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Dixon, G., Green, L. E., & Nicol, C. J. (2006). Effect of diet change on the behavior of chicks of an egg-laying strain. J Appl Anim Welf Sci, 9(1), 41–58.
Abstract: Injurious pecking has serious welfare consequences in flocks of hens kept for egg laying, especially when loose-housed. Frequent diet change is a significant risk for injurious pecking; how the mechanics of diet change influence pecking behavior is unknown. This study investigated the effect of diet change on the behavior of chicks from a laying strain. The study included a 3-week familiarity phase: 18 chick pairs received unflavored feed (Experiment 1); 18 pairs received orange oil-flavored (Experiment 2). All chicks participated in a dietary preference test (P); a diet change (DC); or a control group (C), 6 scenarios. All P chicks preferred unflavored feed. In Experiment 1, DC involved change from unflavored to orange-flavored; Experiment 2, orange- flavored to unflavored. Compared with controls, Experiment 2 DC chicks exhibited few behavioral differences; Experiment 1 DC chicks exhibited increased behavioral event rates on Days 1 and 7. They pecked significantly longer at their environment; by Day 7, they showed significantly more beak activity. There was little evidence of dietary neophobia. Change from more preferred to less preferred feed led to increased activity and redirected pecking behavior.
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Nicol, C. J., Brown, S. N., Glen, E., Pope, S. J., Short, F. J., Warriss, P. D., et al. (2006). Effects of stocking density, flock size and management on the welfare of laying hens in single-tier aviaries. Br Poult Sci, 47(2), 135–146.
Abstract: Management practices, stocking rate and flock size may affect laying hen welfare but there have been few replicated studies in commercial non-cage systems that investigate this. This study used a broad range of physical and physiological indicators to assess the welfare of hens in 36 commercial flocks. Six laying period treatments were examined with each treatment replicated 6 times. It was not possible to randomly allocate treatments to houses, so treatment and house were largely confounded. Three stocking rates were compared: 7 birds/m(2) (n = 2450), 9 birds/m(2) (n = 3150) and 12 birds/m(2) in either small (n = 2450) or large (n = 4200) flocks. In addition, at 12 birds/m(2), in both small and large flocks, birds were subjected to either standard (SM) or modified (MM) management. MM flocks had nipple drinkers and no nest-box lights. Bone strength, fracture incidence, heterophil:lymphocyte (H:L) ratio, live weight, organ weights, serum creatine, serum osmolality, muscle pH and faecal corticosterone were measured on samples of birds at the end of the rearing period and at the end of lay. During the laying period, mortality, production and integument condition were recorded at regular intervals. Birds housed at 9 birds/m(2) had higher mortality than birds housed at 12 birds/m(2) by the end of lay, but not higher than birds housed at 7 birds/m(2). Birds housed at 7 and 9 birds/m(2) had lower percent liver weight, and worse plumage condition than most of the 12 bird/m(2) treatments. Modified management tended to improve plumage condition. There were no clear effects of flock size on the welfare indicators recorded. At the end of the rearing period fracture incidence was almost negligible and H:L ratio was within a normal range. By the end of lay fracture incidence was 60% and H:L ratio was high, with no treatment effect for either measure. This, together with information on faecal corticosterone, feather loss and mortality, suggests that the welfare of birds in all treatments was relatively poor by the end of lay.
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Haslam, S. M., Brown, S. N., Wilkins, L. J., Kestin, S. C., Warriss, P. D., & Nicol, C. J. (2006). Preliminary study to examine the utility of using foot burn or hock burn to assess aspects of housing conditions for broiler chicken. Br Poult Sci, 47(1), 13–18.
