Biomedical subjects

J H Exon

Publications and source records attributed to J H Exon.

At least 19 recordsLinked to original sources

PubMed2003

Effects of sphingomyelin on aberrant colonic crypt foci development, colon crypt cell proliferation and immune function in an aging rat tumor model.

Sphingomyelin (SPM) was assessed in older rats for in vivo effects on multiple immune responses and the development of colon preneoplastic lesions. Fifty-four-week-old rats were injected with 10 mg/kg body weight of the carcinogen azoxymethane (AOM), and then treated with 35 mg/kg body weight SPM orally for 6 weeks beginning 6 weeks after AOM treatment. None of the immune functions tested (antibody formation, delayed-type hypersensitivity or natural killer cell cytotoxicity) were significantly affected by SPM treatment. Natural killer (NK) cell activity was, however, decreased in all rats that were treated with AOM. There was a tendency for decreased aberrant crypt foci (ACF) numbers in the SPM-treated rats but this reduction was only significant for the largest lesions (> nine crypts per foci). The decreased ACF numbers were most evident in the proximal end of the colon. Colonic crypt cell proliferation was also decreased in SPM treated rats. This reduction was primarily in the base of the crypt column. Also, low numbers of ACF developed spontaneously in rats not treated with AOM, but no ACF were present in non-AOM rats that also received SPM. It appears that SPM may have effects on the post-initiation development of preneoplastic lesions in the rat colon but not on the immune functions assessed in this study.

Aging↗

PubMed2003

Selenium toxicity in sheep grazing reclaimed phosphate mining sites.

Phosphate mining operations in southeastern Idaho have exposed selenium (Se) that was originally sequestered in the subsurface. Sheep grazing in these areas have died as a result of high Se concentrations in forage and water. This study was designed to monitor the health status of sheep grazing in a natural environment with known elevated levels of Se. A total of 72 Columbia x Suffolk sheep were divided into 3 treatment groups that included control (Con), low selenium (LoSe) and high selenium (HiSe). The baseline phase of the study was conducted in an area with normal background Se levels in forage and water, and was grazed for 3 w by all sheep groups. The sheep then were moved onto reclaimed mine areas to begin the 4-w exposure phase. This was followed by a 2-w depuration phase where sheep again received normal Se levels in forage and water. The Con group was held on areas with normal Se levels of forage (< 0.32 ppm Se dw) and water (< 1.70 ppb Se). The LoSe group was held in an area of elevated forage Se (< 13.0 ppm Se dw) and normal Se levels in their water (< 1.70 ppb Se) during the exposure phase. The HiSe group was held on mining areas with elevated Se forage (< 49.0 ppm Se dw) and drinking water (340 to 415 ppb Se). Whole blood and serum levels in the HiSe group peaked at 1.32 and 0.99 ppm mean Se, respectively. The LoSe group had mean whole blood and serum Se levels of 0.75 ppm on day 42 and 0.32 ppm on day 35 respectively. The Con group maintained low Se levels in both whole blood and serum that ranged from 0.05 to 0.14 ppm and 0.06 to 0.13 ppm respectively. The Se exposure in the HiSe group was estimated 0.26 mg Se/kg body weight/d. One sheep in the HiSe group died and was diagnosed with Se toxicosis based on clinical signs, histopathology and tissue Se levels. Se in liver (3.90 ppm), kidney (1.90 ppm) and skeletal muscle (0.70 ppm) were indicative of high to toxic Se exposure. Two other sheep necropsied after the exposure phase also had Se concentrations in liver, kidney and skeletal muscle representative of high or toxic Se exposure (5.50, 3.50 and 1.10 ppm Se), but these sheep had no gross or histopathological signs of illness. More research is needed on the toxicology of Se in sheep grazing natural settings.

Alanine Transaminase↗

PubMed2001

Effects of indole-3-carbinol on immune responses, aberrant crypt foci, and colonic crypt cell proliferation in rats.

