Biomedical subjects
K M Nauss
Publications and source records attributed to K M Nauss.
The toxicity of inhaled methanol vapors.
Methanol could become a major automotive fuel in the U.S., and its use may result in increased exposure of the public to methanol vapor. Nearly all of the available information on methanol toxicity in humans relates to the consequences of acute, rather than chronic, exposures. Acute methanol toxicity evolves in a well-understood pattern and consists of an uncompensated metabolic acidosis with superimposed toxicity to the visual system. The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. In short, the toxic syndrome sets in if formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at the anticipated levels of exposure to automotive methanol vapor.
Natural killer cell activity and autologous mixed lymphocyte response of splenic, mesenteric lymph node, and colonic lymphocytes during DMH-induced colon carcinogenesis in the rat.
Two in vitro models of immune surveillance were used to examine the immune status of the gut-associated lymphoid tissue, mesenteric lymph nodes, and spleen during the early stages of 1,2-dimethylhydrazine (DMN)-induced colon tumorigenesis. DMH- and vehicle-treated Fischer rats were sacrificed at one of three time points: one week, two months, or five months after cessation of treatment. Colonic, lymph node, and splenic natural killer cell cytolytic activity toward YAC-1 tumor targets and T-cell response to autologous Ia-induced blastogenesis were measured at each time point. We found little change in natural killer cell activity or T-cell proliferation induced by autologous Ia gene products at these time periods.
Dietary fat and fiber: relationship to caloric intake, body growth, and colon tumorigenesis.
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Effect of beef fat on DMH-induced colon tumorigenesis: influence of rat strain and nutrient composition.
The modulating effect of high levels of dietary fat on chemically induced colon tumorigenesis has been studied in animal models, with conflicting results. The present study was designed to examine the influence of rat strain, stage of tumor development and micronutrient composition of the diet on 1,2-dimethylhydrazine (DMH)-induced intestinal tumorigenesis. Two strains of rats [Sprague-Dawley (SD) and Fischer-344 (F-344)] were fed one of three experimental diets. The diets contained 5 or 20% dietary fat but differed in nutrient composition and nutrient-energy ratio. After receiving the experimental diets for 4 wk, animals were treated with DMH X 2HCl (10 mg/kg body wt) once a week for 20 wk and killed 10 wk after receiving the last dose of carcinogen. Long-term administration of DMH was more toxic to F-344 rats than to SD animals, and the toxicity was potentiated by reductions in the micronutrient composition of the diet. High levels of dietary fat (20%) resulted in a barely significantly higher incidence in colon tumor (but not frequency or size) in SD rats that received the diet promoting optimal growth than did low levels of dietary fat. No effect of 20% beef fat was seen in SD animals fed a diet that produced a slower growth rate or in F-344 animals.
Effect of vitamin A nutriture on experimental esophageal carcinogenesis.
The effect of mild vitamin A deficiency or vitamin A supplementation on methylbenzylnitrosamine (MBN; CAS: 937-40-6)-induced esophageal carcinogenesis was examined in Sprague-Dawley rats. The animals were fed semipurified diets containing levels of retinyl acetate, which were adequate (2.2 mg/kg diet), deficient (0.30 mg/kg diet), or supplemented (29.9 mg/kg diet) with respect to vitamin A content. Carcinogen-treated rats received 2.5 mg MBN/kg (body wt) twice a week for 5 weeks; they were then sacrificed for evaluation of esophageal tumorigenesis 15 weeks later. Liver levels of retinol reflected vitamin A nutriture, but there were no clinical signs of deficiency or toxicity. There were no significant differences in the frequency or incidence of esophageal tumors (either carcinomas or papillomas) among the dietary groups. There was also no indication that either vitamin A deficiency or vitamin A supplementation influenced the formation of preneoplastic lesions. Although the time was short for the neoplastic development, tumors were observed. These data suggest that vitamin A is selective in tissues it may protect from cancer induction and that the esophagus is less involved than other tissues.
Effect of dietary selenium levels on methylbenzylnitrosamine-induced esophageal cancer in rats.
Male Sprague-Dawley rats fed selenium deficient diets received either 0 ppm, 0.15 ppm or 4.0 ppm selenium in the drinking water. Animals were treated with methylbenzylnitrosamine (MBN). Dietary selenium deficiency had no effect on MBN-induced esophageal carcinogenesis. Animals treated with 4 ppm selenium in the drinking water during the initiation and post-initiation period had the same number of tumors as the group which received 0.15 ppm selenium for the entire experimental period. The incidence and frequency of carcinomas was lowest in the group which was supplemented with extra selenium (4.0 ppm) during the period of carcinogen administration and highest in the group which received 4.0 ppm selenium during the post-initiation period.