Abstract: 1. Eleven broiler chicken farms, representing 4 production system types, were visited during the last 5 d of the flock cycle: bird and flock details were recorded. Litter friability was assessed at 9 sites within the house, atmospheric ammonia was measured at three sites and bird cleanliness was assessed on a numerical rating scale. 2. For these flocks, hock burn, foot burn and breast burn were measured at the processing plant by standardised assessors. 3. Significant correlations were identified between the percentage of birds with foot burn and average litter score, average house ammonia concentrations and feather score. 4. No correlation was found between the percentage of birds with hock burn or breast burn and average litter scores, average ammonia concentrations or feather score. 5. No correlation was found between stocking density and foot burn, hock burn or breast burn.6. If confirmed, these findings may have implications for the draft EU Broiler Directive, for which it is proposed that permitted stocking density on farm may be determined by the incidence and severity of contact dermatitis measured on plant.
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Wells, P. G., Bhuller, Y., Chen, C. S., Jeng, W., Kasapinovic, S., Kennedy, J. C., et al. (2005). Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicol Appl Pharmacol, 207(2 Suppl), 354–366.
Abstract: Developmental pathologies may result from endogenous or xenobiotic-enhanced formation of reactive oxygen species (ROS), which oxidatively damage cellular macromolecules and/or alter signal transduction. This minireview focuses upon several model drugs (phenytoin, thalidomide, methamphetamine), environmental chemicals (benzo[a]pyrene) and gamma irradiation to examine this hypothesis in vivo and in embryo culture using mouse, rat and rabbit models. Embryonic prostaglandin H synthases (PHSs) and lipoxygenases bioactivate xenobiotics to free radical intermediates that initiate ROS formation, resulting in oxidation of proteins, lipids and DNA. Oxidative DNA damage and embryopathies are reduced in PHS knockout mice, and in mice treated with PHS inhibitors, antioxidative enzymes, antioxidants and free radical trapping agents. Thalidomide causes embryonic DNA oxidation in susceptible (rabbit) but not resistant (mouse) species. Embryopathies are increased in mutant mice deficient in the antioxidative enzyme glucose-6-phosphate dehydrogenase (G6PD), or by glutathione (GSH) depletion, or inhibition of GSH peroxidase or GSH reductase. Inducible nitric oxide synthase knockout mice are partially protected. Inhibition of Ras or NF-kB pathways reduces embryopathies, implicating ROS-mediated signal transduction. Atm and p53 knockout mice deficient in DNA damage response/repair are more susceptible to xenobiotic or radiation embryopathies, suggesting a teratological role for DNA damage, consistent with enhanced susceptibility to methamphetamine in ogg1 knockout mice with deficient repair of oxidative DNA damage. Even endogenous embryonic oxidative stress carries a risk, since untreated G6PD- or ATM-deficient mice have increased embryopathies. Thus, embryonic processes regulating the balance of ROS formation, oxidative DNA damage and repair, and ROS-mediated signal transduction may be important determinants of teratological risk.
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Nicol, C. J., Adachi, M., Akiyama, T. E., & Gonzalez, F. J. (2005). PPARgamma in endothelial cells influences high fat diet-induced hypertension. Am J Hypertens, 18(4 Pt 1), 549–556.
Abstract: BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands improve human hypertension. However, the mechanism and site of this effect remains unknown, confounded by PPARgamma expression in many cell types, including endothelial cells (ECs). METHODS: To evaluate the vascular role of PPARgamma we used a conditional null mouse model. Specific disruption of PPARgamma in ECs was created by crossing Tie2-Cre+ transgenic (T2T+) and PPARgamma-floxed (fl/fl) mice to generate PPARgamma (fl/fl)T2T+ (PPARgamma E-null) mice. Conscious 8- to 12-week-old congenic PPARgamma (fl/fl)Cre- (wild type) and PPARgamma E-null mice were examined for changes in systolic blood pressure (BP) and heart rate (HR), untreated, after 2 months of salt-loading (drinking water), and after treatment for 3 months with high fat (HF) diet alone or supplemented during the last 2 weeks with rosiglitazone (3 mg/kg/d). RESULTS: Untreated PPARgamma E-nulls were phenotypically indistinguishable from wild-type littermates. However, compared to similarly treated wild types, HF-treated PPARgamma E-nulls had significantly elevated systolic BP not seen after normal diet or salt-loading. Despite sex-dependent baseline differences, salt-loaded and HF-treated PPARgamma E-nulls of either sex had significantly elevated HR versus wild types. Interestingly, rosiglitazone improved serum insulin levels, but not HF diet-induced hypertension, in PPARgamma E-null mice. CONCLUSIONS: These results suggest that PPARgamma in ECs not only is an important regulator of hypertension and HR under stressed conditions mimicking those arising in type 2 diabetics, but also mediates the antihypertensive effects of rosiglitazone. These data add evidence supporting a beneficial role for PPARgamma-specific ligands in the treatment of hypertension, and suggest therapeutic strategies targeting ECs may prove useful.
