Rapid induction of forestomach tumors in partially hepatectomized Wistar rats given butylated hydroxyanisole.

Rats subjected to two-thirds partial hepatectomy (PH) and given the antioxidant butylated hydroxyanisole (BHA) at a dietary concentration of 2% for 3 months developed forestomach lesions. Histologically, these lesions were classified as hyperplasia, dysplasia of the basal cell, papillomas, and carcinomas in situ. In intact rats forestomach carcinomas were seen by other investigators after feeding 2% BHA for 15-20 months. Histochemical studies of tumors revealed a marked increase in the phenotypic expression of the oncofetal enzyme, gamma-glutamyl transpeptidase (GGT) in the tumors of treated rats.

Chronic and subchronic effects of various forms of carrageenan in rats.

The subchronic and chronic toxicity of undegraded (native) carrageenan with respect to botanical source, and type of polymer chain (kappa, lambda, and iota) was investigated in rats for 13 to 39 weeks. The carrageenans were incorporated in the diet at 1 or 5% w/w. In all instances comparable levels of Alphacel were used. In the study designed to determine if there were any differences between various strains of rat, the Osborne-Mendel rat was used in addition to the Sprague-Dawley strain. Only the Sprague-Dawley strain was used in the other studies. Parameters utilized for detecting toxicity included mortality, body weights, fecal occult blood, hematologic indices, clinical chemistry, gross and microscopic histology, and evidence of carrageenan storage. Except for minor changes, no evidence was obtained for any direct effect of the carrageenans on the liver or the gastrointestinal tract.

Effects of ethanol on reproduction and arterial hypertension in spontaneously hypertensive and normotensive rats: a preliminary communication.

Ethanol consumption and spontaneous (essential) hypertension are important fetal and maternal risk factors. Alone, they contribute to embryopathy (fetal alcohol syndrome) or maternal organ pathology and fetal loss in hypertensive pregnancies. Combined, the effects of ethanol consumption on the progress of a hypertensive pregnancy have not been adequately investigated. In the present study, groups of O-A strain genetic hypertensive (SHR: groups 1 and 2) and Wistar-Kyoto normotensive (WKY: groups 3 and 4) pregnant rats were given 20 ml/kg of distilled water by gavage to serve as controls [groups 1 (SHR) and 3 (WKY)] or 3.2 g/kg of ethanol [groups 2 (SHR) and 4 (WKY)] from days 6 to 15 of gestation. During acclimation, hypertension developed in SHR rats (WKY pressures were 105 to 114 mm Hg; SHR pressures were 137 to 148 mm Hg). From day 6 to 15 of gestation, ethanol-consuming rats (groups 2 and 4) had higher arterial pressures than controls (groups 1 and 3). Pregnant SHR rats given ethanol did not experience a prebirthing hypotension. On gestation day 20, most offspring (84%, group 2; 86%, group 4) of alcoholic dams were dead or malformed. Intrauterine growth retardation occurred in group 4. Hydrocephalus, microphthalmia, and mild hydronephrosis and hydroureter were common in live offspring of group 2 dams. Hydronephrosis and hydroureter were increased in group 4 pups. Variant cranial ossification was noted in group 2 and 4 pups. These preliminary data suggest an altered hypertensive response during pregnancy in alcohol-consuming rats and confirm the embryopathic effects of relatively high levels of ethanol consumed during the critical period of organogenesis in two additional strains of rats.

Ploidy patterns in hepatic tumors induced by Mirex.

The effects of chronic exposure to dietary Mirex was investigated in rat livers over a 13 month period. The distribution of ploidy (diploid and tetraploid nuclei) in nodular and nonnodular areas was analyzed in a Coulter Counter fitted with a Channelizer. The nodules, such as adenomas and carcinomas, were identified in histologic sections obtained from companion samples, part of which was used for analysis of nuclear ploidy. The carcinogen disturbed the distribution of nuclei in the ploidy classes, selectively reducing the number of tetraploid cells. This reduction in tetraploid cells corresponded to the nature of the tumor, the most significant effect being noted in hepatocellular carcinomas.

