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Biomedical subjects

T E Hamm

Publications and source records attributed to T E Hamm.

At least 19 recordsLinked to original sources
PubMed1999

Selection and characterization of human immunodeficiency virus type 1 mutants that are resistant to inhibition by the transdominant negative RevM10 protein.

Intracellular immunization with RevM10, a transdominant negative form of the Rev protein, efficiently inhibits human immunodeficiency virus (HIV) replication in vitro and gene therapy protocols that use this modality are currently being evaluated in human clinical trials. Development of resistance to this kind of therapy has not been previously reported. Here we show that RevM10-resistant HIV type 1 (HIV-1) variants can be selected by in vitro passage of HIV-1 in a T-lymphoblastoid cell line constitutively expressing RevM10. Unexpectedly, the selected variants showed changes in the Rev response element (RRE) but no changes in Rev. Replacement of the wild-type RRE with a mutated RRE resulted in a virus that showed increased resistance to RevM10. After repeated passages of the resistant variant in cells expressing RevM10, a virus with an additional mutation in the viral vpu gene was selected. Surprisingly, a virus containing only this vpu mutation also showed some resistance to inhibition by RevM10.

Amino Acid Sequence↗
PubMed1997

Effects of immobilization restraint on Syrian golden hamsters.

Rodent nose-only inhalation toxicology systems comprise whole-body immobilization in plastic restraint tubes. This method of restraint is known to have a variety of effects on animals. In the studies reported here, two independent toxicology laboratories examined the effects of inhalation tube restraint in Syrian golden hamsters, a species that has recently gained importance in inhalation studies of fibrous particulates. Body weight, food and water consumption, core body temperature, and plasma cortisol and corticosterone concentrations were assessed in animals immobilized in nose-only inhalation tubes, and the results were compared with those from unrestrained cage-control animals. Animals were immobilized for either 6 h/ day, 5 days/week for 13 weeks (subchronic), or 4 h/day for 14 consecutive days (subacute), mimicking exposure conditions commonly used in nose-only inhalation studies. Tube restraint was found to induce a marked decrease in body weight, which increased in response to cessation of restraint. The body weight decrement was associated with significant differences in food and water consumption between the restrained and control groups in the subacute study and only food consumption in the subchronic study. During the restraint period, core body temperature in the immobilized animals increased slightly but not above the normal range for this species. Plasma cortisol and corticosterone concentrations were not significantly increased with use of restraint, compared with values in controls. Immobilization-associated body weight depression in Syrian golden hamsters is important for the evaluation of nose-only inhalation study results because many normal physiologic parameters, as well as toxicant-induced effects, are associated with body weight status.

Administration, Inhalation↗
PubMed1996

Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.

Genetic and environmental factors are important in the pathogenesis of clinical and experimental chronic intestinal inflammation. We investigated the influence of normal luminal bacteria and several groups of selected bacterial strains on spontaneous gastrointestinal and systemic inflammation in HLA-B27 transgenic rats. Rats maintained germfree for 3-9 mo were compared with littermates conventionalized with specific pathogen-free bacteria. Subsequently, germfree transgenic rats were colonized with groups of five to eight bacteria that were either facultative or strictly anaerobic. Transgenic germfree rats had no gastroduodenitis, colitis, or arthritis, but developed epididymitis and dermatitis to the same degree as conventionalized rats. Colonic proinflammatory cytokine expression was increased in transgenic conventionalized rats but was undetectable in germfree and nontransgenic rats. Colitis progressively increased over the first 4 wk of bacterial exposure, then plateaued. Only transgenic rats colonized with defined bacterial cocktails which contained Bacteroides spp. had colitis and gastritis. Normal luminal bacteria predictably and uniformly induce chronic colonic, gastric and systemic inflammation in B27 transgenic F344 rats, but all bacterial species do not have equal activities.

Animals↗
PubMed1994

Carcinogenicity and toxicity of inhaled nitrobenzene in B6C3F1 mice and F344 and CD rats.