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Wilkins, L. J., Brown, S. N., Zimmerman, P. H., Leeb, C., & Nicol, C. J. (2004). Investigation of palpation as a method for determining the prevalence of keel and furculum damage in laying hens. Vet. Rec., 155(18), 547–549.
Abstract: Old breaks of the keel and furculum were identified by palpation in 500 end-of-lay hens from 10 flocks housed in free-range and barn systems, and the results were compared with the results obtained by a full dissection and inspection. The method was considered to be sufficiently precise to be used as a diagnostic tool although people using it would need to be trained. The results obtained by dissection indicated that 50 to 78 per cent of the birds in the flocks had breaks of the furculum and keel, but no other breaks of bones were detected.
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Guo, G. L., Moffit, J. S., Nicol, C. J., Ward, J. M., Aleksunes, L. A., Slitt, A. L., et al. (2004). Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci, 82(2), 374–380.
Abstract: The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16alpha-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation.
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Jeong, S., Han, M., Lee, H., Kim, M., Kim, J., Nicol, C. J., et al. (2004). Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. Metabolism, 53(10), 1284–1289.
Abstract: Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARalpha target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice.
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Crosby, M. B., Svenson, J. L., Zhang, J., Nicol, C. J., Gonzalez, F. J., & Gilkeson, G. S. (2005). Peroxisome proliferation-activated receptor (PPAR)gamma is not necessary for synthetic PPARgamma agonist inhibition of inducible nitric-oxide synthase and nitric oxide. J Pharmacol Exp Ther, 312(1), 69–76.
Abstract: Peroxisome proliferation-activated receptor (PPAR)gamma agonists inhibit inducible nitric-oxide synthase (iNOS), tumor necrosis factor-alpha, and interleukin-6. Because of these effects, synthetic PPARgamma agonists, including thiazolidinediones, are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPARgamma agonists range from 10 to 50 microM, whereas their binding affinity for PPARgamma is in the nanomolar range. The specificity of synthetic PPARgamma agonists for PPARgamma at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPARgamma is not necessary for the inhibition of iNOS by synthetic PPARgamma agonists. RAW 264.7 macrophages possess little PPARgamma, yet lipopolysaccharide (LPS)/interferon (IFN)gamma-induced iNOS was inhibited by synthetic PPARgamma agonists at 20 microM. Endogenous PPARgamma was inhibited by the transfection of a dominant-negative PPARgamma construct into murine mesangial cells. In the transfected cells, synthetic PPARgamma agonists inhibited iNOS production at 10 microM, similar to nontransfected cells. Using cells from PPARgamma Cre/lox conditional knockout mice, baseline and LPS/IFNgamma-induced nitric oxide levels were higher in macrophages lacking PPARgamma versus controls. However, synthetic PPARgamma agonists inhibited iNOS at 10 microM in the PPARgamma-deficient cells, similar to macrophages from wild-type mice. These results indicate that PPARgamma is not necessary for inhibition of iNOS expression by synthetic PPARgamma agonists at concentrations over 10 microM. Intrinsic PPARgamma function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation.
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Cheung, C., Akiyama, T. E., Ward, J. M., Nicol, C. J., Feigenbaum, L., Vinson, C., et al. (2004). Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res, 64(11), 3849–3854.
Abstract: Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.
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