UMLS:C0019209 - FACTA Search

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Query: UMLS:C0019209 (hepatomegaly)
5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Groups of 48 adult male F344 rats were maintained on synthetic diets containing 20 ppm (normal), 2 ppm (low), or 200 ppm (high) zinc. After 1 week of acclimation to the various diets, groups of 12 rats from each dietary regimen were gavaged for 13 consecutive days with 0.0 (vehicle), 0.33, 1.0, or 3.0 g/kg di(2-ethylhexyl)phthalate (DEHP). These were selected as relatively nontoxic, mildly toxic, and moderately toxic doses for producing testicular injury in adult male rats. At termination on the 14th day, body weight gain was reduced by 3.0 g/kg DEHP dose in the normal and low-zinc diet groups but not in the high-zinc diet group. The low-zinc diet alone reduced body weight gain, independent of DEHP treatment. DEHP had no perceptible effects on the weights of testis, seminal vesicle, prostate, or epididymis from rats maintained on normal- or high-zinc diets, but reduced the weights of all of these organs from animals on the low-zinc diet in a dose-dependent manner. Lactate dehydrogenase activity, total and free sulfhydryl contents, and zinc concentrations in testes were also reduced, and testicular degeneration was induced by DEHP in the low-zinc diet groups. In contrast, dose-dependent liver enlargement and hypolipidemia (reduction of serum cholesterol and triglyceride concentrations) were produced by equivalent doses of DEHP in all of the three zinc groups. The selectively enhanced susceptibility of adult male F344 rats on a zinc deficient diet to the gonadotoxic effects of DEHP supports the hypothesis that testicular zinc depletion is causally related to the ensuing testicular and accessory sex organ atrophies. Other biological effects of DEHP (e.g., hypolipidemia, hepatomegaly) appear to occur independent of zinc homeostasis.
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PMID:Influence of dietary zinc on di(2-ethylhexyl)phthalate-induced testicular atrophy and zinc depletion in adult rats. 371 59

This study compares changes in the livers of rats treated with di(2-ethylhexyl) phthalate (DEHP) and its straight-chain analogs di(n-hexyl) phthalate (DnHP) and di(n-octyl phthalate (DnOP). Groups of rats were fed diets containing 20,000 ppm of one of these compounds. Subgroups were killed after 3, 10, and 21 days, and the livers were examined by histological, cytological, and biochemical methods. The results show considerable differences between the effects of the branched-chain phthalate ester DEHP and its straight-chain analogs. The major effects on the liver following administration of diets containing DEHP were midzonal and periportal accumulation of small droplets of lipid, hepatomegaly accompanied by an initial burst of mitosis, proliferation of hepatic peroxisomes and of smooth endoplasmic reticulum accompanied by induction of peroxisomal fatty acid oxidation, damage to the peroxisomal membranes as evidenced by increased leakage of catalase to the cytosol, and centrilobular loss of glycogen and falls in glucose-6-phosphatase activity and in low-molecular-weight reducing agents. In contrast, diets containing DnHP or DnOP induced accumulation of large droplets of fat around central veins leading, by 10 days, to mild centrilobular necrosis and a very slight induction of one peroxisomal enzyme and an increase in liver weight, but no significant changes in any other parameters which were affected by DEHP.
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PMID:Comparison of the short-term effects of di(2-ethylhexyl) phthalate, di(n-hexyl) phthalate, and di(n-octyl) phthalate in rats. 396 35