Effect of colon tumor development and dietary fat on the immune system of rats treated with DMH.
We examined the effect of dietary fat and colon tumorigenesis on the morphology and function of the rat mesenteric lymph node (MLN) and spleen at two stages of tumor development. Male Sprague-Dawley rats were fed semipurified diets of varying fat content (5% mixed fat, 24% beef fat, 24% corn oil, or 24% Crisco) and treated for five weeks with either the colon carcinogen 1,2-dimethylhydrazine (DMH) or the vehicle (saline). Animals consuming high-fat diets had an increased incidence of splenic follicular and germinal center hyperplasia. Carcinogen treatment had no significant effect on the histological morphology of the spleen. MLN morphology was not dramatically affected by either diet or DMH treatment. At this time period, the splenic lymphocyte transformation response induced by concanavalin A (Con A), phytohemagglutinin, or pokeweed mitogen was significantly depressed in the group fed 24% corn oil (vehicle-treated) and in the DMH-treated groups fed 5% fat compared with the vehicle-treated group fed 5% fat. In contrast, the MLN transformation response was elevated in the group fed 24% Crisco. DMH treatment did not significantly influence the MLN response. Four months after carcinogen or vehicle treatment, at the point of colon tumor development, no statistically significant differences were seen in the splenic or MLN blastogenic responses of DMH- or saline-treated animals. Splenic natural killer cell cytotoxic activity was also not significantly affected by dietary fat, carcinogen treatment, or tumor development.
Dietary fat and colon cancer: variable results in animal models.
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Rodent models for carcinoma of the colon.
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Comparison of immune status and 1,2-dimethylhydrazine induced tumorigenesis in brown--Norway and Fischer rats. Emphasis on splenic and colonic lymphocyte function.
Sym 1,2-dimethylhydrazine (DMH)-induced colon tumorigenesis was studied in immunologically different strains of rat: the Brown--Norway which is known to be immunologically a low-responder and the Fischer a high-responder. Brown--Norway rats received a total dose of 75, 150 or 225 mg DMH/kg or vehicle and Fischer rats received 150 mg DMH/kg or vehicle over a 3-week period. Rats were killed 5 months after the final treatment. Lymphocytes were isolated from the spleen and colon from rats treated with 150 mg DMH/kg or vehicle. Natural killer (NK) cell activity and the autologous mixed lymphocyte response (AMLR) as well as colon tumor incidence were compared between the two strains. Splenic and colonic intraperithelial lymphocytes (IEL) from the Brown--Norway strain demonstrated low NK activity and reduced splenic T lymphocyte proliferation in response to autologous non-T lymphocytes. As well, colonic lamina propria lymphocyte (LPL) proliferation was low and Brown--Norway rats had a low incidence of DMH-induced colon neoplasms (7%). In comparison, the Fischer rats had more effective splenic and IEL NK killing, enhanced splenic AMLR, enhanced LPL proliferation and a higher incidence of colon tumors (20%).
Interaction of dietary fat and route of carcinogen administration on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats.
Since the results of an earlier study indicating no effect of dietary fat on dimethylhydrazine (DMH)-induced colon cancer in rats differed from those of other investigators, the present study was initiated to determine if the modulating effect of fat intake on colon tumorigenesis was dependent on the route of DMH administration. Male weanling Sprague-Dawley rats (160) were fed one of two nutritionally balanced diets containing 5% or 24% corn oil (CO). Following 3 weeks adaptation to their respective diets, 40 rats from each diet group were treated with five doses of DMH (30 mg/kg) by intragastric (i.g.) gavage or subcutaneous (s.c.) injection, over a 3 week period. Rats were sacrificed when they showed clinical signs of colon tumor and surviving animals were killed 51 weeks after the initial DMH treatment. The cumulative probability of death with colon carcinoma did not differ between the dietary or treatment groups. There was no effect of route of administration or dietary fat on total intestinal tumor incidence. The number of rats with colon carcinoma was: 5% CO.IG = 25; 24% CO.IG = 27; 5% CO.SC = 23; 24% CO.SC = 19. Polypoid tumor incidence was significantly higher in the 24% CO.SC group (12/40) compared to the 5% CO.SC group (3/40) (Chi-squared = 5.25; p less than 0.03) while sessile tumor incidence was the inverse. Marginally significant differences in tumor morphology were noted between the IG groups.
Ocular infection with herpes simplex virus (HSV-1) in vitamin A-deficient and control rats.
