11% in male rats. Ultrastructural studies of the amphophilic cell foci and tumors revealed a marked proliferation of mitochondria and a moderate proliferation of peroxisomes in all lesions. In addition, a very strong peroxisome proliferation was observed in perivenular hepatocytes in the liver of female rats. Peroxisomes usually lacked core and showed flocculent matrices. In male rats, weak peroxisomal proliferation was observed. Typical morphological abnormalities of these peroxisomes were paracrystalline inclusions of striated appearance. Although the most prominent peroxisome proliferation was observed in perivenular hepatocytes, these cells did not seem to be involved in tumor development. In contrast, the morphological similarity of the amphophilic cell foci and the amphophilic/tigroid cell adenomas and carcinomas, their coincident localization near portal tracts, and the sequential appearance of these lesions suggest that the amphophilic cell foci represent an early stage in DHEA-induced hepatocellular neoplasia. Mitochondrial proliferation as the most prominent feature in all stages of this model of hepatocarcinogenesis may offer a new approach for analysis of hepatocarcinogenesis induced by DHEA and possibly other peroxisomal proliferators.

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

“…35 This type of cell focus is mainly induced by peroxisome proliferators, eg, by hypolipidemic drugs and the adrenal steroid hormone dehydroepiandrosterone (DHEA). 36,37 Most peroxisome proliferators exert their actions through peroxisome proliferator-activated receptors, which belong to the receptor superfamily of steroid hormone receptors. 38,39 However, several important differences between the hepatocellular alterations observed in this experiment and amphophilic preneoplastic foci deserve consideration:…”

“…The peroxisome proliferation caused by the peroxisome proliferator DHEA is much more pronounced in perivenular hepatocytes, whereas amphophilic foci and hepatocellular adenomas develop almost exclusively in the vicinity of portal tracts, so that the proliferation of peroxisomes itself does not seem to be an important early event in neoplastic development elicited by peroxisome proliferators. 36 2. The alterations of enzyme activities in the altered liver acini differ in some respects from those observed in amphophilic cell foci induced by peroxisome proliferators.…”

Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

“…DHEA gained special interest in cancer research because of its anticarcinogenic properties proven in various organs of laboratory rats including the liver (34,35,43; summarized in 7,19). Conversely, DHEA showed unfavorable effects in rat liver such as hepatomegaly and peroxisome proliferation, and after long-term treatment hepatocellular carcinomas developed (10,24,31,32,33). In this contribution we give a short overview on cellular and molecular changes occurring during hepatocarcinogenesis induced by DHEA in rat, and focus on some aspects of the paradoxical antihepatocarcinogenic but tumor enhancing effects of DHEA that were observed when the compound was administered in combination with the liver carcinogen N -nitrosomorpholine (NNM).…”

Comparative Aspects of Rat and Human Hepatocellular Preneoplasia and Neoplasia

“…On the other hand, the "eosinophilic cell focus of cellular alteration" depicted in Fig. 10 is most probably poor in, or free of, glycogen, being consistent with "amphophilic" FAH potentially progressing to HCA and HCC in rats exposed to certain chemicals, especially "peroxisome proliferators" 8,9 . Changes resembling these amphophilic lesions have also been observed in cirrhotic human livers, but in this case their significance for neoplastic development has remained obscure 10 .…”