The potential carcinogenicity and toxicity of inhaled nitrobenzene were evaluated following chronic (2-year) exposure in mice and rats. Male and female B6C3F1 mice were exposed to 0, 5, 25, or 50 ppm nitrobenzene, while male and female F344 rats and male CD rats were exposed to 0, 1, 5, or 25 ppm nitrobenzene. All exposures were for 6 hr/day, 5 days/week excluding holidays, for a total of 505 days over 2 years. Survival was not adversely affected by nitrobenzene exposure, and only mild exposure-related decreases in body weights (< 10% of control) were occasionally noted. Nitrobenzene exposure resulted in increased incidence of neoplasia in male B6C3F1 mice (pulmonary alveolar/bronchiolar and thyroid follicular cell neoplasms), female B6C3F1 mice (mammary gland neoplasms), male F344 rats (hepatocellular and renal neoplasms), female F344 rats (endometrial stromal neoplasms), and male CD rats (hepatocellular neoplasms). In addition, there were marginal increases in the incidence of hepatocellular neoplasia in female B6C3F1 mice and thyroid follicular neoplasia in male F344 rats. Groups of nitrobenzene-exposed mice and rats with increased incidence of renal and thyroid neoplasia also had increased incidences of hyperplasia in these tissues. Toxicity resulting from chronic inhalation of nitrobenzene was manifested by methemoglobinemia, anemia, and adaptive or degenerative changes in the nose, liver, and testis. The results indicate that inhaled nitrobenzene is carcinogenic and toxic in mice and rats, and that the spectrum of these responses in animals is dependent on species, sex, and genetic background.

Administration, Inhalation↗
PubMed1992

Inactivated whole-virus vaccine derived from a proviral DNA clone of simian immunodeficiency virus induces high levels of neutralizing antibodies and confers protection against heterologous challenge.

We tested the ability of macaques vaccinated with inactivated whole simian immunodeficiency virus (SIV) to resist challenge with either homologous or heterologous cell-free uncloned SIV administered by the intravenous route. The vaccine virus was derived from a proviral DNA clone and thus was considered genetically homogeneous. Sixteen macaques received either hepatitis B surface antigen (n = 6) or the inactivated whole-SIV vaccine (n = 10) at weeks 0, 4, and 49 of the study. All SIV vaccine recipients developed high levels of homologous and heterologous neutralizing antibodies in response to vaccination. At the time of challenge (week 53), vaccinees were further stratified to receive either homologous (n = 10) or heterologous (n = 6) uncloned live SIV. The envelope glycoproteins of the homologous and heterologous challenge viruses were 94% and 81% identical to the vaccine virus, respectively. Regardless of challenge inoculum, all vaccinees in the control group (hepatitis B surface antigen) became infected, whereas all SIV vaccinees were protected against detectable infection. These data support the concept that an efficacious vaccine for HIV might be possible, and suggest that genetic variation of HIV might not be an insurmountable obstacle for vaccine development.

Animals↗
PubMed1991

The genetic fate of molecularly cloned simian immunodeficiency virus in experimentally infected macaques.

We have examined genetic variation of the simian immunodeficiency virus (SIV) in four macaques inoculated with virions derived from molecular clones of proviral DNA. Our data demonstrated that the SIV genome is capable of rapid and extensive genetic variation. This variation was especially large in the env gene, where nucleotide substitution frequencies were as high as 10(-1)/site/year. In some env clones, a high G to A transition rate was observed that accounted for up to 79% of the observed nucleotide substitutions. Moreover, in env clones with a high G to A transition rate, multiple in-frame stop codons were generated exclusively at tryptophan codons. Another interesting observation was the lack of variation in the region analogous to the V3 loop in the HIV-1 Env protein. Considered together, these data have important implications for studies of pathogenesis and vaccine development in the SIV model system.

Amino Acid Sequence↗
PubMed1989

Effects of elevated serum insulinlike growth factor-II on growth hormone and insulinlike growth factor-I mRNA and secretion.

