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Biomedical subjects

J A Hoyt

Publications and source records attributed to J A Hoyt.

14 recordsLinked to original sources
PubMed2006

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.

BACKGROUND: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. OBJECTIVE: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. METHODS AND RESULTS: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. CONCLUSION: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

Animals↗
PubMed1994

Reproductive and developmental toxicity of the dopamine agonist pergolide mesylate in mice.

Pergolide (Permax, LY127809, CAS 66104-23-2) a dopamine agonist for the treatment of Parkinson's disease, was evaluated for reproductive and developmental toxicity. Pergolide was administered in the diet at levels of 0, 5, 15, or 50 ppm to male and female ICR mice. In the F0 generation, the males were treated for 9 weeks prior to mating and throughout mating. The females were treated for 2 weeks prior to mating and throughout mating, gestation, and location (postnatal segment only). Females assigned to the teratology segment were killed on gestation day 18 for evaluation of fetal viability, weights, and morphology. Females assigned to the postnatal component were allowed to deliver and maintain their offspring throughout a 21-day lactation period. One male and one female were selected from each litter to continue as the F1 generation. Possible exposure of the F1 generation to pergolide ended at weaning. Growth of the F1 animals was monitored and reproductive performance evaluated. Treatment-related effects in the F0 generation were consistent with the pharmacologic effects of a dopamine agonist. These effects included pregnancy blockage at the 50-ppm dietary level and dose-related body weight depression in lactating dams and suckling progeny at the 15- and 50-ppm dietary levels. An increase in progeny mortality at the 50-ppm dietary level was attributed to lactation failure of the treated dams. The F1 mice of the 15- and 50-ppm groups remained smaller than the control mice until termination at approximately 20 weeks of age, although weight gains following weaning were not depressed and no impairment of mating performance or fertility was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Survival differences among freeze-dried genetically engineered and wild-type bacteria.

Because the death mechanisms of freeze-dried and air-dried bacteria are thought to be similar, freeze-drying was used to investigate the survival differences between potentially airborne genetically engineered microorganisms and their wild types. To this end, engineered strains of Escherichia coli and Pseudomonas syringae were freeze-dried and exposed to air, visible light, or both. The death rates of all engineered strains were significantly higher than those of their parental strains. Light and air exposure were found to increase the death rates of all strains. Application of death rate models to freeze-dried engineered bacteria to be released into the environment is discussed.

Air↗
PubMed1993

A review of the toxicology of the antibiotic MICOTIL 300.

MICOTIL 300 is a new macrolide antibiotic for the treatment of Bovine Respiratory Disease complex. As with other macrolides used in human and veterinary medicine, overdoses of MICOTIL do not produce pathognomonic lesions. The toxicity dose response varies among laboratory animal and domestic livestock species. However, clinical evidence of MICOTIL toxicity due to large doses is generally a manifestation of the positive chronotropic and negative inotropic cardiovascular effects. No adverse environmental effects are expected from the use of MICOTIL in cattle.

Animals↗
PubMed1991

Comparative effects of disulfiram and N-methyltetrazolethiol on spermatogenic development in young CD rats.

N-Methyltetrazolethiol (NMTT) and NMTT-containing cephalosporin antibiotics cause characteristic testicular lesions in young but not adult rats. In addition, NMTT-containing cephalosporins inhibit aldehyde dehydrogenase and have been associated with a disulfiram-like reaction in humans and animals. Therefore, the potential testicular toxicity of disulfiram (10, 30, or 100 mg/kg) was evaluated in 37-day-old rats given oral doses on Postpartum Days 6 through 36, and was compared to the toxicity induced by NMTT (100 mg/kg). NMTT and each dose of disulfiram caused a decrease in testes weight. By DNA flow cytometry, testicular cell suspensions from rats given 100 mg/kg of NMTT had a 40% reduction in spermatids while those from rats given 10, 30, or 100 mg/kg of disulfiram had reductions of 52, 61, or 89%, respectively. Microscopically, the testes of rats given either NMTT or disulfiram had qualitatively similar changes, characterized by delayed maturity of the leading waves of germinal cells which had reached early maturation phase in control animals. Moderate to severe reduction occurred in the total number of spermatids with complete absence of acrosome phase and maturation phase spermatids. There was also a prominent reduction in the number of spermatocytes. Reduction in number of spermatogonia was minimal. While the mechanism of toxicity is not known for either compound, it is possible that the toxicity was related to the enzyme-inhibitory effects which both compounds possess. By defining the mechanism of testicular toxicity for compounds which cause a NMTT-like testicular toxicity in rats, biological differences in the spermatogenic process between the young and adult rat may be further understood. Direct extrapolation of the testicular effects in neonatal rats to man is not possible because of the substantial differences in initiation of spermatogenesis between rodents and humans.