Male Sprague-Dawley rats were treated orally with indole-3-carbinol (13C) for 7 wk at levels of 150, 100, and 50 mg/kg body weight. The rats were injected with 10 mg/kg body weight of the colon carcinogen, azoxymethane (AOM) on d 2 and 9 of 13C treatment. At termination of the study, all rats were assessed for immune function (humoral immunity, specific cell-mediated immunity, and nonspecific cell-mediated immunity). Colonic tissue was collected and examined for the presence of aberrant crypt foci (ACF) and proliferation of crypt cells. Antibody responses to antigen challenge were significantly suppressed in the animals exposed to the high dose of 13C. Delayed-type hypersensitivity responses, natural killer cell activity, the number and multiplicity of ACF, and cell proliferation parameters were not significantly different from those of the controls. Therefore, there was no clear protective or enhancing effect of 13C on ACF numbers or colonic cell proliferation indices. There was no strong correlation between changes in immune responses and the preneoplastic biomarkers of colon cancer.

Animals↗

PubMed2001

Multiple immune functions in rats fed Echinacea extracts.

This study evaluated acquired-immune functions representing the three major branches of the immune system in male rats fed a commercially available echinacea product. An additional comparison of effects on antibody formation in male and female rats was done using the commercial echinacea product and two echinacea tinctures marketed by local herbalists. In initial testing, we found no evidence of altered natural killer cell activity, T cell-mediated delayed-type hypersensitivity, or specific antibody formation in male rats given either a 225 mg/kg or 50 mg/kg of the commercial echinacea for 6 weeks. Antibody formation was significantly suppressed in female but not male rats given 250 mg/kg for 2 weeks of the commercial echinacea. The local products tested had no effect on antibody formation. We concluded that our study provided no supporting evidence for immunostimulatory activity by the echinacea preparations we examined and, in fact, may be immunosuppressive under some conditions.

Adjuvants, Immunologic↗

PubMed2000

Increased susceptibility of adult rats to azoxymethane-induced aberrant crypt foci.

The purpose of this study was to compare azoxymethane-induced aberrant crypt foci development in the colons of young and adult rats. Young (4 weeks of age) and adult (50 weeks of age) Sprague-Dawley rats were treated with two weekly injections of azoxymethane or saline. Rats were killed either 6 or 14 weeks following the first injection, and the number, size and location of aberrant crypt foci were determined. At both the 6- and 14-week time points, the number of aberrant crypt foci in older rats was significantly greater than in young rats (P<0.01). A higher percentage of aberrant crypt foci were found in the region from the mid-colon to the cecum in older rats as compared to young rats. Colonic cell proliferation was evaluated using bromodeoxyuridine immunohistochemistry. Colonic cell proliferation indices in the rectal, mid-colon and cecal regions of young and older rats were similar in young compared to adult rats. Ten large ACF from each group were screened for mutations in the beta-catenin gene (Ctnnb1) by PCR single strand conformation polymorphism. No mutations were detected. These results demonstrate that older female rats are more susceptible to the induction of aberrant crypt foci by azoxymethane than young female rats. Differences in colonic cell proliferation or beta-catenin mutations in these two age groups do not appear to be responsible for differences in aberrant crypt foci development.

Age Factors↗

PubMed2000

Dietary indole-3-carbinol alters immune functions in rats.

To further elucidate the physiological mechanisms that may contribute to the dichotomy of effect of indole-3-carbinol (I3C) on cancer development, we examined immune functions representative of the three major branches of the immune system in rats fed either a high (150 mg/kg) or low (50 mg/kg) dose of I3C. Animals fed the high dose of I3C daily for 7 wk had significantly reduced natural killer cell activity. In contrast, T-cell-mediated delayed-type hypersensitivity was significantly elevated. Antibody production in response to the antigen keyhole limpet hemocyanin was not significantly altered compared to controls. These results indicate that exposure to I3C may have differential effects on major immune responses. The significance of these immune function alterations in tumor development will require additional investigation of the effects of dietary I3C on immune functions in appropriate tumor models.

