Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

2005 ◽  
Vol 24 (5) ◽  
pp. 289-299 ◽  
Author(s):  
Carla E. Torrey ◽  
James A. Campbell ◽  
Debie J. Hoivik ◽  
Richard T. Miller ◽  
Jane S. Allen ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Transitional Cell ◽  
Clinical Signs ◽  
Positive Control ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Cell Hyperplasia ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carcinogenic Potential ◽  
Kidney Liver

This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) α agonist, following oral administration to p53+ /− heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+ /− than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+ /− mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+ /−mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+ /− mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.

Evaluation of the Carcinogenic Potential of Clofibrate in FVB/Tg.AC Mouse After Oral Administration—Part I

2005 ◽  
Vol 24 (5) ◽  
pp. 313-325 ◽  
Author(s):  
Carla E. Torrey ◽  
Henry G. Wall ◽  
James A. Campbell ◽  
Puntipa Kwanyuen ◽  
Debie J. Hoivik ◽  
...  
Keyword(s):  
Oral Administration ◽  
Prostate Gland ◽  
Cystic Degeneration ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Cell Hyperplasia ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carcinogenic Potential ◽  
Wild Type Male ◽  
Lymphoid Depletion

This study was conducted as part of the International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) α agonist following oral administration to Tg.AC (transgenic) and wild-type FVB (nontransgenic) mice for a minimum for 6 months. Clofibrate was well tolerated at doses up to 500 (males) and 650 (females) mg/kg/day. Oral administration of clofibrate to Tg.AC or FVB (wild-type) male and female mice for 6 months did not result in the increased formation of neoplastic lesions. Epithelial hyperplasia in the urinary bladder (Tg.AC and FVB) and prostate gland (Tg.AC only), and interstitial-cell hyperplasia in the testes (Tg.AC) were noted at 500 mg/kg/day. Non-neoplastic nonproliferative findings included hepatic hypertrophy and hematopoietic changes (myeloid hyperplasia, myelodysplasia, lymphoid depletion, and erythropoiesis) in Tg.AC and FVB mice of both sexes; reproductive (cystic degeneration and dilatation, hypospermia, spermatocele, dilated inspissated protein) and urogenital (tubular-cell hypertrophy, degenerative/regenerative nephropathy, necrosis/fibrosis) changes in Tg.AC and FVB male mice; congestion in the lung in male Tg.AC mice; gall bladder dilatation in female Tg.AC mice; and adrenal (intracellular lipofuscinosis and atrophy) and heart (eosinophillic myofibers) findings in Tg.AC mice of both sexes and in female FVB mice. The results of this study indicate that the clofibrate is not carcinogenic when administered to Tg.AC mice by oral gavage for 6 months at doses up to 500 (males) and 650 (females) mg/kg/day, which did produce liver hypertrophy.

Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

2005 ◽  
Vol 24 (5) ◽  
pp. 327-339 ◽  
Author(s):  
Carla E. Torrey ◽  
Henry G. Wall ◽  
James A. Campbell ◽  
Puntipa Kwanyuen ◽  
Debie J. Hoivik ◽  
...  
Keyword(s):  
Systemic Exposure ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carcinogenic Potential ◽  
Increased Sensitivity ◽  
Mean Time ◽  
Skin Papillomas ◽  
Dermal Application ◽  
Positive Controls

This study was conducted as part of the International Life Sciences Institute (ILSI) Alternatives to Carcinogenicity Testing program and evaluated the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) α agonist following dermal application to transgenic Tg.AC and nontransgenic FVB mice for a minimum of 26 weeks. Clofibrate doses of 12, 28, or 36 mg/200 μl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 μl), and 12- o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 μl]). Clofibrate was tolerated at doses up to 36 mg/200 μl. In Tg.AC mice, clofibrate produced a dose-related increase in the incidence of mice with cutaneous papillomas; and dose-related decreases in mean time to first tumor, mean multiplicity of tumors per mouse, and mean weeks to maximal yield, as well as numerous nonneoplastic microscopic lesions in the liver, kidney, spleen, and skin. Benzene and TPA induced both neoplastic and/or non-neoplastic proliferative lesions in Tg.AC mice. Clofibrate did not increase the incidence or multiplicity of papillomas, or any other tumors in FVB mice. These data show that the Tg.AC dermal model has increased sensitivity in detecting skin papillomas caused by the nongenotoxic rodent carcinogen, clofibrate, compared to wild type FVB mice, at systemic exposures that are 3× higher than the systemic exposure observed in humans taking clofibrate (AUC = 1100 μg ·h/ml) at the recommended maximum therapeutic dose of 500 mg. In addition, this study supports the proposed concept that Tg.AC model may detect compounds with nongenotoxic carcinogenic potential in a shorter timeframe than conventional mouse carcinogenicity bioassays.

