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Wells, P.G.; Bhuller, Y.; Chen, C.S.; Jeng, W.; Kasapinovic, S.; Kennedy, J.C.; Kim, P.M.; Laposa, R.R.; McCallum, G.P.; Nicol, C.J.; Parman, T.; Wiley, M.J.; Wong, A.W. |
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Title |
Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species |
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Journal Article |
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Year |
2005 |
Publication |
Toxicology and applied pharmacology |
Abbreviated Journal |
Toxicol Appl Pharmacol |
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207 |
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2 Suppl |
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354-366 |
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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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Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada |
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English |
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0041-008X |
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PMID:16081118 |
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refbase @ user @ |
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68 |
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Abeyesinghe, S.M.; Nicol, C.J.; Hartnell, S.J.; Wathes, C.M. |
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Can domestic fowl, Gallus gallus domesticus, show self-control? |
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Journal Article |
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Year |
2005 |
Publication |
Animal Behaviour. |
Abbreviated Journal |
Anim. Behav. |
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70 |
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1 |
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1-11 |
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An important aspect of cognition is whether animals live exclusively in the present or can anticipate the future. Defined as self-control, the ability to choose a large, remote reinforcer over a small, proximate reinforcer available at the same frequency has been examined in a number of species, often proving difficult to demonstrate. We investigated self-control for food in domestic fowl using a standard two-key operant task and an equivalent two-choice return maze (TCRM) task. When hens chose between a 2-s delay to a 3-s feed access (impulsive) and a 6-s delay to a 7-s feed access (self-control), they appeared unable to discriminate in the TCRM but were impulsive in the operant task. We explored reasons for not choosing self-control in the operant task, first by examining the relation between feed access time and actual feed intake. A second operant experiment examined whether failure to show self-control could be attributed to an inability to combine the delay and access (quantity) reward information associated with choices to reach overall predictions of value. New hens chose between a 2-s delay to a 3-s feed access (impulsive) and either a 22-s delay to a 22-s feed access (standard self-control) or a 6-s delay to a 22-s feed access (jackpot self-control). While hens were impulsive in the standard condition, they showed significant and pronounced self-control in the jackpot condition, eliminating the possibility of an absolute cognitive constraint. Impulsive behaviour can instead be explained by temporal discounting: perceived depreciation of reward value as a function of the uncertainty associated with delay. Implications for welfare are discussed. |
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Equine Behaviour @ team @ |
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