Adrianne E. Rogers

Rodent models for carcinoma of the colon

ConclusionRodent models for colon cancer have contributed information on many aspects of the disease that may be applicable to prevention and treatment. Data of major importance on factors that retard or enhance tumorigenesis are now within reach. There are several basic research needs in the further development of animal models. Major questions, such as the controversies over the role of dietary fat and fiber, will be resolved only if investigators use comparable, consistent regimens and protocols, report full results, and use comparable endpoint and statistical analyses. If the deceptively simple controversies in the animal models can be resolved, we shall have powerful tools for further investigation of carcinogenesis in the intestine.

Lipotrope deficiency in experimental carcinogenesis

Abstract Diets deficient in lipotropes (methionine, choline, and folate) and high in fat increase hepatocarcinogenesis by many chemicals, including aflatoxin B1 (AFB1) and N‐2‐fluor‐enylacetamide (AAF). The increase can be corrected in most cases by lipotrope supplementation, but the degree of correction appears to be influenced by the type of fat in the diet. A lipotrope‐deficient, high‐fat diet also increases dimethylhydrazine carcinogenesis in the colon, an effect due to the dietary fat content, not to lipotrope deficiency. In contrast, mammary carcinogenesis by dimethylbenzanthrene or AAF is decreased or unchanged in rats fed the deficient diet. Hepatic microsomal oxidase activity, cytochrome P450 and conversion of AFB 1 to a bacterial mutagen all are decreased in assays in vitro using tissues from lipotrope‐deficient rats. However, urine mutagen content is increased after AFB1 treatment, as is urine content of activated AAF. AFB1 binding to hepatic DNA in vivo is unchanged or is slightly decreased. T...

Diet and aflatoxin B1 toxicity in rats

Abstract The effects of aflatoxin B 1 (AFB 1 ) in rats are markedly influenced by diet. Fischer and Sprague-Dawley male rats were fed either a complete synthetic diet or a synthetic diet marginally deficient in lipotropes, which had enhanced AFB 1 carcinogenesis in earlier studies. Deficient rats of both strains were resistant to the toxicity of a single dose of AFB 1 (7 or 9 mg/kg), which killed 60–100% of rats fed the complete diet. In contrast, the deficient rats were more sensitive to the acute toxicity of repeated small doses of AFB 1 . The dietary influence may be explained by the low resting levels of the hepatic drug-metabolizing enzymes and by the failure of the enzyme levels to respond to repeated doses of AFB 1 in the livers of deficient rats.

Functional and morphologic changes in the lungs of guinea pigs exposed to freshly generated ultrafine zinc oxide

Guinea pigs were exposed by nose only for 3 hr/day for 6 days to freshly formed zinc oxide (ZnO) particles (projected area diameter = 0.05 micron, sigma g = 2.0) at 5 mg/m3, the currently recommended threshold limit value (TLV). Ventilation, lung mechanics, lung volumes, and diffusing capacity for carbon monoxide (DLCO) in anesthetized, tracheostomized animals at 1, 24, 48, or 72 hr after the end of the last exposure were evaluated. At the same time intervals lung weight, lung fluid content, respiratory epithelial permeability to horseradish peroxidase, gross and microscopic appearance, and [3H]thymidine labeling of nuclei of bronchial and bronchiolar epithelial cells in other groups of animals were measured. Vital capacity, functional residual capacity, alveolar volume, and DLCO were all decreased following the last exposure and did not return to normal values by 72 hr. Increases in flow resistance and decreases in compliance and total lung capacity returned to normal by 72 hr. Lung weights were elevated due to inflammation involving the proximal portion of the alveolar ducts and adjacent alveoli. These changes were still present at 72 hr. [3H]Thymidine labeling of bronchiolar epithelial cell nuclei was increased for 48 hr. Respiratory epithelial permeability to horseradish peroxidase was not affected by the exposures. These results suggest that the current TLV for ZnO may not be adequate.

Influence of light, riboflavin, and carotene on the response of rats to the acute toxicity of aflatoxin and monocrotaline☆

Abstract Weanling male Sprague-Dawley rats were fed either a control diet or a diet marginal in lipotropes and dosed with either aflatoxin B 1 or monocrotaline. Some from each group were given an excess of either riboflavin or carotene prior to administration of the toxins and then exposed for 2 hr to artificial sunlight. The marginal lipotrope diet gave protection from the acute effects of both toxins. Exposure to light enhanced the toxicity of aflatoxin, and light plus riboflavin synergistically increased the toxicity. Carotene alone or with light protected against aflatoxin. Light protected the rats from the acute toxicity of monocrotaline, but riboflavin had no further significant effect. These studies indicate interactions between light, vitamins and hepatotoxins. The general implication is that environmental factors may influence the potency of drugs and chemicals.

Lasiocarpine: Factors influencing its toxicity and effects on liver cell division

The effect of the pyrrolizidine alkaloid lasiocarpine on the liver has been examined in male, Sprague-Dawley rats which were subjected to one of the following additional treatments: (1) fed adequate or lipotrope-deficient diets, (2) given sulfhydryl or other antioxidant compounds, or (3) given the carcinogen N-2-fluorenylacetamide (AAF). Two principal manifestations of the hepatotoxicity of lasiocarpine are inhibition of cell division and induction of necrosis of liver cells. Liver damage and mortality following a single dose of lasiocarpine were decreased by lipotrope deficiency and by administration of mercaptoethylamine, but not by administration of α-tocopherol or ubiquinone. Inhibition by lasiocarpine of liver cell DNA synthesis and mitosis following partial hepatectomy was not significantly affected by any of the above experimental procedures. These results suggested that liver cell necrosis and inhibition of cell division were caused by different metabolites of lasiocarpine or by the parent compound and one or more metabolites. Lasiocarpine, given in a dose which depressed liver cell division after partial hepatectomy did not affect the induction of either hyperplasia or neoplasia by AAF.