The hypolipidaemic agents ciprofibrate and Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) and the phthalate-ester plasticizer di-(2-ethylhexyl)-phthalate (DEHP), like other peroxisome proliferators, produce a significant hepatomegaly and induce the peroxisomal fatty acid beta-oxidation enzyme system together with profound proliferation of peroxisomes in hepatic parenchymal cells. Changes in the profile of liver proteins in rats following induction of peroxisome proliferation by ciprofibrate, Wy-14,643 and DEHP have been analysed by high-resolution two-dimensional gel electrophoresis. The proteins of whole liver homogenates from normal and peroxisome-proliferator-treated rats were separated by two-dimensional gel electrophoresis using isoelectric focusing for acidic proteins and nonequilibrium pH gradient electrophoresis for basic proteins. In the whole liver homogenates, the quantities of six proteins in acidic gels and six proteins in the basic gels increased following induction of peroxisome proliferation. Peroxisome proliferator administration caused a repression of three acidic proteins in the liver homogenates. By the immunoblot method using polyspecific antiserum against soluble peroxisomal proteins and monospecific antiserum against peroxisome proliferation associated Mr 80000 polypeptide (polypeptide PPA-80), the majority of basic proteins induced by these peroxisome proliferators appeared to be peroxisomal proteins. Polypeptide PPA-80 becomes the most abundant protein in the total liver homogenates of peroxisome-proliferator-treated rats. These results indicate that ciprofibrate, DEHP and Wy-14,643 induce marked changes in the profile of specific hepatic proteins and that some of these changes should serve as a baseline to identify a set of gene products that may assist in defining the specific 'peroxisome proliferator domain'.
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PMID:Specific changes in the protein composition of rat liver in response to the peroxisome proliferators ciprofibrate, Wy-14,643 and di-(2-ethylhexyl)phthalate. 400 98

Young male Sprague-Dawley rats and Syrian hamsters were treated with 25-1000 mg/kg/day di-(2-ethylhexyl) phthalate (DEHP) orally for 14 days. Liver enlargement was observed in both species, the magnitude being greater in the rat than in the hamster. In the rat there was a marked dose-dependent induction of the peroxisomal marker cyanide-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. Little effect was observed on the mitochondrial markers carnitine palmitoyltransferase and succinate dehydrogenase. Whereas in the rat, increased peroxisomal enzyme activities were observed after treatment with 100 and 250 mg/kg/day DEHP, much less effect was observed in the hamster even after 1000 mg/kg/day DEHP. Parallel morphological investigations demonstrated a greater increase in hepatic peroxisome numbers in the rat than in the hamster. 14C-labeled DEHP was found to be more rapidly hydrolyzed by rat than hamster hepatic and small intestinal mucosal cell preparations and differences were also observed in the absorption and excretion of oral doses of [14C]DEHP. Studies with mono-(2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, and a hypolipidemic drug clofibrate also resulted in a greater increase in hepatic peroxisomal enzymes in the rat compared to the hamster. The results demonstrate that while DEHP, MEHP, and clofibrate induced hepatic peroxisome proliferation in both species, there was a marked species difference in response. Comparative long-term studies in these species may thus help to clarify the role of peroxisome proliferation in the hepatocarcinogenicity of DEHP.
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PMID:Comparative studies on di-(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation in the rat and hamster. 671 Apr 84

Three-week oral administration of 4-(decahydro-6-methyl-3-oxo-cyclopenta(f)quinoline-7-yl)valeric acid (32-1328) in the diet supplemented at concentrations of 0.1% or 0.3% was associated with hepatomegaly and hypotriglyceridemia in male F344 rats. Electron microscopic examination of the liver revealed a remarkable increase of peroxisomes in hepatocytes both in number and size. Biochemically, there were increased activities of peroxisomal marker enzymes including the heat-labile enoyl-CoA hydratase and catalase while the mitochondrial enoyl-CoA hydratase activity was unchanged after feeding of 32-1328. These findings indicate that 32-1328 can exert peroxisome-proliferating activity to rat liver in a manner similar to typical peroxisome proliferators such as clofibrate or di(2-ethylhexyl)phthalate.
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PMID:Peroxisome proliferation of hepatocytes in rats by a microbial degradation product of cholic acid, 4-(decahydro-6-methyl-3-oxocyclopenta(f)quinoline-7-yl)valeric acid. 798 70