Paternal effects of ethanol in the long-evans rat.

Ten male Long-Evans rats were given 20% v/v ethanol in the drinking water for 60 consecutive days. Ten other males were given distilled water and served as controls. Each male was then allowed to mate with three virgin female Long-Evans rats, once per week for three consecutive weeks. The males were necropsied after the third mating, the females were killed on d 20 of gestation, and the offspring were examined for parameters of fetal growth, skeletal ossification, and soft-tissue anomalies. Ethanol caused testicular weight reductions and gross testicular atrophy in 1 of 10 males. Five matings of alcoholic male rats proved infertile. Total embryonic deaths (resorptions and preimplantation loss) were increased by ethanol, while implantations and litter size were significantly decreased. Fetuses fathered by alcoholic male rats were malformed: 55% had soft-tissue anomalies (microcephalus, microphthalmia, cranial fissure, and hydronephrosis). Litter weight and average pups weights were also reduced by paternal ethanol consumption. No recovery in reproductive function was evident over the 21-d post-ethanol mating period.

Renal effects of indoprofen in rhesus monkeys.

The non-steroidal anti-inflammatory analgesic alpha-[4-(1-oxo-2-iso-indolinyl)-phenyl]propionic acid (indoprofen) was given p.o. in gelatin capsules to six groups of six Rhesus monkeys (three males and three females/group) for 15 months. Group I (five males and five females) served as control and was given empty gelatin capsules. The following daily doses were used: Group 2--20 mg/kg b.i.d.; Group 3--40 mg/kg q.d.; Group 4--30 mg/kg b.i.d.; Group 5--60 mg/kg q.d.; Group 6--40 mg/kg b.i.d. and Group 7--80 mg/kg q.d. Except for some elevated blood urea nitrogen levels after 12 months in the animals of Group 7, no changes in clinical function test values, absolute and relative kidney weights or renal gross abnormalities were found. The renal papillae and pelves were normal and not affected in all monkeys. The microscopic examination revealed a focal chronic interestitial nephritis in some of the monkeys. In the survivors the incidence of this disease increased from one out of ten control animals to three out of five monkeys in Group 7 (80 mg/kg/d). However, this quantal, statistically significant difference became biologically irrelevant and no longer statistically significant when these microscopic changes were quantified. The most severe case was seen in the control animal and the least pronounced in monkeys having received 80 mg/kg/d. When these cases of interstitial nephritis were further evaluated using a multifactorial point sampling procedure, no significant quantitative changes in renal tissue components, indicative of analgesic-induced nephropathy, were detectable.

The presence of intranuclear lipid inclusions in hepatocytes of mice after chronic ingestion of polybrominated biphenyl.

Electron microscopic study of livers from mice fed 167 ppm polybrominated biphenyl (PBB) for 12 weeks showed hepatocytes with nuclei containing varied amounts of lipid inclusions. The inclusions appeared as spherical vacuoles free in the nuclear matrix. This is the first report of the induction of lipid inclusions within the nucleus by a halogenated hydrocarbon.

The presence of hepatic intramitochondrial crystalline inclusions in polybrominated biphenyl-treated mice.

Electron microscopic study of livers from mice fed 167 ppm polybrominated biphenyl (PBB) revealed mitochondrial abnormalities which consisted of both alterations in size and the formation of crystalline-like inclusions within the mitochondrial matrix. These inclusions appeared as parallel arrays of rods and were found in elongated mitochondria which contained few cristae. The findings are briefly described and the possible significance of such inclusions in relation to mitochondrial aberrations are discussed.

A spontaneous metastasizing exocrine adenocarcinoma of the pancreas in the rat.

A naturally occurring adenocarcinoma of the exocrine pancreas was found in a male, 12-month-old rat. The tumor was found in the mesentery adjacent to the stomach. It consisted of highly anaplastic cells in combination with large strands of collagenous connective tissue indicating desmoplastic properties. Local metastases were found in the mesentery. Distant metastases were seen in the heart, lungs, mediastinal lymph nodes, liver, spleen, both kidneys, one adrenal, one testis and the sternum. This is the first reported tumor of the exocrine portion of the pancreas in which zymogen granules were demonstrated and multiple distant metastases were found in a rat.

