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D L Dillehay

Publications and source records attributed to D L Dillehay.

At least 37 records · Page 2Linked to original sources
PubMed1997

Importance of sphingolipids and inhibitors of sphingolipid metabolism as components of animal diets.

Sphingolipids are highly bioactive compounds that participate in the regulation of cell growth, differentiation, diverse cell functions, and apoptosis. They are present in both plant and animal foods in appreciable amounts, but little is known about their nutritional significance. Recent studies have shown that feeding sphingomyelin to female CF1 mice treated with a colon carcinogen (1,2-dimethylhydrazine) reduced the number of aberrant colonic crypt foci; longer-term feeding also affected the appearance of colonic adenocarcinomas. Therefore, dietary sphingolipids should be considered in studies of the relationships between diet and cancer. Sphingolipids have also surfaced as important factors in understanding the mechanism of action of a recently discovered family of mycotoxins, termed fumonisins. Fumonisins are produced by fungi commonly found on maize and a few related foods, and their consumption can result in equine leukoencephalomalacia, porcine pulmonary edema and a number of other diseases of veterinary animals and, perhaps, humans. A cellular target of fumonisins is the enzyme ceramide synthase, and disruption of sphingolipid metabolism by fumonisins has been established by studies with both cells in culture and animals that have consumed these toxic mycotoxins. These findings underscore the ways in which sphingolipids and agents that affect sphingolipid utilization should be given consideration in selecting animal diets for nutritional and toxicological studies.

Animal Feed↗
PubMed1996

Sphingomyelin consumption suppresses aberrant colonic crypt foci and increases the proportion of adenomas versus adenocarcinomas in CF1 mice treated with 1,2-dimethylhydrazine: implications for dietary sphingolipids and colon carcinogenesis.

Sphingolipids are hydrolyzed in the gastrointestinal tract to ceramide, sphingosine, and other metabolites that can modulate cell growth, differentiation, and apoptosis. To characterize the effects of dietary sphingolipids on colon carcinogenesis, female CF1 mice were administered 1,2-dimethylhydrazine and then fed an essentially sphingolipid-free diet supplemented with 0 to 0.1% (w/w) sphingomyelin (SM) purified from milk. As was found in a previous pilot study (D. L. Dillehay et al., J. Nutr., 124: 615-620, 1994), SM (@ 0.1%) reduced the number of aberrant colonic crypt foci (by 70%, P < 0.001) and aberrant crypts per focus (by 30%, P < 0.003), which are early indicators of colon carcinogenesis. In longer term studies, SM had no effect on colon tumor incidence or multiplicity; however, up to 31% of the tumors of mice fed SM were adenomas, whereas all of the tumors of mice fed the diet without SM were adenocarcinomas. These findings demonstrate that milk SM suppresses the appearance of more advanced, malignant tumors as well as early markers of colon carcinogenesis. Although the sphingolipid content of foods has not been widely studied, several foods (e.g., milk and soybeans) contain the sphingolipid levels used in these investigations; therefore, this class of compounds could be significant contributors to the cancer preventive effects of some foods.

1,2-Dimethylhydrazine↗
PubMed1996

Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities.

Our recent studies have shown that the cellular gene at the mouse mammary tumor virus integration site in the int-5 locus is aromatase. To study the role of int-5/aromatase in normal mammary development and mammary neoplasia, we have generated transgenic mice that overexpress int-5/aromatase under the control of mouse mammary tumor virus enhancer/promoter. All the transgenic virgin (n = 10) and postlactational (n = 15) females that overexpress int-5/aromatase show various histological abnormalities. Overexpression of int-5/aromatase in mammary glands of virgin females leads to the enlargement of 40% of ducts, of which 65% had hyperplastic lesions, 20% had dysplastic lesions, and 15% had fibroadenoma lesions. Overexpression of int-5/aromatase in involuted mammary glands of transgenic females induces hyperplasia in 75-80% of ducts and glands that exhibit a range of morphological abnormalities, including formation of hyperplastic alveolar nodule (10%), ductal and glandular hyperplasia (70-80%), ductal and lobular dysplasia (15%), and nuclear abnormalities (2-5%) such as multinucleation and karyomegaly, which are all indicative of preneoplastic changes. Our results show that early exposure of mammary epithelium to in situ estrogen and continued exposure to in situ estrogen as a result of overexpression of int-5/aromatase appears to predispose mammary tissue to preneoplastic changes, which may, in turn, increase the risk of developing neoplasia and increase susceptibility to environmental carcinogens. These findings support clinical and experimental data that suggest that early estrogen exposure increases breast cancer risk.

Animals↗
PubMed1996

Intravenous vs. intraprostatic administration of N-methyl-N-nitrosourea to induce prostate cancer in rats.