An experimental model was developed for studying ocular infections with herpes simplex virus (HSV) type 1 in vitamin A-deficient (-A) and pair-fed control (+A) rats. The severity and course of the disease was evaluated by clinical examination, slit lamp biomicroscopy and histopathologic observations. Experimental animals were in good health and were infected in the early stages of vitamin deficiency (either prior to or at the beginning of the weight plateau). In all trials the onset of herpetic keratitis was more rapid and the clinical disease more severe in -A rats compared to +A controls. Mean slit lamp scores (which assessed the severity of the corneal disease) increased from 3 to 10 d after infection and were higher (P less than 0.002) in -A rats at all time points and doses of virus tested. The inflammatory response in the cornea and uveal tract of -A rats was significantly higher than that of +A animals. Since ocular HSV disease is a common cause of blindness, the availability of a rat model should be valuable in studies of the role of nutritional factors in host susceptibility and response to viral challenge. Mild vitamin A deficiency increased the severity of experimental corneal HSV infections and resulted in a high incidence of epithelial ulceration and necrosis.
Local and regional immune function of vitamin A-deficient rats with ocular herpes simplex virus (HSV) infections.
Experimental ocular herpes virus (HSV) infections are more severe in vitamin A-deficient rats (-A) compared with normal pair-fed controls (+A). In an effort to determine whether alterations in specific or nonspecific immune responses were responsible for the increased susceptibility of -A rats, cell-mediated responses and natural killer cell (NK) activity were monitored during the course of ocular herpetic infections in -A and +A rats. Prior to infection the concanavalin A (Con A)-induced response of splenic lymphocytes from -A rats was significantly less than that of +A animals. Three days following topical application of HSV to abraded corneas, the Con A-induced splenic response decreased in both -A and +A animals and remained at low levels for 10 d following infection. The cervical lymph node (CLN) response to Con A was depressed 7 d following infection but was higher in the -A group than in the +A group at all time points. In vitro response to inactivated HSV antigen appeared on d 7 in the spleen and d 10 in the CLN. The responses were higher in -A animals compared with +A pair-fed controls and were related to the severity of the disease rather than to dietary treatment. Splenic NK cytotoxic responses were higher in +A than -A animals and decreased in both groups during the 10-d post-infection period. Cervical lymph node NK responses were unaffected by diet or ocular HSV infection.
Immunological changes during progressive stages of vitamin A deficiency in the rat.
The immune status of rats fed a vitamin A-deficient diet (-A) was studied before they reached the weight plateau (stage 1), during the first 5 d of the weight plateau (stage 2) and during late stages of vitamin A deficiency (stage 3). Compared to vitamin A-supplemented (+A) animals, there were no significant differences in the relative splenic weights during the early and later stages of deficiency, but the total yield of isolated splenocytes was lower in -A rats during stages 2 and 3. The weights of the cervical and mesenteric lymph nodes were higher during the later stages of deficiency. In the spleen, concanavalin A (Con A)-induced responses were significantly depressed in -A rats at all three stages of deficiency. In stages 2 and 3 splenic pokeweed mitogen (PWM) responses were lower in -A than in +A rats. There were no changes in lymph node responses in stage 1. The Con A and PWM-induced responses of cervical lymph nodes of -A animals were higher in stages 2 and 3. Mesenteric lymph node responses were also higher in -A rats in stage 3. The alterations in the transformation responses of -A rats could not be explained by changes in the relative proportions of T-cell subsets.
The effect of vitamin A deficiency on the in vitro cellular immune response of rats.
The effect of vitamin A deficiency on the response of splenic lymphocytes to mitogenic stimulation was determined in an experimental rat model. Male Lewis rats were divided into three groups. The ad libitum group (AL) was fed unlimited amounts of a vitamin A-supplemented diet. The vitamin A-deficient group (DEF) received a commercial vitamin A-free diet. The pair-fed group (PF) received a vitamin A-containing diet equivalent in amount to that consumed by the DEP group. During the early stages of vitamin A deficiency (determined by cessation of weight gain), the rats were killed and the isolated splenic lymphocytes subjected to mitogenic stimulation. Lymphocytes from DEF rats had one-third the transformation response to the mitogens Concanavalin A, Phytohemagglutinin and E. coli Lipopolysaccharide S of the AL and PF groups. When the DEF rats were supplemented with vitamin A, the transformation response returned to control values within 3 days. In addition to the alterations in the immune response, the DEF rats showed a marked leukopenia, a decrease in the number of circulating lymphocytes and an increase in the number of circulating neutrophils.