The insulinlike growth factors (IGF) appear to exert feedback control over their own production. In an effort to determine the physiologic mechanisms for this feedback modulation, we utilized a previously developed in vivo model in which rIGF-II secreting tumor cells are transplanted into immunodeficient rats to form IGF-II secreting tumors. The tumor-bearing rat have serum IGF-II concentrations sevenfold greater than those in controls (119 +/- 16 ng/mL [mean +/- SE] v 17 +/- 2 ng/mL, P less than .0001). Serum IGF-I concentrations were reduced among the tumor-bearing rats (438 +/- 42 ng/mL v 606 +/- 32 ng/mL, P = .002) and were negatively correlated with IGF-II concentrations (r = -.47, P = .025), suggesting that IGF-II suppressed the secretion of IGF-I. Increased serum IGF-II concentrations, however, did not affect basal growth hormone concentrations (tumor-bearing, 44 +/- 12 ng/mL; control 33 +/- 6 ng/mL, P = 0.96). The GH response to GH releasing factor was likewise similar in both groups. Moreover, pituitary GH mRNA level were not different in the two groups, suggesting that IGF-II does not have a significant effect on GH secretion in this in vivo model. There was no association between serum glucose and serum IGF-I or IGF-II concentrations. To examine the effect of IGF-II on IGF-I production from the liver, we measured IGF-I mRNA levels in a subset of animals. Despite these differences in serum IGF-I concentrations, the tumor-bearing rats did not have significantly lower liver IGF-I mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

One-year inhalation toxicity study of chlorine in rhesus monkeys (Macaca mulatta).

Chlorine (Cl2) gas is a potentially lung-damaging irritant which is used in the chemical, plastics, and paper industries. There are no data published using experimental animals on the chronic inhalation toxicity of chlorine. The purpose of this study was to investigate the chronic effects of Cl2 inhalation in Rhesus monkeys (Macaca mulatta). Rhesus monkeys were exposed to concentrations of 0, 0.1, 0.5, or 2.3 ppm Cl2 for 6 hr per day. 5 days per week for 1 year. Pulmonary physiology (pulmonary diffusing capacity and distribution of ventilation), body weights, urinalysis, electrocardiographs, hematology, and clinical chemistry were evaluated monthly during the study. Blood gas evaluations were performed at 3-month intervals during the study. Histopathologic, ophthalmologic, and neurologic parameters were evaluated after the 1-year exposure period. Monkeys exposed to 2.3 ppm Cl2 exhibited signs of ocular irritation during the daily exposures and a superficial conjunctival irritation was present in the 2.3 ppm group after the 1-year exposure regimen. Treatment-induced lesions revealed by histopathology were confined to the respiratory tract. Lesions associated with the nasal parasite Anatrichosoma spp. were present in the region of squamous epithelium of the nasal vestibule and did not interfere with interpretation of Cl2-induced effects. Treatment-induced histopathologic changes were found in the respiratory epithelium of the nasal passages and trachea and were limited to focal, concentration-related epithelial hyperplasia with loss of cilia and decreased numbers of goblet cells in affected areas. These changes in the nose and trachea were focal and mild in monkeys exposed to 2.3 ppm and were not found in all animals in these exposure groups. Tracheal lesions were confined to the 2.3 ppm group. The lesions observed at 2.3 ppm were not present in all animals. At the lower Cl2 concentrations, similar though less prominent respiratory epithelial lesions were observed. The latter changes were very minimal and were confined to the nasal passages of some treated monkeys and one male control animal. The results of this study indicate that 2.3 ppm chlorine acts as an upper respiratory irritant in monkeys, while 0.5 and 0.1 ppm induce changes of questionable clinical significance. Furthermore, the monkey appears to be less sensitive than the rat to chlorine toxicity.

Administration, Inhalation↗
PubMed1987

Di(2-ethylhexyl)phthalate: lack of initiating activity in the liver of female F-344 rats.

Di(2-ethylhexyl)phthalate (DEHP) is a peroxisome proliferator that was hepatocarcinogenic in female rats in a National Toxicology Program 2-year bioassay. However, DEHP was negative for promotional activity when tested using the same sex and strain of rat and dosing regimen that resulted in hepatocarcinogenicity. The carcinogenic response of peroxisome proliferators may be related to excess production of reactive oxygen species in the cell. In view of this and the negative promotion data, the initiating activity of DEHP was examined after single and sub-chronic dosing. No initiating activity was found when DEHP was administered in a single, oral dose (10 g/kg) or after 12 weeks of feeding at a dietary concentration of 1.2% when each was followed by a promotion regimen. There was no increase in number or mean volume of foci when liver sections were examined using multiple histologic markers and no tumors were identified.

Animals↗
PubMed1987

Transplantation of insulin-like growth factor-II-secreting tumors into nude rodents.

