Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver.

Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of proapoptotic genes and decreased expression of antiapoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY).

The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARalpha in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARalpha-null mice. Primary hepatocytes from wild-type but not PPARalpha-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat.

Zonal distribution of cell proliferation in the liver of untreated B6C3F1 and C57BL mice.

To determine the lobular distribution of hepatocellular proliferation, S-phase response was measured in untreated adult male B6C3F1 and C57BL mice at ages 11, 14, and 23 weeks. The percentage of cells in S-phase (labeling index, LI) was evaluated using immunohistochemical detection of 5-bromo-2'-deoxyuridine (BrdU). The BrdU was delivered either by a single ip injection 2 hr prior to sacrifice or via an osmotic minipump implanted subcutaneously for 3 or 7 days.

Evaluation of potential modes of action of inhaled ethylbenzene in rats and mice.

Potential factors underlying the tumorigenic activity of ethylbenzene (EB) were examined in F344 rats and B6C3F1 mice inhaling 750 ppm EB vapor 6 h/day, 5 days/week, for one or four weeks. Target tissues (kidneys of rats and livers and lungs of mice) were evaluated for changes in organ weights, mixed function oxygenases (MFO), glucuronosyl transferase activities, S-phase DNA synthesis, apoptosis, alpha2u-globulin deposition, and histopathology. In male rats, kidney weight increases were accompanied by focal increases in hyaline droplets, alpha2u-globulin, degeneration, and S-phase synthesis in proximal tubules.

Tumor induction in mouse liver: di-isononyl phthalate acts via peroxisome proliferation.

Recently several chronic toxicity/carcinogenicity studies of di-isononyl phthalate (DINP) have been reported. These studies defined effect levels for liver tumors in male and female F344 rats at dietary levels exceeding 700 mg/kg/day; the no effect levels were 359 mg/kg/day in males and 442 mg/kg/day in females. Similar results were found in male B6C3F1 mice, but in female mice a significant increase in liver tumors was found at 336 mg/kg/day, making 112 mg/kg/day the NOAEL for liver tumors in that sex and species.

Investigations on cell proliferation and enzyme induction in male rat kidney and female mouse liver caused by tetrahydrofuran.

To elucidate possible mechanism(s) of carcinogenic action of tetrahydrofuran (THF) that had been demonstrated in previous inhalation studies, groups of male F344 rats and female B6C3F(1) mice were exposed to dynamic atmospheric concentrations of 0, 600, 1800, or 5400 mg/m(3) for 6 h per day, either for 5 consecutive days or for a period of 4 weeks (5 days per week). The reversibility of treatment-related changes was investigated in rats and mice exposed for 5 days and sacrificed 21 days after the last exposure. Female B6C3F(1) mice exposed to 5400 mg/m(3) showed significantly increased cytochrome P450 content, increased ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase activities, increased cell proliferation (5-bromo-2'-deoxyuridine-method) and an increased mitotic index in liver zones 2 (midzonal region) and 3 (central vein region).

Different patterns of kidney toxicity after subacute administration of Na-nitrilotriacetic acid and Fe-nitrilotriacetic acid to Wistar rats.

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrilotriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract.

Lobule-dependent zonal measurement (LZM) method for the determination of cell proliferation in the liver.

Using the conventional method of measurement (randomly distributed fields) there is a risk of overlooking a biologically relevant effect due to the different zonal expression of cell proliferation. Therefore a lobule-dependent zonal measurement (LZM) method was developed that guaranteed the independent evaluation of the hepatic zones in lobules of a comparable size. With this method, applied in a 3-month-study, a statistically significant increase in cell proliferation after one week (71%) and a distinct increase after six weeks (49%) and thirteen weeks (32%) of exposure could be proved, whereas the conventional method revealed after one week only a slight increase (22%), after six weeks a distinct but not statistically significant increase (56%) and after thirteen weeks even a decrease of 24%.

Control of Filaroides hirthi infections in Beagle dogs by ivermectin.

The efficacy of ivermectin against Filaroides hirthi was evaluated in a series of three trials using Beagle dogs of a breeding colony known to be endemically infected with this lungworm. Ivermectin was subcutaneously given at a dosage of 1 mg kg-1 bodyweight once to 40 (group A) or, at a one week interval, twice to 32 dogs (group B) 14-15 weeks prior to necropsy; another 40 dogs (group C) remained untreated. All animals were necropsied and lungs were digested using the pepsin-hydrochloride method and qualitatively examined for Filaroides spp.

RITA--registry of industrial toxicology animal-data--guides for organ sampling and trimming procedures in rats.

RITA (Registry of Industrial Toxicology Animal-data) is a pathology data base for the collection of validated histopathological data on tumours and potentially pre-neoplastic lesions observed in laboratory rodents. To enable a better comparison of information, standardized techniques for the preparation of histological slides have been established for all organs. The current paper describes the guidelines for organ sampling and trimming procedures applied in the RITA project, i.

Lungworm infection in a beagle colony: Filaroides hirthi, a common but not well-known companion.

116 beagle dogs of both sexes were examined for infection with Filaroides hirthi within the framework of several toxicological studies. 98% of the animals demonstrated lung-worm-associated lesions. Most of the macroscopic visible lesions can be subdivided into four groups, representing different histopathological pictures ranging from living worms, different types of granulomatous inflammation to tumorlike lesions.

[Myocardial fibrosis of cattle in Hesse].

Between 1986 and 1989 there were 9 cases of idiopathic congestive heart failure at this clinic. Normally heifers in the last 1/3 of pregnancy and young cows aged between 2.5 and 3.

[Fibrosarcoma of the nasal surface in a cat--cosmetically pleasing healing after surgical removal].

In a seven year old male domestic cat diagnosis, therapy and healing of a nasal fibrosarcoma is described. After two surgical treatments no recurrence was seen in a time period of 10 months. Even with this unfavourable localization of the tumor a functionally and cosmetically satisfactory result was achieved.

[Immunohistologic photometric quantification of pyruvate kinase content of rat tumors].

86 benign and malignant tumours were investigated histologically and immunohistologically. Staining intensity was measured by scanning-photometry. The computed optical density was digitalized and evaluated with an image analysis system.