To develop an improved model of human prostate cancer, 16-wk-old Wistar rats were treated orally for 18 days with the antiandrogen, flutamide (50 mg/kg body weight [BW]/day), followed by 3 days of s.c. testosterone (100 mg/kg BW). There were the only treatments the control animals received (Group 1, n = 10). On the day after the third testosterone injection, N-methyl-N-nitorsourea (MNU) was administered via the tail vein at a dose of 50 mg/kg BW (Groups 2, n = 40 and 3, n = 20); in some rats, a second dose was delivered by the same route 22 wk later (Group 3). A smaller dose of MNU (15 mg/kg BW) was administered intraprostatically (Group 4, n = 20) to a fourth group. In Groups 2, 3, and 4, silastic capsules containing testosterone were implanted s.c. approximately every 6 wk beginning 1 wk post-MNU. Accessory sex gland tumors arose in MNU-treated rats in Group 2 (12/40, 30%). Group 3 (8/20, 40%), and Group 4 (8/20, 40%); 90% were macroscopic (25/28). There were no neoplasms in these organs in the control rats (Group 1, 0/10). These accessory sex gland neoplasms were adenocarcinomas or undifferentiated carcinomas which appeared to be derived from the prostate based on location and histological characteristics, although the size and spread of some of the tumors precluded definitive localization of the tissue of origin. The incidence of these neoplasms was similar in rats given a single dose of MNU intraprostatically or two doses of MNU i.v., but the animals treated intraprostatically maintained higher body weights and developed fewer extraneous tumors. The average (+/- SD) latent period for clinical or postmortem detection of prostate neoplasia after MNU was shortest in the rats given two i.v. doses (39 +/- 3 wk) compared with the single i.v. dose (45 +/- 6 wk) or an intraprostatic dose (56 +/- 7 wk). In 57% of the cases (16/28), the prostate tumors metastasized to distant sites. An activating point mutation was detected in codon 12 of the Ki-ras oncogene in the MNU-induced primary prostate tumors (8/10 examined), and metastases arising from these prostate tumors (2/3) but was absent in normal prostate tissue (0/6). This study demonstrates that two systemic doses of MNU increase the incidence and decrease the latency of prostate neoplasms compared with a single dose, and that a single dose of MNU injected intraprostatically induces prostate adenocarcinoma without many of the other tumors and weight loss typically found after i.v. administration.

Adenocarcinoma↗
PubMed1996

Streptococcus pyogenes infection in mice.

We inoculated 5 to 7-week-old female C3HeB/FeJ mice with Streptococcus pyogenes strain B514-Sm (type M50) by both an intranasal and intratracheal route and characterized the resulting illness. Following intranasal inoculation, the animals developed signs of illness within 1 to 8 days post-inoculation which correlated with acute, suppurative, bronchopneumonia during histopathologic analysis; however, the relationship of response to dose was non-linear, as seen previously in a small group of mice. Intratracheal inoculations were then performed to increase the quantitative reliability of the model. Following intratracheal inoculation, the animals succumbed to an illness that was indistinguishable from that seen after intranasal inoculation, and the incidence of pneumonia followed a steep dose response curve. The dose at which 50% of the animals exhibited signs of respiratory illness within 72 h was 1.0 x 10(7) colony forming units. All of the animals that appeared ill had lung lesions as determined by gross and histopathologic examination. Bacteraemia followed pneumonia in two-thirds of the intratracheally inoculated animals, indicating that the S. pyogenes had crossed tissue barriers. We hope that this model will be useful in future studies concerning the role of suspected streptococcal virulence factors in the later stages of pathogenesis of invasive S. pyogenes infection.

Animals↗
PubMed1996

The role of human adenovirus early region 3 proteins (gp19K, 10.4K, 14.5K, and 14.7K) in a murine pneumonia model.

Products of human adenovirus (Ad) early region 3 (E3) inhibit both specific (cytotoxic T lymphocytes [CTLs]) and innate (tumor necrosis factor alpha [TNF-alpha]) immune responses in vitro. The E3 gp19K protein prevents CTL recognition of Ad-infected fibroblasts by sequestering major histocompatibility complex class I proteins in the endoplasmic reticulum. E3 proteins 10.4K, 14.5K, and 14.7K function to protect infected cells from TNF-alpha cytolysis. To address the in vivo functions of these proteins, Ad mutants that lack the E3 genes encoding these proteins were inoculated intranasally into C57BL/10SnJ (H-2b) mice. Mutants that lack the gp19K gene failed to alter CTL generation or to affect Ad-induced pulmonary infiltrates. Since gamma interferon (IFN-gamma) is capable of overcoming gp19K suppression of CTL lysis in vitro, mice were depleted of IFN-gamma and inoculated with gp19K mutants. Even when IFN-gamma was depleted, gp19K was incapable of altering pulmonary lesions. These resuls are not in accord with the function of gp19K in vitro and suggest that gp19K does not affect immune recognition in vivo during an acute virus infection, yet they do not exclude the possibility that gp19K blocks immune recognition of Ad during a persistent infection. In contrast, when mice were inoculated with Ad mutants that lack the TNF resistance genes (14.7K and either 10.4K or 14.5K), there was a marked increase in alveolar infiltration and no change in the amounts of perivascular/peribronchiolar infiltration compared with wild-type-Ad-induced pathology. These findings demonstrate the importance of TNF susceptibility and TNF by-products for recruiting inflammatory cells into the lungs during Ad infections.