Response of guinea pig respiratory tract to inhalation of submicron zinc oxide particles generated in the presence of sulfur dioxide and water vapor

Guinea pigs were exposed for 3 hr to submicron zinc oxide aerosols generated in the presence of water vapor and 1 ppm sulfur dioxide. After exposure to the aerosol containing 5 mg/m3 of zinc oxide, the animals developed transient pulmonary edema accompanied by increased permeability of the respiratory epithelium to macromolecules and increased DNA synthesis in the terminal bronchioles, indicated by an elevated labeling index on autoradiographs. Peribronchiolar edema with cellular infiltrates was present after exposure to the aerosol containing 25 mg/m3 of zinc oxide and significant increases in the labeling index were noted for epithelial cells of the bronchi, bronchioles, and alveoli. The changes coincided with functional abnormalities detected in complementary physiological studies.

Effects of a low-lipotrope diet on the response of young male rats to the pyrrolizidine alkaloid, monocrotaline

Abstract Effects of monocrotaline, one of the pyrrolizidine alkaloids, were studied in rats fed a normal diet or a diet low in lipotropic factors. The low-lipotrope diet protected the animals against the acute toxic effects of monocrotaline but not the effects of a pyrrole metabolite of monocrotaline. Protection was evaluated by mortality, histologic changes in the liver, and dissociation of polysomes. Animals fed the low-lipotrope diet were less sensitive than the controls to monocrotaline by all three criteria. The pyrrole metabolite caused dissociation of polysomes and equally severe histologic changes in both groups. Polysomes were much slower to reassemble in rats fed the low-lipotrope diet than in those fed the control diet. A partial explanation for the protective effect of the low-lipotrope diet was provided by the observation that rats fed the diet converted less monocrotaline to the active pyrrole metabolite and had consistenly lower concentrations of N-demethylating enzymes in the liver. These results were consistent with the current theory that monocrotaline exerts its major hepatotoxic effect after conversion to the active pyrrole. The liver of rats fed low-lipotrope diets was incapable of converting the parent compound to its active metabolite at a sufficient rate to allow the characteristic expression of toxicity.

Toxicity of Anguidine in Mice

A characteristic of the trichothecene mycotoxin, anguidine, is its extreme toxicity to organs with populations of rapidly dividing cells. In preparation for evaluation of compounds that may protect against anguidine toxicity, we measured the LD50 of anguidine administered by gastric gavage (ig) or intraperitoneal injection (ip) and studied the dose- and time-dependent effects of anguidine on lymphohematopoietic organs, intestine, and testis, and measured hematocrit and peripheral blood leukocyte counts in male CD-1 mice. The ig LD50 at 96 hr was 15.5 mg/kg; after ip administration the LD50 at 96 hr was 20.0 mg/kg. Characteristic changes caused by sublethal doses of anguidine were cell depletion and necrosis in lymphohematopoietic organs, multifocal necrosis of intestinal epithelium, and diffuse necrosis of germinal epithelium followed by progressive tubule degeneration in the testes. There was leukocytosis due to both lymphocytosis and neutrophilia in the first few hours following anguidine exposure, followed by lymphopenia, neutropenia, and anemia by 3 days. After lethal doses, the intestinal necrosis was transmural, and there was extensive necrosis of lymphohematopoietic organs. There was rapid recovery after sublethal anguidine exposure of all anguidine-sensitive organs except for testis where decreased weights and abnormal spermatogenesis persisted for the 2-week observation period. Our results suggest that intestinal necrosis is an important cause of death following anguidine exposure. Atrophy of seminiferous tubules may have some value as an indicator of prior anguidine exposure, but the testicular changes are not unique to this compound.

Lung injury in guinea pigs caused by multiple exposures to submicron zinc oxide mixed with sulfur dioxide in a humidified furnace

Sulfur dioxide, water vapor, and ultrafine particles rich in oxides of zinc and other surface-deposited trace elements are important products of coal combustion. In order to study the toxicity of zinc oxide generated under conditions simulating combustion, guinea pigs were exposed in a nose-only apparatus for 3 h on 6 consecutive days to 6 mg/m3 of submicron zinc oxide particles (count median diameter of 0.05 micron, sigma g 2.0), which were generated in a humid furnace and mixed with 1 ppm sulfur dioxide. The exposures caused increases in lung weight and [3H] thymidine labeling index of terminal bronchiolar cell nuclei and inflammation of the proximal portion of the alveolar duct. The lung weights and labeling index had returned to normal and inflammatory changes had nearly resolved by 72 h after the last exposure. Total lung capacity, vital capacity, functional residual volume, alveolar volume, and diffusing capacity for carbon monoxide were decreased following exposure and had not returned to normal by 72 h after the last exposure. Large airways were not affected by the repeated exposures, as indicated by normal morphology of trachea and bronchi, unchanged secretory cell concentration, and unaltered epithelial permeability to horseradish peroxidase. These results are essentially identical to changes we reported in guinea pigs exposed to zinc oxide alone, suggesting that surface-deposited sulfur compounds, which are important determinants of the response to a single exposure to these ultrafine particles, become less important as exposure progresses.