Toxicologic Evaluation of Streptozotocin (NSC 85998) in Mice, Dogs and Monkeys

Levine, Barry; Henry, Malcolm C.; Port, Curtis D.; Rosen, Elliot T.

doi:10.3109/01480548009108283

Cited by 37 publications

(32 citation statements)

References 4 publications

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“…Diabetes induction using other non-STZ agents, e.g., diphtheria toxin in rat insulin promoter diphtheria toxin receptor (RIP-DTR) transgenic mice, has been associated with a reduction in leukocytes and splenocytes. 16 STZ-induced changes in the haematopoietic and reticuloendothelial systems of mice, dogs, and monkeys were documented by Levine et al 18 The maximum dose of STZ used on monkeys in their study was 80 mg/kg, which is less than that used in most nonhuman primate islet transplant models. The median lethal dose of STZ for monkeys in Levine's study (80 mg/kg) was found to cause necrosis of lymphoid tissue, bone marrow hypoplasia, anemia, and neutrophilia.…”

Section: Discussionmentioning

confidence: 88%

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Streptozotocin-associated lymphopenia in cynomolgus monkeys

Nagaraju

Bertera

Funair

et al. 2014

Islets

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Section: Discussionmentioning

confidence: 88%

“…17 Levine et al studied the toxicological effects of STZ in mice and in large animals (dogs and rhesus monkeys), and reported necrosis of lymphoid organs, and bone marrow hypoplasia. 18 The present report consists of our observations in cynomolgus monkeys.…”

Section: Introductionmentioning

confidence: 93%

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Nagaraju

Bertera

Funair

et al. 2014

Islets

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“…STZ treatment had little effect on AdipoR1/R2 mRNA levels in the liver, whereas insulin significantly decreased the AdipoR1/R2 mRNA levels in the liver of STZ-treated mice (data not shown). These results may be explained by the observations that inflammation may decrease AdipoR1/R2 mRNA levels 2 and that STZ treatment may induce inflammation in the liver (23).…”

Section: Fasting Increased But Refeeding Decreased Adipor1/r2mentioning

confidence: 78%

Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity

Tsuchida

Yamauchi

Ito

et al. 2004

Journal of Biological Chemistry

495

415

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Adiponectin/Acrp30 is a hormone secreted by adipocytes, which acts as an antidiabetic and antiatherogenic adipokine. We reported previously that AdipoR1 and -R2 serve as receptors for adiponectin and mediate increased fatty acid oxidation and glucose uptake by adiponectin. In the present study, we examined the expression levels and roles of AdipoR1/R2 in several physiological and pathophysiological states such as fasting/refeeding, obesity, and insulin resistance. Here we show that the expression of AdipoR1/R2 in insulin target organs, such as skeletal muscle and liver, is significantly increased in fasted mice and decreased in refed mice. Insulin deficiency induced by streptozotocin increased and insulin replenishment reduced the expression of AdipoR1/R2 in vivo. Thus, the expression of AdipoR1/R2 appears to be inversely correlated with plasma insulin levels in vivo. Interestingly, the incubation of hepatocytes or myocytes with insulin reduced the expression of AdipoR1/R2 via the phosphoinositide 3-kinase/Foxo1-dependent pathway in vitro. Moreover, the expressions of AdipoR1/R2 in ob/ob mice were significantly decreased in skeletal muscle and adipose tissue, which was correlated with decreased adiponectin binding to membrane fractions of skeletal muscle and decreased AMP kinase activation by adiponectin. This adiponectin resistance in turn may play a role in worsening insulin resistance in ob/ob mice. In conclusion, the expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyperinsulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.Adiponectin/Acrp30 (1-4) is a hormone secreted by adipocytes, which acts as an antidiabetic (5-12) and antiatherogenic (8, 12, 13) adipokine. This insulin-sensitizing effect of adiponectin appears to be mediated by an increase in fatty acid oxidation via activation of the 5Ј-AMP-activated protein kinase (AMPK) 1 (10, 11) and peroxisome proliferator-activated receptor-␣ (5, 6, 12). Very recently, we have reported the cloning of complementary DNAs encoding adiponectin receptors AdipoR1 and -R2 by expression cloning (14). AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. AdipoR1 and -R2 are predicted to contain seven transmembrane domains (14) but to be structurally and functionally distinct from G-protein-coupled receptors (15-17). AdipoR1 and -R2 serve as receptors for globular and full-length adiponectin and mediate increased AMPK (10, 11), peroxisome proliferator-activated receptor-␣ ligand activities (12), and fatty acid oxidation and glucose uptake by adiponectin (14).It has not yet been determined whether the expressions of AdipoR1 and -R2 are altered in physiological and pathophysiological states. To address these questions, we first studied the expressions of AdipoR1 and -R2 during fasting and refeeding. We also analyzed the expressions of Ad...