Adenoviridae Infections↗
PubMed1995

Intravesical suramin in the prevention of transitional cell carcinoma.

OBJECTIVES: To examine the effects of intravesical suramin on N-methyl-N-nitrosurea (MNU)-induced bladder tumors in Fischer 344 rats. METHODS: Multiple cohorts of female rats received four biweekly intravesical instillations of MNU. A control group received no other treatment, the experimental group received 25 mg/kg intravesical suramin twice a week beginning at week 6. RESULTS: After 18 weeks from the first instillation of MNU, 60% to 65% of control animals developed papillary transitional cell carcinoma, compared with only 0% to 10% of the suramin-treated animals (P = 0.01 to P = 0.0007). There was no local or systemic toxicity observed. CONCLUSIONS: Intravesical suramin is an effective chemopreventative therapy for transitional cell carcinoma in vivo with minimal toxicity.

Administration, Intravesical↗
PubMed1995

Role of dietary sphingolipids and inhibitors of sphingolipid metabolism in cancer and other diseases.

Sphingolipids are found in all eukaryotic and some prokaryotic organisms and participate in the regulation of cell growth, differentiation, and diverse cell functions including cell-cell communication, cell-substratum interactions and intracellular signal transduction. Nonetheless, the field of nutrition has given scant attention to these compounds so that little is known about the following fundamental questions: What is the fate of sphingolipids that are consumed in food? Does consumption of dietary sphingolipids affect the behavior of cells in the gastrointestinal tract or other organs? How do other factors in the diet affect sphingolipid metabolism? Several recent findings underscore the importance of these questions, for examples: 1) Sphingolipids are digested throughout the GI tract to ceramide and sphingosine, which are highly bioactive compounds that affect cellular regulatory pathways; 2) addition of sphingomyelin to a standard AIN diet (which is essentially devoid of sphingolipids) reduces the appearance of aberrant colonic crypts, and perhaps the number of tumors, in mice treated with a colon carcinogen; and 3) an enzyme of sphingolipid metabolism has been discovered to be the target of a class of toxic and carcinogenic mycotoxins called fumonisins. Given these recent findings, it is possible that some of the confusion that has arisen regarding the relationships between dietary fat and disease might be due to the lack of consideration of the sphingolipids that are also present.

Animals↗
PubMed1995

Pulmonary alveolar proteinosis in SCID mice.

Pulmonary alveolar proteinosis (PAP) is an uncommon disorder of unknown origin in which the alveoli are filled with lipoproteinaceous material, including surfactant. We have characterized a spontaneously occurring lesion in the lungs of CB.17 scid/scid mice which resembles PAP in humans. Lungs from 45 severe combined immunodeficient (SCID) mice were evaluated by light and electron microscopy and immunohistochemistry. Lung lavage fluid was evaluated biochemically and for the presence of surfactant protein A (SP-A) and B (SP-B) by enzyme-linked immunosorbent assay and Western blot. Light microscopy showed varying amounts of a homogeneous to granular proteinaceous material in alveolar spaces. This material was eosinophilic by hematoxylin and eosin stain and was periodic acid-Schiff (PAS) positive. Ultrastructurally, the material was predominantly homogeneous with areas of a lamellated pattern that resembled surfactant. Biochemical analysis revealed 2.7- and 3.6-fold increases in the surfactant-associated phospholipids phosphatidylcholine and disaturated phosphatidylcholine respectively, when affected SCID mice were compared with control mice. Immunohistochemical staining of lung tissue and Western blot and enzyme-linked immunosorbent assay of lavage fluid showed marked increases in SP-A and SP-B in comparison with controls. These results suggest that SCID mice have a defect in surfactant homeostasis that resembles PAP in humans and may serve as an animal model in further elucidating the pathogenesis of this disease.

Animals↗
PubMed1995

Isolation of mycoplasmas from prairie voles (Microtus ochrogaster).