Animals↗

PubMed1998

Effect of dietary chlorogenic acid on multiple immune functions and formation of aberrant crypt foci in rats.

Adult male Sprague-Dawley rats were fed 70 mg/kg body weight chlorogenic acid (CHA) for 7 wk. One CHA-fed group was also given 2 injections of the colon carcinogen azoxymethane (AZO) on d 2 and 9 of CHA treatment. Three major types of immune responses were assessed: antibody production, specific cell-mediated immunity, and nonspecific cell-mediated immunity. The formation of AZO-induced aberrant crypt foci (ACF) in the colon were observed, as was colonic cell proliferation. There were no significant effects of CHA treatment on any of the immune parameters examined or on formation of preneoplastic lesions or cell proliferation in the colon. The overall nonsignificant trends in immune function, colon cell proliferation, and ACF development were, however, more consistent with immunosuppression and enhanced preneoplasia.

Animals↗

PubMed1998

Dietary quercetin, immune functions and colonic carcinogenesis in rats.

Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1 x 10(-13)M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.

Animals↗

PubMed1997

Dietary curcumin enhances antibody response in rats.

The effects of dietary curcumin on three major types of immune function were examined in rats. Antibody (IgG) production, delayed-type hypersensitivity and natural killer cell activity were evaluated after 5 weeks of dietary exposure to 1, 20 or 40 mg/kg curcumin. The highest dose of curcumin significantly enhanced IgG levels. Rats receiving lower dietary concentrations (1 or 20 mg/kg) of curcumin were not different in IgG production from rats receiving no curcumin in their diet. Neither delayed-type hypersensitivity nor natural killer cell activity was different from control values at any dietary concentration of curcumin. In vitro incubation of YAC-1 and EL4 tumor cells and normal splenocytes in varying concentrations of curcumin for varying times revealed differences between cell types in curcumin's effects on cell proliferation and viability. No cytotoxic effect was seen in EL4 cells at 125 micrograms/ml curcumin at 4, 24 and 48 hrs incubations, however, cell proliferation was reduced by almost 50% at 24 hrs. YAC-1 cell viability and cell numbers were diminished at longer incubations. A lower curcumin concentration (1.25 micrograms/ml) enhanced cell growth in the YAC-1 cells at 24 and 48 hr. This enhancement was not seen in spleen or EL4 cells.

Administration, Oral↗

PubMed1994

Characterization of a chemically induced tumor model and the effects of natural killer cell depletion by antiasialo GM-1.

A tumor model in the Sprague-Dawley rat has been developed and characterized in our laboratory using the polycyclic aromatic hydrocarbon 3-methylcholanthrene (3MC). Interactions between the tumorigenic process and the natural killer cell (NK) response were investigated in this study. Rats given a single injection of 1.5 mg 3MC had reduced NK activity the first three weeks after injection when compared to vehicle treated controls. Tumor incidence in this group reached 45% and 76% 12 and 20 weeks, respectively, after the 3MC injection. Cell lines were established from six of these tumors and were tested for in vitro lysis by NK cells. Sensitivity of these cells ranged from 2.9 to 12.2% compared to 32.3 to 37.5% for the NK sensitive YAC-1 target cells. Rabbit antiasialo GM-1 antibody (ASGM-1) was used to effect in vivo reductions of NK function at arbitrarily selected times after 3MC injection. Tumor incidence in the group of rats treated to reduce NK activity at the time of initiation (0-2 weeks) reached 100% in 20 weeks compared to 67% in the companion 3MC treated controls. The number of days to tumor was also decreased from 93 to 77 days in this group. Rats treated to reduce NK activity at other times (5-7 weeks or 10-12 weeks) did not have alterations in tumor incidence or latency that were different from controls. The study supports a role for NK cells in the early detection and removal of transformed cells and points out the dangers of transient immunosuppression.

Animals↗

PubMed1991

Effects of subchronic exposure of rats to 2-methoxyethanol or 2-butoxyethanol: thymic atrophy and immunotoxicity.