Evaluation of the Carcinogenic Potential of Clofibrate in the Neonatal Mouse

2005 ◽  
Vol 24 (5) ◽  
pp. 341-348 ◽  
Author(s):  
Sarah R. Nesfield ◽  
Thomas C. Williams ◽  
Debie J. Hoivik ◽  
Richard T. Miller ◽  
Jane S. Allen ◽  
...  
Keyword(s):  
Harderian Gland ◽  
Positive Control ◽  
Peroxisome Proliferator ◽  
Oral Gavage ◽  
Carcinogenic Effect ◽  
Peroxisome Proliferator Activated Receptor ◽  
Neonatal Mice ◽  
Carcinogenic Potential ◽  
Neoplastic Lesions ◽  
Myocardial Degeneration

This study was conducted in support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of clofibrate, a nongenotoxic peroxisome proliferator-activated receptor (PPAR) α agonist, following oral administration to neonatal mice. Male and female neonatal CD-1 mice were dosed with clofibrate at doses of 100, 250, and 500 mg/kg or with the positive control, diethyl-nitrosamine (DEN), at 2 mg/kg by oral gavage on days 9 and 16 post birth and observed for approximately 1 year for the development of tumors. Plasma levels of clofibric acid after the second administration increased with dose, but were not dose proportional. Clofibrate administered by gavage on litter days 9 and 16 to neonatal mice at doses of 100, 250, or 500 mg/kg did not produce a carcinogenic effect. The positive control DEN did produce tumors in the liver and lung (single and multiple adenomas and carcinomas) and harderian gland (adenoma) of both sexes. Non-neoplastic lesions related to DEN treatment were confined to myocardial degeneration/fibrosis and testicular interstitial hyperplasia in males, and to glomerulonephrosis and gastritis in both sexes.

scholarly journals Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2176-2183 ◽  
Author(s):  
Bianca Hemmeryckx ◽  
Rita van Bree ◽  
Berthe Van Hoef ◽  
Lisbeth Vercruysse ◽  
H. Roger Lijnen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Adrenergic Receptors ◽  
Growth Factor Receptor ◽  
Placental Growth Factor ◽  
Peroxisome Proliferator ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipocyte Hypertrophy ◽  
Endothelial Growth Factor

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF−/−) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF−/− pregnancies. PlGF−/− mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1 was decreased accordingly. Moreover, PlGF−/− mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF−/− and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-γ2) and thermogenesis (β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF−/− mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.

scholarly journals Angiogenic Deficiency and Adipose Tissue Dysfunction Are Associated with Macrophage Malfunction in SIRT1−/− Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1706-1716 ◽  
Author(s):  
Fen Xu ◽  
David Burk ◽  
Zhanguo Gao ◽  
Jun Yin ◽  
Xia Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Sirtuin 1 ◽  
Vascular Density ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor

The histone deacetylase sirtuin 1 (SIRT1) inhibits adipocyte differentiation and suppresses inflammation by targeting the transcription factors peroxisome proliferator-activated receptor γ and nuclear factor κB. Although this suggests that adiposity and inflammation should be enhanced when SIRT1 activity is inactivated in the body, this hypothesis has not been tested in SIRT1 null (SIRT1−/−) mice. In this study, we addressed this issue by investigating the adipose tissue in SIRT1−/− mice. Compared with their wild-type littermates, SIRT1 null mice exhibited a significant reduction in body weight. In adipose tissue, the average size of adipocytes was smaller, the content of extracellular matrix was lower, adiponectin and leptin were expressed at 60% of normal level, and adipocyte differentiation was reduced. All of these changes were observed with a 50% reduction in capillary density that was determined using a three-dimensional imaging technique. Except for vascular endothelial growth factor, the expression of several angiogenic factors (Pdgf, Hgf, endothelin, apelin, and Tgf-β) was reduced by about 50%. Macrophage infiltration and inflammatory cytokine expression were 70% less in the adipose tissue of null mice and macrophage differentiation was significantly inhibited in SIRT1−/− mouse embryonic fibroblasts in vitro. In wild-type mice, macrophage deletion led to a reduction in vascular density. These data suggest that SIRT1 controls adipose tissue function through regulation of angiogenesis, whose deficiency is associated with macrophage malfunction in SIRT1−/− mice. The study supports the concept that inflammation regulates angiogenesis in the adipose tissue.

scholarly journals Susceptibility and pathological consequences of catla, Catla catla (Hamilton) experimentally infected with Edwardsiella tarda

2016 ◽  
Vol 24 (4) ◽  
pp. 209-217 ◽  
Author(s):  
Thongam Bidya Devi ◽  
T. Jawahar Abraham ◽  
Dibyendu Kamilya
Keyword(s):  
Lethal Dose ◽  
Clinical Signs ◽  
Infected Fish ◽  
Edwardsiella Tarda ◽  
Catla Catla ◽  
Cell Hyperplasia ◽  
Hydropic Degeneration ◽  
Leucocyte Infiltration ◽  
Gill Lamellae ◽  
Kidney Liver

AbstractThe present study tested the susceptibility and pathological changes of catla, Catla catla (Hamilton) infected with Edwardsiella tarda (ET-PG-29). The bacterium was isolated from the kidney of a diseased pangas catfish. To determine the median lethal dose (LD50), C. catla were challenged with this bacterium (108-103CFU ml-1), and the LD50was calculated as 105.5CFU ml-1. Another set of healthy C. catla were injected intraperitoneally with the LD50dose to induce edwardsiellosis. The clinical signs of the infected C. catla were observed and recorded. Tissues such as kidney, liver, intestine, heart, and gill from the infected fish with clinical signs of edwardsiellosis were used for histopathology. The clinical and gross signs were first visible at 1 d post-injection, and the infected fish showed typical signs of hemorrhagic septicemia. The most striking histopathological features were found in the kidney which showed multi-focal necrosis with the formation of granuloma indicating an inflammatory response against the pathogen. The intestine displayed goblet cell hyperplasia, the liver showed hydropic degeneration with hyperemic central veins, and there was inflammation of gill lamellae and cardiac myositis associated with leucocyte infiltration. Collectively, the results confirmed the susceptibility of C. catla to E. tarda infection and that this bacterium is a threat to C. catla in aquaculture practices.

scholarly journals Peroxisome-proliferator-activated receptor-α (PPARα) deficiency leads to dysregulation of hepatic lipid and carbohydrate metabolism by fatty acids and insulin

2002 ◽  
Vol 364 (2) ◽  
pp. 361-368 ◽  
Author(s):  
Mary C. SUGDEN ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Brian L. KNIGHT ◽  
Mark J. HOLNESS
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Carbohydrate Metabolism ◽  
Plasma Insulin ◽  
Hepatic Glycogen ◽  
Peroxisome Proliferator ◽  
Hepatic Lipogenesis ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Lipid

