Can seeds help mice with the daily grind?

Some laboratory mice gnaw food pellets without ingesting much of the gnawed material, resulting in the production of waste material called 'orts'. The fact that this food grinding behavior is not seen in all individuals of a particular strain suggests that it might be abnormal, and thus indicate a welfare concern. Furthermore, the increased rate of feed consumption and cage soiling is undesirable from a husbandry perspective. To try to determine possible motivations for the behavior, and identify potential treatments, outbred Crl:CD1(Icr) mice exhibiting food grinding were selected for one of three treatments placed in the feeder: no enrichment, a chewing device, or sunflower seeds. Both enrichment groups showed a significant decrease (P < 0.05) in ort production when compared with baseline measurements, but only mice provided with sunflower seeds maintained the decreased rate of food wastage after the treatment was withdrawn. A relationship between body weight and ort production was also found, in that cages with greater average body weights had lower levels of ort production. This suggests that a simple need to gnaw cannot alone explain food grinding, and that a nutritional motivation may also be involved.

Origin and distribution of potassium bromate-induced testicular and peritoneal mesotheliomas in rats.

Tissue sections were examined from a 2-year bioassay of male Fischer 344 rats treated with potassium bromate administered in drinking water. All animals exhibiting peritoneal mesotheliomas also had mesotheliomas of the tunica vaginalis testis mesorchium (the reverse was not true), and the correlation of these 2 types of mesotheliomas was highly significant (r2 = 0.98). Mapping of the tunica vaginalis tumors at all time points and at all bromate concentrations revealed a pattern of increasing incidence of tumor formation on the mesothelium of the tunica vaginalis testis as a function of proximity to the mesorchial ligament. Thus, the mesorchium appears to be the major mesothelial target site for potassium bromate-mediated carcinogenesis. The frequency of occurrence of mesotheliomas by location was tunica vaginalis testis (25%), mesosplenium (20%), mesentery (10%), mesojejunum/mesocolon (8%), bladder (6.5%), mesogastrium (13%), liver serosa (5%), and kidney, small intestine, and rectum (1% each). A complete cross-section of the rat testis was prepared and used to construct a complete map of the mesothelium. Any attempt to determine the role of local dose and tissue susceptibility for the purpose of interspecies risk extrapolation must take into account the complex anatomy and physiology of this region of the visceral and testicular suspensory apparatus. Improved histologic approaches are needed for adequate assessment of this delicate suspensory system.

Morphologic analysis correlates with gene expression changes in cultured F344 rat mesothelial cells.

The gene expression pattern of mesothelial cells in vitro was determined after 4 or 12 h exposure to the rat mesothelial, kidney, and thyroid carcinogen and oxidative stressor potassium bromate (KBrO(3)). Gene expression changes observed using cDNA arrays indicated oxidative stress, mitotic arrest, and apoptosis in treated immortalized rat peritoneal mesothelial cells. Increases occurred in oxidative stress responsive genes HO-1, QR, HSP70, GADD45, GADD153, p21(WAF1/CIP16), GST's, GAPDH, TPX, and GPX-1(0); transcriptional regulators c-jun, c-fos, jun B, c-myc, and IkappaB; protein repair components Rdelta, RC10-II, C3, RC-7, HR6B ubiquitin-conjugating enzyme and ubiquitin; DNA repair components PCNA, msh2, and O-6 methylguanine DNA methyltransferase; lipid peroxide excision enzyme PLA2; and apoptogenic components TNFalpha, iNOS1 and FasL. Decreases occurred in bcl-2 (antiapoptotic), bax alpha, bad, and bok (proapoptotic) and cell cycle control elements (cyclins). Cyclin G and p14ink4b (which inhibit entry into cell cycle) were increased. Numerous signal transduction, cell membrane transport, membrane-associated receptor, and fatty acid biosynthesis and repair components were altered. Morphologic endpoints examined were number of mitotic figures, number of apoptotic cells, and antibody-specific localization of HO-1 (which demonstrated increased HO-1 protein expression). PCR analysis confirmed HO-1, p21(waf1/cip1), HSP70, GPX1, GADD45, QR, mdr1, PGHS, and cyclin D1 changes. A model for KBrO(3)-induced carcinogenicity in the F344 rat mesothelium is proposed, whereby KBrO(3) generates a redox signal that activates p53 and results in transcriptional activation of oxidative stress and repair genes, dysregulation of growth control, and imperfect DNA repair leading to carcinogenesis.

The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction.

AIMS/HYPOTHESIS: Although retinoid X receptor (RXR) and peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have antidiabetic effects in hyperinsulinaemic animals, little information exists on their effects after pancreatic beta-cell failure. Thus, we examined if RXR and PPARgamma agonists alter distinct metabolic pathways in animals suffering from impaired insulin secretion. METHODS: Adverse side effects and antidiabetic responses were measured in db/db mice treated from 14-16 weeks of age with the RXR agonist, LG100268, and/or the PPARgamma agonists, BRL49653 or GW1929. RESULTS: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent. Both of these agonists were equally effective at increasing insulin accumulation in beta cells, although neither agent had an effect on serum insulin concentrations. In contrast, the RXR agonist was less effective than the PPARgamma agonists at lowering serum triglycerides and non-esterified fatty acids and increasing interscapular brown fat and body weight. Further, LG100268 increased serum alkaline phosphatase and liver mass, hepatic fat accumulation, lauric acid hydroxylase activity, catalase-immunostaining and peroxisomal number more than the PPARgamma agonists. Moreover, co-treatment with the RXR and PPARgamma agonists reduced glucose, triglycerides, non-esterified fatty acids and cholesterol more than either agent alone. CONCLUSION/INTERPRETATION: These data suggest 1) RXR and PPARgamma agonists decrease islet degeneration, cardiovascular risk and cachexia during later stages of diabetes, 2) RXR agonists are less effective than PPARgamma agonists at decreasing serum lipids and causing weight gain and 3) RXR agonists have a more pronounced effect on liver metabolism (e.g. peroxisome accumulation and hepatomegaly) than PPARgamma agonists.