Restricted supplies of insulin-like growth factor II (IGF-II) have severely limited investigation of the in vivo actions of this hormone. To circumvent this problem, we have developed an in vivo rodent model in which rat (r) IGF-II-secreting cells (18, 54-SF) are transplanted into congenitally immunodeficient (nude) rats and mice. These cells proliferate and form discrete tumors that contain rIGF-II and abundant IGF-II receptors. The tumors also secrete rIGF-II into the circulation, resulting in plasma rIGF-II concentrations many-fold greater than those in control rodents (81 +/- 19 vs. less than 10 ng/ml, rats; 159 +/- 28 vs. 18 +/- 5 ng/ml, mice; P less than 0.05, both groups). There was no significant difference between the tumor-bearing and control rodents in either body weight or tail length. The tumor-bearing rodents did have significantly lower concentrations of IGF-I (296 +/- 23 vs. 527 +/- 67 ng/ml, rats; 300 +/- 26 vs. 482 +/- 70 ng/ml, mice; P less than 0.05, both groups), suggesting that the increased concentrations of rIGF-II may have inhibited IGF-I production or secretion. This animal model may be used to explore the biological effects of increased plasma IGF-II concentrations.

Adenoma↗
PubMed1986

The effect of diet on 2,6-dinitrotoluene hepatocarcinogenesis.

Pectin-induced changes in microflora have been shown to elevate the covalent binding of 2,6-dinitrotoluene (2,6-DNT)-related materials to total rat hepatic macromolecules. Therefore, the effect of diets varying in pectin content on the induction of foci and hepatic tumors induced by 2,6-DNT was studied in male F344 rats. 2,6-DNT (3.0-3.5 and 0.6-0.7 mg/kg/day) was incorporated into NIH-07 (NIH), an open formula cereal-based diet high in pectin content, AIN-76A (AIN), a purified pectin-free diet, or AIN-76A supplemented with 5% pectin (AP). Hepatic foci were scored after histochemical staining for gamma-glutamyl transpeptidase (GGT), canalicular adenosine triphosphatase or glucose-6-phosphatase following administration of test diets for 3, 6 and 12 months. The number of foci per cm3 of liver increased in a dose- and time-department manner following incorporation of 2,6-DNT into test diets with NIH greater than AP greater than AIN. In the NIH diet, 2,6-DNT did not alter the phenotypic distribution of foci. Animals fed control or 2,6-DNT-containing AIN and AP diets had few or no GGT foci throughout the study. Hepatocellular carcinomas and neoplastic nodules were observed only in rats fed NIH containing 2,6-DNT. The concentrations of 2,6-DNT-related material covalently bound to hepatic macromolecules after a single oral dose of radiolabeled 2,6-DNT given after 12 months on the diets increased in control rats and in rats receiving low dose 2,6-DNT in the diet with AIN less than AP less than NIH. These studies show that the carcinogenicity of 2,6-DNT differs depending on whether rats are fed an NIH or AIN (+/- pectin) diet. The results suggest that diet-induced alterations in the covalent binding of 2,6-DNT are not the sole factor in determining the carcinogenic response to 2,6-DNT. Furthermore, unidentified contaminants in cereal-based diets may influence foci and tumor production in rat liver during carcinogen treatment.

Adenosine Triphosphate↗
PubMed1985

Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. I. Mating performance and dominant lethal assay.

Methyl chloride (MeCl) is a direct-acting mutagen in bacteria, induces renal adenocarcinomas in male mice, and is a potent reproductive toxicant in the male Fischer 344 (F-344) rat. A dominant lethal assay was performed to examine the possibility that MeCl may be a germ cell mutagen in the F-344 male rat. Groups of 40 rats each were exposed to 0, 1000, or 3000 ppm MeCl 6 hr/day for 5 consecutive days, or received a single ip injection of 0.2 mg triethylenemelamine (TEM)/kg as a positive control. Each male was bred to a single female weekly for 8 weeks, and the standard criteria of dominant lethal tests were recorded. Exposure to 1000 ppm MeCl caused no consistent change in any parameter relative to control values. TEM caused increases in pre- and postimplantation loss indices in Weeks 1 to 5 postexposure, corresponding to sperm exposed in the epididymis and as early to late stage spermatids in the testis. Exposure to 3000 ppm MeCl caused a slight increase in postimplantation loss at Week 1 postexposure only, i.e., in sperm exposed in the epididymis or vas deferens, and increases in preimplantation loss throughout the 8 weeks postexposure. Fertility of the 3000 ppm MeCl-exposed males was significantly decreased by Week 2 after exposure, and never recovered to control values during the period of observation. It is suggested that the increased preimplantation losses are due, at least in part, to cytotoxic rather than genotoxic effects. High concentrations of inhaled MeCl, however, do induce dominant lethal mutations (reflected as an increased level of postimplantation fetal deaths) in sperm located within the vas deferens and epididymis at the time of exposure.