The plasticizer di(2-ethylhexyl) phthalate (DEHP), to which humans are extensively exposed, was found to be hepatocarcinogenic in rats and mice. DEHP is potentially set free from objects made of synthetic materials (e.g., those used in medicine). Chronically, the greatest amounts are transferred to persons undergoing hemodialysis (up to 3.1 mg/kg b.w. per day) who would thus be considered the individuals most endangered by tumorigenesis. Although toxicokinetics seem to play a certain unclear role in the course of DEHP-related toxicity, toxicodynamic factors appear more decisive. DEHP is a representative of "peroxisome proliferators" (PP), a distinct group of substances that, in rodents, do not only induce peroxisomes but also specific enzymes in other organelles, organ growth, and DNA synthesis. The cluster of the characteristic effects of PP is generally, although perhaps not quite appropriately summarized as "peroxisome proliferation," and is strongest in the liver. The lowest observed effect level (LOEL) and the no observed effect level (NOEL) of peroxisome proliferation in the rat, as determined by the induction of specific enzymes (peroxisomal beta-oxidation, carnitine-acetyl-transferase, cytochrome P-452), DNA synthesis, and hepatomegaly, may be assumed as 50 and 25 mg/kg b.w. per day, respectively. DEHP and other carcinogenic PP are neither genotoxic nor tumor initiators, but they appear to be tumor promoters, also implicating a threshold level for the carcinogenic effect. Although a causal relationship between a particular effect of peroxisome proliferation and hepatocarcinogenesis is as yet unknown, peroxisome proliferation as a whole phenomenon appears to be associated with the potential of tumor induction, as shown by comparison of the relative strength of individual PP and by comparison of species and organ specificities. Likewise, LOEL and NOEL of rodent carcinogenesis, that is, 300 and 50 to 100 mg/kg b.w. per day, respectively, are above but not too far from the corresponding values for the investigated parameters of peroxisome proliferation. Thus, with respect to dose alone, worst-case exposure in hemodialysis patients is at least 16-fold below the LOEL of any characterized PP-specific effect of DEHP and approximately 100-fold below that of DEHP-related tumorigenesis. Also, primates are less responsive to PP than rats with respect to the investigated biochemical and morphological parameters. If this lower primate responsiveness is extrapolated to estimate carcinogenicity in humans, we might thus arrive at an even larger safety margin than when based on exposure alone. Doses of PP hypolipidemics that had clearly induced several indicators of peroxisome proliferation in rats did not cause any clear-cut enhancements in the peroxisomes of patients, even though most of these hypolipidemics were considerably stronger PP than DEHP. Thus, an actual threat to humans by DEHP seems rather unlikely. Accordingly, hepatocarcinogenesis was neither enhanced in workers exposed to DEHP nor in patients treated with hypolipidemics.
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PMID:Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk. 881 83

The subchronic oral toxicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP) was studied. Groups of 10 male and 10 female Sprague-Dawley rats were administered DEHP in the diet at 0, 5, 50, 500 or 5000 ppm for 13 wk. In a separate study, groups of 10 male and 10 female Sprague-Dawley rats were given DNOP (5, 50, 500 and 5000 ppm) in the diet while control groups received basal diet containing 4% corn oil and positive control groups were fed a diet containing 5000 ppm DEHP. Growth rate and food consumption were not affected by treatment with either compound. Hepatomegaly was observed in the highest dose groups of both sexes administered DEHP but not in the DNOP-treated animals. At the highest dose, DNOP caused threefold (females) and 12-fold (males) increases in liver ethoxyresorufin-O-deethylase activity while DEHP did not. Mild changes in serum biochemistries were mostly confined to rats in the highest dose group of DEHP, and included increased serum albumin and albumin/globulin ratio in both sexes and decreased cholesterol in female rats. Mild vacuolations in the Sertoli cells were observed in male rats exposed to 500 ppm DEHP. At 5000 ppm DEHP, there was mild to moderate seminiferous tubule atrophy and Sertoli cell vacuolation in males, and rats of both sexes showed hepatic peroxisome proliferation. Both DEHP and DNOP at 5000 ppm caused mild histological changes in the thyroid consisting of reduced follicle size and colloid density, and the liver consisting of endothelial nuclear prominence, nuclear hyperchromicity and anisokaryosis. There was accentuation of zonation of the hepatic lobules and increased perivenous cytoplasmic vacuolation in DNOP-treated rats. Trace quantities (3-5 ppm) of DEHP and DNOP were detected in the liver, and 15-31 ppm were found in adipose tissue of the highest dose groups. The no observed-effect-level was judged to be 50 ppm in the diet or 3.7 mg/kg body weight/day for DEHP, and 500 ppm or 36.8 mg/kg body weight/day for DNOP.
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PMID:Subchronic oral toxicity of di-n-octyl phthalate and di(2-Ethylhexyl) phthalate in the rat. 914 36