Male Sprague-Dawley rats were exposed to either 2000 or 6000 ppm of 2-methoxyethanol (ME) or 2-butoxyethanol (BE) and females were exposed to either 1600 or 4800 ppm of these compounds in the drinking water for 21 days. Body weights were decreased in male rats exposed to the high doses of both chemicals, while body weights of females exposed to either dose of BE were decreased. Male and female rats exposed to either concentration of ME had a dose-related reduction in thymus weights. Testis weight was significantly lower in male rats exposed to the high dose of ME. Dose-related increases in natural killer (NK) cell cytotoxic activities and decreases in specific antibody production were observed in all rats treated with ME. Rats exposed to the low dose of BE also had enhanced NK cell activity. Splenocyte production of interferon-gamma was decreased in male rats exposed to either dose of ME and in females treated with the high dose of ME. Spleen cell numbers were reduced in males exposed to the high dose of ME and females given either dose of ME. It appears that the immune system is a sensitive target of ME but not BE. The effects of ME on immune function differ depending on the immune parameter assessed. Enhanced NK cell activity may partially explain the observations of others that certain glycol ethers have antitumor effects in vivo.

Animals↗

PubMed1991

Effect of cyclosporine on 3-methylcholanthrene-induced carcinogenesis and immune responses in the rat.

Cyclosporine A (CsA) was used to immunosuppress male Sprague-Dawley rats treated with the chemical carcinogen 3-methylcholanthrene (3MC). Rats treated with low doses of CsA (2.5 or 5 mg/kg) given 2 days prior to an injection of 3MC, and then daily for 2 weeks or twice weekly for 10 weeks did not develop tumors. Rats treated with 2.5 mg/kg CsA for 2 weeks beginning 5 days after a single 3MC injection had tumor incidence similar to rats treated with 3MC only. To further examine the effects of CsA on immune function, groups of rats were then treated with 2.5, 5, 10 or 20 mg/kg CsA daily for 14 days and immune function assessed by measuring delayed-type hypersensitivity (DTH), natural killer cell (NK) activity, and production of interleukin 2 (IL-2), interferon (IFN), prostaglandin E2 (PGE2) and specific IgG antibody. Natural killer cell cytotoxicity was enhanced and antibody production was suppressed in rats treated with all doses of CsA tested. Interleukin 2 production was elevated at the two lower doses, but antibody production, DTH reactions and synthesis of IL-2 and IFN were suppressed with the higher dose treatments (10, 20 mg/kg CsA). The enhanced NK activity seen in rats treated with the lower doses of CsA may be due to the increase in IL-2 production, while enhancement of NK activity at higher doses may be due to other mechanisms. The tumor data suggest that CsA does not prevent tumor formation in our chemical-induced model due to an increase in NK activity, since this enhancement was seen even when tumors did develop normally.

Animals↗

PubMed1991

Effects of bromocriptine treatment on immune responses and 3-methylcholanthrene-induced tumorigenesis in rats.

Seven-week-old male Sprague-Dawley rats were given a single injection of 1.5 mg of 3-methylcholanthrene (3MC) to induce in situ fibrosarcomas. The rats were also treated with the dopamine agonist bromocriptine (BCR) from two days prior to 14 days after 3MC treatment and again for 14 consecutive days beginning at week 5. Tumor incidence was markedly increased and latency decreased in BCR-3MC rats compared to 3MC controls. Natural killer (NK) cell cytotoxicity responses and production of interleukin 2 (IL2) was enhanced at two weeks in rats treated with only BCR. Natural killer cell activity was suppressed at two weeks in rats treated with only 3MC. This effect was reversed by BCR treatment. Rats treated with 3MC and BCR had suppressed NK cell responses and production of IL2 and interferon-gamma (IFN) at 12 weeks. In another study, rats injected with 1, 3 or 5 mg/kg BCR for 14 consecutive days had increased NK cell activity and IL2 production at all doses and increased IFN production at the two high doses. Antibody (IgG) responses to an injected antigen and delayed-type hypersensitivity reactions were not affected by BCR treatment. Animals treated with the two high doses of BCR had decreased serum prolactin (PRL) levels. Serum growth hormone (GH) concentrations were markedly increased in the group treated with 3 mg/kg BCR. These data suggest that BCR enhances 3MC-induced tumorigenesis. The mechanism of this effect is apparently not mediated by suppression of the immune system since BCR-treated rats had selectively enhanced immune function. Enhancement of immune responses by BCR has not been previously reported.