Aldehyde Dehydrogenase↗
PubMed1989

Animal activism.

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Animal Welfare↗
PubMed1985

Streptococcal enteropathy in infant rats.

A spontaneous outbreak of enteric disease with high morbidity and mortality occurred in preweanling rats on a multigeneration toxicity study. The rats had a large number of gram-positive cocci on the surface of villi in the small intestine without associated inflammatory change. Ultrastructural study identified filamentous attachments between adjacent bacteria, and between bacteria and morphologically normal microvilli. The organism was isolated and identified as Streptococcus sp. The disease was reproduced in rat pups by inoculating dams and newborn rats with pure cultures of the Streptococcus. Streptococcal enteropathy is a previously unreported disease in rats.

Animals↗
PubMedDate not supplied

Utilization of a short-term male reproductive toxicity study design to examine effects of alpha-chlorohydrin (3-chloro-1,2-propanediol).

alpha-Chlorohydrin (ACH) was administered to rats in a short-term male reproductive toxicity study to examine the usefulness of the method and to provide reference data with a substance that is known to elicit adverse effects on both sperm production and sperm quality within or following a 2-week treatment period. Adult male CD rats (10 per group) were administered ACH orally by gavage at doses of 0, 1, 5, or 25 mg/kg/day for 14 days. Males were killed on Test Day (TD) 15 or 29. A 2-week period without treatment was included to distinguish between testicular and posttesticular effects. At each time point, the reproductive system was evaluated by comparing testes weight, DNA ploidy distributions of testicular cell suspensions, testicular and epididymal histopathology, and epididymal sperm concentration, motility, morphology, and breakage. Beginning on TD 14, males to be killed on TD 29 were cohabited with untreated females (1:2). Females were killed on Gestation Day 13 and examined for pregnancy status. During the treatment period, minor depressions in body weight and relative food consumption occurred in rats administered 25 mg/kg ACH. Testicular and epididymal lesions also occurred at this dose level. DNA ploidy distributions determined by flow cytometry were predictive of testicular damage, with effects more pronounced on TD 29 than on TD 15. The preparation methods used selected for the most motile and vigorous population of epididymal sperm. Sperm motion was altered at the 5- and 25-mg/kg dose levels on TD 15. The percentage of motile sperm and the percentage of progressively motile sperm were markedly depressed at both the 5- and 25-mg/kg dose levels where antifertility effects occurred. Sperm velocities and amplitude of lateral head displacement were depressed at the 25-mg/kg dose level on both TD 15 and 29. Additionally, decreased epididymal sperm concentrations and increased breakage were recorded at this dose level. The findings in this study are consistent with the scientific literature for ACH and demonstrate posttesticular effects on epididymal sperm and delayed expression of testicular lesions. They also support the use of this methodology for an initial assessment of male reproductive effects.

Animals↗
PubMedDate not supplied

Short-term male reproductive toxicity study with sulfasalazine in the rat.

Sulfasalazine (2-hydroxy-5-[[4-[(2-pyridinylamino) sulfonyl] phenyl]azo]benzoic acid; SASP) was administered to rats in a short-term male reproductive toxicity study to further examine the utility of this grouping of techniques and to generate reference data with a substance that is known to cause reversible infertility in men. Adult male CD rats (10/group) were orally administered 0, 150, 300, or 600 mg SASP/kg body weight in divided doses for 14 d followed by a 2-week period without treatment. Males were killed on test day (TD) 15 or 29. At each time point, the reproductive system was evaluated by comparing testicular and epididymal weights, DNA ploidy distributions of testicular cell suspensions, testicular and epididymal histopathology, and epididymal sperm concentrations, motion, morphology, and breakage. Adding time as a factor in the protocol aids in distinguishing testicular from posttesticular effects. Changes in sperm quality after 2 weeks of test article administration (TD 15) predominantly reflect effects that occurred after the sperm entered the epididymis, while testicular effects predominated on TD 29. Beginning on TD 14, males to be killed on TD 29 were cohabited with untreated females (1:2). Females were killed at midgestation and examined for pregnancy status. Body weight gain was depressed in all SASP groups during the first 3 d of test article administration. Food consumption was depressed at the 300- and 600-mg/kg dose levels. No changes were seen in testicular weight, but epididymal weight was depressed at the 600-mg/kg dose level. DNA ploidy distributions determined by flow cytometry did not indicate that the kinetics of spermatogenesis were disturbed. However, alterations in sperm release, which have not previously been reported, were seen at all SASP dose levels. On TD 29, the percentage of progressively motile sperm was depressed and beat/cross frequency was increased at the 600-mg/kg dose level. No changes were observed in sperm morphology or breakage. Fertility was slightly depressed at the 600-mg/kg dose level. In this study, testicular histopathology provided the most sensitive endpoint for reproductive toxicity. The impairment of fertility immediately after treatment was stopped, when no changes were apparent in sperm release or sperm motion, suggested that decreased sperm concentrations and altered motility, while contributory, may not be the primary causes of SASP-mediated infertility.