Animals↗
PubMed1985

Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. II. Spermatogonial toxicity and sperm quality.

Studies were performed to assess the effects of inhaled methyl chloride (MeCl) on sperm quality and testicular histopathology in the Fischer 344 rat. Adult male F-344 rats were exposed to 1000 or 3000 ppm MeCl 6 hr/day for 5 days, or received an ip injection of 0.2 mg triethylenemelamine (TEM)/kg on the afternoon of Day 5. Five males from a control group and each of the three treatment groups were killed weekly for 8 weeks, and five more from the control and 3000 ppm groups at Week 16 postexposure. Male rats from the 1000 ppm MeCl- and TEM-exposed groups exhibited no consistent difference from control males in any parameter measured. In the 3000 ppm MeCl group, over 50% of the males had uni- or bilateral sperm granulomas in the cauda epididymis. Testes weights were significantly depressed in these males by 3 weeks postexposure, and remained depressed as late as 8 weeks after treatment. Testicular spermatid head counts were significantly lower by 2 weeks postexposure, and the testes showed a characteristic cytotoxic response to MeCl exposure, including a delay in spermiation, chromatin margination in round spermatids, epithelial vacuolation, luminal exfoliation of spermatogenic cells, and multinucleated giant cells. Counts of repopulating seminiferous tubule cross sections and of testicular sperm heads at 7 weeks postexposure indicated that 60 to 70% of the spermatogonial stem cells had been killed by MeCl exposure. Sperm isolated from the vasa deferentia had significantly depressed numbers and an elevated frequency of abnormal sperm head morphology by Week 1 postexposure, and significantly depressed sperm motility and an elevated frequency of headless tails by Week 3 postexposure. All parameters measured in the testes and in vasa deferentia sperm showed varying degrees of recovery, and all were near the normal range by Week 16 postexposure except sperm count. These data suggest that the previously reported high preimplantation loss caused by methyl chloride exposure may be primarily due to cytotoxic effects on the testis and epididymal epithelium, rather than to direct genotoxic effects on the sperm.

Animals↗
PubMed1985

The toxicity of dimethylamine in F-344 rats and B6C3F1 mice following a 1-year inhalation exposure.

Dimethylamine is a widely used commodity chemical, for which there are few chronic toxicity data. Male and female F-344 rats and B6C3F1 mice were exposed by inhalation to 0, 10, 50, or 175 ppm dimethylamine (DMA) for 6 hr/day, 5 days/week for 12 months. Groups of 9-10 male and female rats and mice were necropsied after 6 and 12 months of exposure. No male mice were sacrificed at 12 months due to a high incidence of early deaths in that group. The mean body weight gain of rats and mice exposed to 175 ppm DMA was depressed to approximately 90% of control after 3 weeks of exposure. The only other treatment-related changes were concentration-related lesions in the nasal passages. Two distinct locations in the nose were affected: the respiratory epithelium in the anterior nasal passages, and the olfactory epithelium, especially that lining the anterior dorsal meatus. There was focal destruction of the anterior nasoturbinate and nasal septum, local inflammation, and focal squamous metaplasia of the respiratory epithelium in rats and mice. Mild goblet cell hyperplasia was observed only in rats. The olfactory epithelium exhibited extensive loss of sensory cells with less damage to sustentacular cells. There was also loss of olfactory nerves, hypertrophy of Bowman's glands, and distension of the ducts of these glands by serocellular debris in regions underlying degenerating olfactory epithelium. At the 175-ppm exposure level, rats had more extensive olfactory lesions than mice, with hyperplasia of small basophilic cells adjacent to the basement membrane being present in rats but not mice. After 12 months of exposure to 10 ppm DMA, minimal loss of olfactory sensory cells and their axons in olfactory nerve bundles was observed in the nasal passages of a few rats and mice. These results indicate that the olfactory sensory cell is highly sensitive to the toxic effects of DMA, with minor lesions being produced in rodents even at the current threshold limit value of 10 ppm.

Air Pollutants↗