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“…However, it is also known that SZ has acute toxic effects on many organs in some animal species (Levine et al, 1980) and leads to delayed-type renal toxicity in rats (Rakieten et al, 1968;Okawa & Doi, 1983). This suggests that full attention should be paid to histopathological changes in other organs as well as the pancreas when SZ-treated animals are used for studies on diabetes.…”

Section: Abstract: Mice; Streptozotocin; Diabetes Mellitus Experimenmentioning

confidence: 99%

Histopathology of streptozotocin-induced diabetic DBA/2N and CD-1 mice

Honjo

Doi

et al. 1986

Lab Anim

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SummaryHistopathological examinations were carried out on femaie DBA/2N and CD·l mice which were autopsied 4 and 12 weeks after six daily intraperitoneal injections of streptozotocin (SZ). Histopathological changes related to SZ treatment were found in the pancreas, liver and kidneys. Little difference was observed between the two strains in the histological changes of the pancreas (a decrease in size of the islets, and degranulation and a decrease in the number of B cells) and liver (hypertrophy of hepatocytes and cytoplasmic invagination into hepatocyte nuclei). With regard to the changes in the kidneys, DBA/2N mice showed characteristic inclusions positive to periodic acid-Schiff reagent in the distal tubule epithelial cells, while CD-l mice showed remarkable luminal dilatation and epithelial cell deformation of distal tubules. SZ-induced diabetes had no innuence on the development of spontaneous cardiovascular lesions in DBA/2N mice under the present experimental conditions. Keywords: Mice; Streptozotocin; Diabetes mellitus, experimental; Pancreatic diseases; Liver diseases; Kidney diseasesStreptozotocin (SZ), which was originally developed as an antibiotic and antitumour agent, is now widely used to induce insulin-dependent diabetes mellitus in rodents because of its toxic action on islet B cells (Like et al., 1978). However, it is also known that SZ has acute toxic effects on many organs in some animal species (Levine et al., 1980) and leads to delayed-type renal toxicity in rats (Rakieten et al., 1968;Okawa & Doi, 1983). This suggests that full attention should be paid to histopathological changes in other organs as well as the pancreas when SZ-treated animals are used for studies on diabetes. There are only a few reports, however, on the systemic histopathology of SZ-induced diabetic animals (Arison et al., 1967) generally said that diabetes accelerates the progression of existing cardiovascular lesions in humans.In this paper we report the histopathology of the main organs in SZ-induced diabetic DBA/2N and CD-l mice and the influence of hyperglycaemia on the development of spontaneous cardiovascular lesions in DBAl2N mice (Doi et al., 1985;Maeda, Doi & Mitsuoka, 1986) up to 12 weeks after SZ treatment.Materials and methods 43 female DBA/2NCrj (DBA/2N) mice weighing 10-14 g each and 20 female CRJ:CD-l (CD-I) mice weighing 17-21 g each were obtained from Charles River Japan Inc., Atsugi, Kanagawa, at 4 weeks of age. The mice were housed in an animal room at a temperature of 23 ± 2°C with a relative humidity of 55 ± 5% and were fed CRF-l (Charles River Japan Inc.) and water ad libitum.At 5 weeks of age, 23 DBA/2N and 10 CD-l mice received SZ at 50 mg/kg of bodyweight per day for six consecutive days. SZ (Sigma Chemical Company, St. Louis, MO, USA) was dissolved in citrate buffer (pH 4·5) immediately before daily intraperitoneal injection. The remaining mice of each strain received citrate buffer alone in the same way and served as controls. Bodyweight and food and water intake for 24 h were measured weekly...

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Toxicologic Evaluation of Streptozotocin (NSC 85998) in Mice, Dogs and Monkeys

Cited by 37 publications

References 4 publications

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity

Histopathology of streptozotocin-induced diabetic DBA/2N and CD-1 mice

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