Animals↗

PubMed1990

Alterations of rat natural killer (NK) cell cytotoxicity and cytokine production by 3-methylcholanthrene (3-MC).

The carcinogen 3-methylcholanthrene (3-MC) was found to exert immunosuppressive effects both in vitro and in vivo in this study. Spleen cells from 8-week-old male, Sprague-Dawley (S-D) rats exposed to 1, 10 or 100 micrograms/ml 3-MC in vitro for 18 h exhibited a dose-dependent decrease in natural killer (NK) cell cytotoxicity against the YAC-1 tumor target cells in a 4 h 51Cr-release assay. Peritoneal macrophage production of prostaglandin E2 (PGE2) was significantly decreased at all three 3-MC concentrations following a 24 h exposure in vitro. No effect of 3-MC on splenic interleukin-2 (IL-2) production was observed. A separate group of rats was inoculated with a single subcutaneous dose of 5 or 10 mg 3-MC and cytotoxic activity of spleen NK cells was examined at 1, 2, 3, 7, 14, 21, 28, 60, 120 and 180 days after the 3-MC injection. Natural killer cell cytotoxicity was suppressed as early as 24 h after 3-MC injection and persisted up to 21 days. This decrease in NK activity was accompanied by a decreased production of splenic interferon and elevated production of PGE2 by peritoneal macrophages. Natural killer cell cytotoxicity was elevated in the 3-MC-treated rats at 28 and 60 days post-treatment. At 120 and 180 days post-3-MC treatment, when the rats were bearing palpable chemically-induced tumors, NK activity was again significantly depressed. In addition, 3-MC-induced tumors were surgically removed and cultured in vitro. Supernatants from these tumor cell lines were shown to markedly inhibit NK cytotoxicity when tested in vitro. Preliminary results indicate that this inhibition may be mediated by prostaglandins.

Animals↗

PubMed1990

Immunotoxicity testing in the rat: an improved multiple assay model.

Improvements have been made in the multiple assay model for assessing immunotoxicity in the rat which were previously reported (Exon, J.H., Koller, L.D., Talcott, P.A., O'Reilly, C.A. & Henningsen, G.M. (1986). Immunotoxicity testing: an economical multiple-assay approach. Fund. appl. Toxic., 7, 387-397). This improved model differs from the original in that: (1) the use of Freund's adjuvant has been eliminated from the antigen treatment schedule; (2) the same antigen, keyhole limpet hemocyanin (KLH), is used to induce both the delayed-type hypersensitivity (DTH) and specific antibody responses instead of separate antigens for each; and (3) the timing of antigen injections have been adjusted so that the DTH response is measured at the same time other assays are performed. These modifications have thus reduced the chance of non-specific stimulation of the immune system by Freund's adjuvant and eliminated possible antigen competition by using a single antigen to induce antibody synthesis and a DTH reaction. In addition, all immunoassays, including the DTH reaction, are performed at the same time, which allows for better comparison between responses and improves application to short-term repeated dose studies. Also, the immune parameters measured were shown to be sensitive to known immunosuppressants, cyclophosphamide and dexamethasone.

Animals↗

PubMed1990

Subchronic 90 day toxicity of dichloroacetic and trichloroacetic acid in rats.