The aim of the present study was to determine whether peroxisome-proliferator-activated receptor-α (PPARα) deficiency disrupts the normal regulation of triacylglycerol (TAG) accumulation, hepatic lipogenesis and glycogenesis by fatty acids and insulin using PPARα-null mice. In wild-type mice, hepatic TAG concentrations increased (P<0.01) with fasting (24h), with substantial reversal after refeeding (6h). Hepatic TAG levels in fed PPARα-null mice were 2.4-fold higher than in the wild-type (P<0.05), increased with fasting, but remained elevated after refeeding. PPARα deficiency also impaired hepatic glycogen repletion (P<0.001), despite normal insulin and glucose levels after refeeding. Higher levels of plasma insulin were required to support similar levels of hepatic lipogenesis de novo (3H2O incorporation) in the PPARα-null mice compared with the wild-type. This difference was reflected by corresponding changes in the relationship between plasma insulin and the mRNA expression of the lipogenic transcription factor sterol-regulatory-element-binding protein-1c, and that of one of its known targets, fatty acid synthase. In wild-type mice, hepatic pyruvate dehydrogenase kinase (PDK) 4 protein expression (a downstream marker of altered fatty acid catabolism) increased (P<0.01) in response to fasting, with suppression (P<0.001) by refeeding. Although PDK4 up-regulation after fasting was halved by PPARα deficiency, PDK4 suppression after refeeding was attenuated. In summary, PPARα deficiency leads to accumulation of hepatic TAG and elicits dysregulation of hepatic lipid and carbohydrate metabolism, emphasizing the importance of precise control of lipid oxidation for hepatic fuel homoeostasis.

scholarly journals Bifidobacterium animalis subsp. lactis A6 Alleviates Obesity Associated with Promoting Mitochondrial Biogenesis and Function of Adipose Tissue in Mice

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1490
Author(s):  
Yanxiong Huo ◽  
Xuhong Lu ◽  
Xiaoyu Wang ◽  
Xifan Wang ◽  
Lingli Chen ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Uncoupling Protein ◽  
Positive Control ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bifidobacterium Animalis ◽  
Mitochondrial Biosynthesis ◽  
And Function ◽  
Estrogen Related Receptor

Probiotics are widely known for their health benefits. Mitochondrial dysfunction is related to obesity. The aim of this study was to illuminate whether Bifidobacterium animalis subsp. lactis A6 (BAA6) could improve obesity due to increased mitochondrial biogenesis and function of adipose tissues. Four-week-old male C57BL/6 mice were fed with a high-fat diet (HFD) for 17 weeks. For the final eight weeks, the HFD group was divided into three groups including HFD, HFD with BAA6 (HFD + BAA6 group), and HFD with Akkermansia muciniphila (AKK) (HFD + AKK group as positive control). The composition of the microbiota, serum lipopolysaccharides (LPS), and mitochondrial biosynthesis and function of epididymal adipose tissues were measured. Compared with the HFD group, body weight, relative fat weight, the relative abundance of Oscillibacter and Bilophila, and serum LPS were significantly decreased in the HFD + BAA6 and HFD + AKK groups (p < 0.05). Furthermore, the addition of BAA6 and AKK increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (by 21.53- and 18.51-fold), estrogen-related receptor α (ERRα) (by 2.83- and 1.24-fold), and uncoupling protein-1 (UCP-1) (by 1.51- and 0.60-fold) in epididymal adipose tissues. Our results suggest that BAA6 could improve obesity associated with promoting mitochondrial biogenesis and function of adipose tissues in mice.

scholarly journals Expression of peroxisome proliferator-activated receptor-γ in macrophage suppresses experimentally induced colitis

2007 ◽  
Vol 292 (2) ◽  
pp. G657-G666 ◽  
Author(s):  
Yatrik M. Shah ◽  
Keiichirou Morimura ◽  
Frank J. Gonzalez
Keyword(s):  
Clinical Symptoms ◽  
Body Weight Loss ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Wild Type ◽  
Targeted Disruption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Cytokine Analysis ◽  
Increased Susceptibility

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-γ is expressed in several different cell types, and mice with a targeted disruption of the PPAR-γ gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-γ ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-γ intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-γ in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-γ in macrophages (PPAR-γΔMφ) and wild-type littermates (PPAR-γF/F) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-γΔMφ mice displayed an increased susceptibility to DSS-induced colitis compared with wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1β, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-γΔMφ mice treated with DSS were higher than in similarly treated PPAR-γF/F mice. The present study has identified a novel protective role for macrophage PPAR-γ in the DSS-induced IBD model. The data suggest that PPAR-γ regulates recruitment of macrophages to inflammatory foci in the colon.

Sign in / Sign up

Export Citation Format

Share Document