Metabolic changes induced by 2,2'-(decamethylenedithio)diethanol (tiadenol) and di-(2-ethylhexyl)phthalate (DEHP) in the biosynthesis of phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) in rat liver were compared with changes induced by p-chlorophenoxyisobutyric acid (clofibric acid). Treatment of rats with either tiadenol or DEHP increased the hepatic contents of PtdCho and PtdEtn, as was observed with clofibric acid treatment. The administration of tiadenol, DEHP, or clofibric acid slightly, but significantly, increased, in common, the activity of CTP:phosphocholine cytidylyltransferase, a key enzyme for the synthesis de novo of PtdCho, and suppressed the activity of PtdEtn N-methyltransferase. With regard to the enzymes involved in the synthesis of PtdEtn, the three peroxisome proliferators enhanced the activity of phosphatidylserine (PtdSer) decarboxylase and markedly decreased the activity of CTP:phosphoethanolamine cytidylyltransferase. Treatment of rats with the three compounds markedly increased, in common, the content and the proportion of the molecular species of PtdCho containing oleic acid (18:1), but considerably decreased the proportion of the molecular species of PtdCho containing linoleic acid (18:2) in the liver, resulting in a striking decrease in the concentration of the molecular species of PtdCho containing 18:2 in the serum. The present study suggests that the administration of peroxisome proliferators to rats increases the contents of hepatic PtdCho and PtdEtn for hepatomegaly and proliferation of organelles by the same mechanism, irrespective of their chemical structures.
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PMID:Effects of tiadenol and di-(2-ethylhexyl)phthalate on the metabolism of phosphatidylcholine and phosphatidylethanolamine in the liver of rats: comparison with clofibric acid. 1008 19

Phthalate esters, now regarded as endocrine disruptors, are widely used in the plastics industry. In particular, di-(2-ethylhexyl) phthalate (DEHP) is produced in large quantities, and is used in blood storage bags, catheters and haemodialysis instruments. Previous studies have demonstrated that treatment of rats with DEHP induces testicular atrophy with liver enlargement, although the precise nature and mechanism of the action of DEHP on these organs remains unclear. In the present study, we produced an experimental model of DEHP-induced spermatogenic disturbance in rats by feeding them a DEHP-containing diet. Liver enlargement occurred in rats fed either a 1 or 2% DEHP-containing diet. However, testicular atrophy accompanied by aspermatogenesis was induced by feeding with the 2% but not with the 1% DEHP-containing diet. This suggests that the critical DEHP dose for gonadotoxicity is higher than that for hepatotoxicity. Using the 2% DEHP-dose, the effect of simultaneous administration of antioxidant vitamins (= vitamins C and E) was next examined. It was found that the vitamin supplementation significantly prevented the testicular injury. The results suggest that antioxidant vitamins can protect the testes from DEHP-toxicity.
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PMID:Spermatogenic disturbance induced by di-(2-ethylhexyl) phthalate is significantly prevented by treatment with antioxidant vitamins in the rat. 1076 34

In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the nongenotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the noncarcinogen acetaminophen (AAP), were investigated in guanine phosphoribosyltransferase (gpt) delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-wk treatment, glutathione S-transferase placental form (GST-P)-positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred, although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ- and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0 x 10(-6) and 56.5 x 10(-6), approximately 35-fold and 10-fold higher, respectively, than that of nontreatment control rats (5.5 x 10(-6)). There were no increases in MFs in the DEHP- or AAP-treated rats as compared to the nontreatment control value. IQ induced mainly base substitutions leading to G:C to T:A transversions (56.9%) and deletions of G:C base pairs. In contrast, NPYR primarily caused specific A:T to G:C transitions (49.3%), which are very rare in the other groups. These data provided support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a nongenotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses with transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.
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PMID:In vivo mutational analysis of liver DNA in gpt delta transgenic rats treated with the hepatocarcinogens N-nitrosopyrrolidine, 2-amino-3-methylimidazo[4,5-f]quinoline, and di(2-ethylhexyl)phthalate. 1548 47

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