Environmental chemical-induced immune dysfunction.

Antibody formation, endotoxin sensitivity, and resistance to a challenge malarial infection were evaluated in mice fed a diet containing polychlorinated biphenyl (PCB) (Aroclor 1242) or hexachlorobenzene (HCB). Antibody synthesis to the antigen sheep RBC (SRBC) was significantly depressed in the PCB- and HCB-treated (167 ppm) animals as evidenced by the fact that control mice elicited an approximate twofold increase in antibody formation over the chemical-treated mice. Serum IgA concentrations in the PCB- and HCB-treated mice were consistently 40--80 mg/dl lower than control values. Gram-negative endotoxin (Salmonella typhosa) sensitivity in PCB- and HCB-treated mice was increased 5.2- and 32-fold, respectively, following the dietary administration of 167 ppm of Aroclor 1242 or HCB for 6 weeks. An endotoxin hypersusceptibility was also noted at 3 weeks after dietary administration. Decreased resistance to a malaria challenge was also demonstrated in the xenobiotic-treated mice. A 20% decrease in mean survival time of mice fed Aroclor 1242 for 3 to 6 weeks and inoculated with Plasmodium berghei (NYU-2) was observed. Infected mice which had received HCB for 3 or 6 weeks manifested reductions in mean survival time of 24 and 31%, respectively. The data indicated that environmental chemical contaminants impair host resistance and, since no concomitant histopathological alterations were observed in the treated mice, the evaluation of immune parameters may possibly be a sensitive indicator of toxicity.

Impaired host resistance to endotoxin and malaria in polychlorinated biphenyl- and hexachlorobenzene-treated mice.

The in vivo effect of polychlorinated biphenyl (PCB) and hexachlorobenzene (HCB) on murine endotoxin sensitivity and resistance to malaria (Plasmodium berghei NYU-2) infection was studied. The dietary administration of 167 ppm (167 microgram/g) of PCB 1242 or HCB for 3 weeks resulted in an enhanced sensitivity to gram-negative endotoxin (Salmonella typhosa), which was further increased in animals maintained on the diets for 6 weeks. By 6 weeks, a 5.2- or 32-fold increase in endotoxin sensitivity was seen in mice fed PCB or HCB, respectively. A 20% decrease in mean survival time of mice fed PCB 1242 for 3 or 6 weeks and inoculated with malaria was demonstrated. Infected mice that received HCB for 3 or 6 weeks manifested a reduction in mean survival time of 24 or 31%, respectively. Histopathological examination revealed a normal thymus, spleen, mesenteric lymph nodes, and lungs. Centrilobular and pericentral hepatocyte hypertrophy, common to organochlorine exposure, was observed. Electron capture gas chromatographic analysis for PCB 1242 or HCB in the tissues examined histologically revealed a significant deposit of the xenobiotics. HCB concentration was approximately 16 to 25 times greater than that of PCB. The data indicate that environmental chemicals impair host resistance and that the alteration may be related to the presence of the chemicals in the lymphoreticular organs.

Fluorescence histochemistry of the surface epithelium and stroma in the rhesus monkey ovary.

The surface epithelium and stromal elements in the ovary of the rhesus monkey were studied with a variety of fluorescence-histochemical procedures to determine the relative distribution of specific chemical moieties. The surface (germinal) epithelium displayed high levels of cytoplasmic RNA and specifically intense fluorescence with methods that demonstrate basic, SH and SS groups of protein. The underlying basement membrane demonstrated an intense reaction when fluorochromed with hydroxynaphthoic acid hydrazide directed toward side-chain carboxyl groups of protein. The fluorescence pattern displayed by the underlying connective tissue was heterogeneous and related to its anatomical localization. It is suggested that this heterogeneity reflects specific, but as yet undefined, chemical differences in the fibrous elements of the ovary.