A new species of mycoplasmas was isolated from the lungs and nasopharyngeal washings of prairie voles (Microtus ochrogaster). Clinical signs of disease and microscopic lesions were not observed at the time of this isolation. The organism was cultured in SP4 medium; it grew aerobically, anaerobically, and in 5% CO2 in 5 to 7 days, and fermented glucose. Transmission electron microscopy revealed the organism to lack a cell wall and to have typical mycoplasmal ultrastructural morphology. The complete nucleotide sequence of the 16S rRNA gene from an isolate was determined by amplification with polymerase chain reaction and by sequencing with the dideoxynucleotide chain termination method. The sequence did not match any known sequences in the GenBank of the National Institutes of Health. The 16S rRNA sequence of the organism, Mycoplasma volis (proposed species novum), is unique and most closely resembles that of M. muris and M. iowae. Because this vole colony will be housed in rooms with other rodents, pathogenicity studies of this new species of mycoplasmas in mice and rats are underway.

Animals↗
PubMed1994

Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice.

Sphingolipids are in all eukaryotic cells and modulate cell growth, differentiation, and transformation; however, little is known about the physiological effects of their consumption. Mice were fed diets supplemented with milk sphingomyelin to determine effects on colon carcinogenesis. Cancer was initiated in CF1 mice by 1,2-dimethylhydrazine. Mice were then fed AIN76A diets supplemented with 0.025 to 0.1 g sphingomyelin/100 g for 28 wk until the supply of sphingomyelin was depleted and then fed unsupplemented diet for 24 wk. Sphingomyelin did not affect weight gain. Mice fed sphingomyelin had a 20% incidence of colon tumors compared with 47% in controls (P = 0.08 for all sphingomyelin-fed mice vs. controls). Tumors were adenomas or adenocarcinomas and located in the distal third of the colon. In shorter-term studies, colonic epithelial cell proliferation was significantly greater than controls in mice fed 0.025 g sphingomyelin/100 g diet, but not in those fed higher amounts of sphingomyelin. The number of aberrant crypts was significantly lower in 1,2-dimethylhydrazine-treated mice fed 0.05 g sphingomyelin/100 g diet than in controls. These results demonstrate that consumption of sphingomyelin affects the behavior of colonic cells. Because sphingolipids are present in food, the reduction in 1,2-dimethylhydrazine-induced premalignant lesions and the incidence of colon tumors in CF1 mice implies that these compounds may be another important class of nutritional modulators of carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1994

Uptake and metabolism of sphingolipids in isolated intestinal loops of mice.

Sphingolipids are found in all eukaryotic organisms. However, little is known about the digestion, uptake and subsequent metabolism of these constituents of food. In this study, radiolabeled sphingolipids were placed in isolated intestinal segments of female CF1 mice, and the metabolism and distribution of the radiolabel were followed. Most of the sphingomyelin was degraded to ceramide and other products in all regions of the intestine, and increasing amounts of several [3H]-labeled sphingolipids appeared in the tissues. Small amounts of the radiolabel disappeared from the intestinal loops and appeared in liver within the first 30 to 60 min implying that neither intact sphingomyelin nor its metabolites are transported very efficiently from the intestine to other organs. There were different degrees of uptake and metabolism of sphingomyelin, [4,5-3H-sphinganyl]ceramide, and [3H]sphingosine. The [3H]sphingomyelin was also administered by gavage and the appearance along the intestine measured. After 90 min, 12% was found in the cecum and colon. These results establish that some of the sphingomyelin that enters the gastrointestinal tract is hydrolyzed and taken up by the intestine, with the lipid backbone being degraded or reutilized for complex sphingolipid synthesis; however, at least a portion passes into the large intestine. The appearance of bioactive compounds throughout the gastrointestinal tract may alter the behavior of intestinal cells.

Administration, Oral↗
PubMed1994

Enterocecocolitis associated with Escherichia coli and Campylobacter-like organisms in a hamster (Mesocricetus auratus) colony.

Sporadic diarrhea and weight loss were observed in a breeding colony of Syrian hamsters during a 2-year period. Thirteen adult hamsters with diarrhea, anorexia, and weight loss were examined. Histologic lesions consisted of diffuse nonsuppurative enterocecocolitis and multifocal epithelial proliferation in the cecum and colon. Goblet cell hyperplasia was extensive in the colonic mucosa of many hamsters. The hamsters in this colony had not been treated with antibiotics nor was Clostridium difficile isolated from any of the hamsters. In contrast to typical proliferative ileitis in hamsters, most hamsters involved in this outbreak were mature adults rather than weanlings, and lesions were predominantly inflammatory rather than proliferative and involved small intestine, cecum, and colon rather than ileum. The isolation of beta-hemolytic Escherichia coli and demonstration of Campylobacter-like organisms by transmission electron microscopy and Warthin-Starry staining suggest that these two agents were involved in the pathogenesis of this disease. Further studies, however, are needed to investigate the pathogenesis of this enteric syndrome in hamsters.

Animals↗