Animals↗
PubMedDate not supplied

The selective estrogen receptor modulator, raloxifene: reproductive assessments in adult male rats.

Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed for postmenopausal osteoporosis. Reproductive toxicity of raloxifene was examined in adult male CD rats after the oral administration of doses of 0, 10, 30, or 100 mg/kg/d. In the first study, males (12/group) were treated for 2 weeks followed by 2 weeks without treatment. After dose administration on Day 13, 6 males/group were cohabited with untreated females (1:2) for up to 7 d. Males were killed on Day 14 or 28 (6/group each day). Sperm were collected from the right cauda epididymis and evaluated for relative concentration, motion characteristics, and breakage. The kinetics of spermatogenesis were examined by DNA flow cytometry. The left testis and epididymis were preserved for histopathologic evaluation. Females were examined for reproductive status on Gestation Day 13. In a second study, males (20/group) were treated for 7 weeks (4 weeks prior to cohabitation during a 2-week cohabitation period, and for 1 additional week). Treated males were cohabited with untreated females (1:1). On Gestation Day 20, untreated females were examined for reproductive status and fetuses were examined for viability, weight, gender, and morphology. At necropsy, male reproductive tissues were collected, weighed, and preserved for histopathologic evaluation. In both studies, male body weight gain and food consumption were depressed at all dose levels. There was no indication in either study that raloxifene caused important changes in sperm production, sperm quality, or male reproductive performance at doses as high as 100 mg/kg/d.

Administration, Oral↗
PubMedDate not supplied

The selective estrogen receptor modulator, raloxifene: reproductive assessments following premating exposure in female rats.

Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed as a therapeutic agent for postmenopausal osteoporosis. Two studies were conducted that examined the effects of premating exposure to raloxifene HCl. In the first study, adult female CD rats (20/group) were given diets containing 0, 0.01, or 0.1% raloxifene (providing an average of 0, 6, or 63 mg/kg/d, respectively) for 2 weeks, after which the treated diets were replaced with control diet. Following a 2-week period without treatment, each female that had displayed at least three conversions in vaginal cytology from cornified cells to leukocytes was cohabited for 1 to 2 d with an untreated male as she entered proestrus. Females were killed at midgestation and examined for evidence of pregnancy. In the second study, adult female CD rats (40/group) were given oral gavage doses of raloxifene (0, 0.1, 1, or 10 mg/kg/d) for 4 weeks. Immediately or following a 2-week period without treatment, 20 females/group were cohabited with untreated males (1:1) for up to 3 weeks. The females were allowed to deliver and rear their offspring until Postpartum Day 21. Progeny survival, growth, and development were evaluated. Maternal body weight, body weight gain, and food consumption were depressed in all raloxifene treatment groups. Doses > or =1 mg/kg caused disruptions in estrous cycles. In Study 1, 90% of the females treated with raloxifene resumed normal cycling, and fertility was not significantly affected. Although there were no statistically significant differences in time-to-mating, fertility, or liveborn indices in Study 2, females in the 10-mg/kg immediate-cohabitation group had slightly increased gestation lengths and smaller litter sizes. Progeny from these litters were larger on Postpartum Day 1 and had advanced incisor eruption and eye opening. In addition, slight delays were seen in physical landmark appearance in the 0.1- and 1-mg/kg immediate-cohabitation groups and in the 1- and 10-mg/kg delayed-cohabitation groups. Progeny viability, growth, and negative geotactic performance were not adversely affected. In these studies of maternal premating exposure to raloxifene, findings were consistent with established pharmacologic activity of the test chemical. Reproductive effects (disrupted estrous cycles and decreased litter size) occurred at doses > or =1 mg/kg and were generally reversible. Effects on offspring were seen at doses > or =0.1 mg/kg, were of minor importance, and were resolved during the lactation period.

Analysis of Variance↗