Male Sprague-Dawley rats were treated with either dichloroacetic acid (DCA) or trichloroacetic acid (TCA) in the drinking water at levels of 0, 50, 500 and 5000 ppm for a period of 90 days to determine the toxicities associated with subchronic exposure. All animals were sacrificed and examined for gross and histopathologic lesions, serochemical changes, immune dysfunction, hepatic peroxisomal and mixed function oxidase enzyme induction and organ-body weight changes. Animals treated with DCA had decreased body weight gains (500 and 5000 ppm) and decreased total serum protein (all doses). Rats given either TCA (5000 ppm) or DCA (500 or 5000 ppm) had increased liver and kidney organ to body weight ratios. Rats offered DCA had significantly elevated alkaline phosphatase (500 and 5000 ppm) and alanine-amino transferase (5000 ppm). No consistent immunotoxicity was observed in animals exposed to either compound. Rats treated with 5000 ppm TCA or DCA had significantly increased hepatic peroxisomal beta-oxidation activity. These data, along with histopathologic changes, suggest that TCA and DCA produce substantial systemic organ toxicity to the liver and kidney during a 90-day subchronic exposure, although only at doses greater than those expected to occur in the environment.

Alanine Transaminase↗

PubMed1990

Hypophysectomy and growth hormone replacement effects on multiple immune responses in rats.

Male Fischer 344 rats were hypophysectomized at 8 weeks of age. At 10 weeks of age, one group of these animals was treated with 40 micrograms of bovine somatotropin given daily sc for 13 days. A third group was sham-operated and injected daily with saline. All animals were sacrificed on Day 14 and multiple immune responses were assessed in each rat. Immune responses assayed included specific antibody production and delayed-type hypersensitivity (DTH) reactions to antigen, natural killer (NK) cell cytotoxicity, and production of interleukin 2 (IL2). Body and lymphoid organ weights, hematologic parameters, and spleen cell numbers were also recorded. Hypophysectomized (Hx) rats had reduced antibody synthesis, DTH reactions, NK cytotoxicity, IL2 (or IL4) production, body and organ weights, rbc counts, packed cell volumes, and hematocrits compared to sham-operated controls. White blood cell counts were elevated. Treatment of Hx animals with GH restored antibody and IL2 production and thymic weights and partially restored DTH reactions. These data indicate the pituitary is important in maintaining normal immune functions, and part of this effect may be via production of GH. It is postulated that GH may act through stimulation of IL2 (or IL4).

Animals↗

PubMed1990

The effects of methylnitrosourea (MNU) on natural killer (NK) cell cytotoxicity and cytokine production in rats.

Eight-week-old male Sprague-Dawley rats were exposed to the carcinogen methylnitrosourea (MNU) via gastric intubation at doses of either 10 or 20 mg/kg body wt. Rats were treated once a week for 4 weeks, then once every 2 weeks for 1 month, for a total of 6 treatments. MNU was found to exert no consistent significant immunosuppressive effects in vivo as measured by spleen natural killer (NK) cell cytotoxicity, interleukin-2 (IL-2) production by splenic lymphocytes and prostaglandin E2 (PGE2) production by adherent peritoneal macrophages. In contrast, splenic NK cell cytotoxicity and IL-2 production of MNU-treated rats were actually elevated at several of the later sampling periods. PGE2 production was also elevated in MNU-treated rats in the later sampling periods. Body weights of MNU-treated rats were markedly decreased as early as 4 weeks following the initial MNU treatment. This suppression persisted throughout the study. The most dramatic change in organ weights was seen in the thymus. Thymus weights of all MNU-treated rats were significantly decreased 1 day after treatment and persisted for 4 weeks. By the 60 day sampling period, thymus weights were not significantly different from controls. However, by 120 and 180 days, thymus weights again were significantly lowered in those rats receiving MNU. These changes in thymus weights were accompanied histologically by initial cortical thinning and progressive loss of cortical thymocytes followed by the appearance of hyperplastic and neoplastic cells. It thus appears that the carcinogenic effect of MNU is not related to a depression of the immune surveillance system, at least as measured by NK cell activity.

Animals↗