No description available.

No description available.

No description available.

No description available.

Oxidative stress and reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which is detoxified by catalase, are implicated in fetal death and birth defects, but embryonic levels of catalase are only about 5% of adult activity, and its protective role is unknown. Our approach involved the use of mice genetically modified to either: (1) express low levels of endogenous catalase (acatalasemic, aCat); or, (2) express human catalase resulting in elevated levels of embryonic catalase activity (hCat). Using these mouse models we investigated the protective importance of constitutive embryonic catalase against endogenous ROS and the ROS-initiating teratogen phenytoin in embryo culture and in vivo. We hypothesized that aCat mice would be more sensitive to endogenous embryonic and phenytoin-enhanced ROS production, while hCat embryos would be less sensitive. aCat and hCat embryos respectively exhibited reduced and enhanced catalase activity compared to wild-type (WT) controls, with conversely enhanced and reduced spontaneous and phenytoin-enhanced embryopathies and DNA oxidation. Among aCat embryos exposed to phenytoin, embryopathies increased with decreasing catalase activity, and were completely blocked by addition of exogenous catalase. The alterations in phenytoin embryopathies were not due to pharmacokinetic differences, as drug concentrations in maternal and fetal tissues were similar among all strains. However, phenytoin concentrations in fetal brain exceeded those in fetal liver or maternal tissues, which may explain the predominance of cognitive deficits over structural birth defects in children exposed in utero to phenytoin. Similarly in untreated aged mice (about 18 months), female aCat mice showed a substantial loss in motor coordination compared to WT controls in the rotarod test. Following in utero exposure to phenytoin, the effect of altered embryonic catalase activity on postnatal neurodevelopment was assessed by several pre- and post-weaning tests. Catalase deficiency (aCat), independent of drug treatment, reduced performance in surface righting, negative geotaxis tests and rotarod tests. Conversely, high catalase expression (hCat) enhanced performance in the surface righting, negative geotaxis, air righting and rotarod tests. Our results provide the first evidence that the quantitatively minor amounts of antioxidative enzymes like catalase in the embryo and fetus provide important protection against the molecular damage and adverse fetal effects caused by developmental and drug-enhanced oxidative stress. Accordingly, interindividual variation in embryonic/fetal activities of catalase, and possibly other antioxidative enzymes, likely constitute an important determinant of risk for adverse developmental outcomes.

Oxidative stress and reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which is detoxified by catalase, are implicated in fetal death and birth defects, but embryonic levels of catalase are only about 5% of adult activity, and its protective role is unknown. Our approach involved the use of mice genetically modified to either: (1) express low levels of endogenous catalase (acatalasemic, aCat); or, (2) express human catalase resulting in elevated levels of embryonic catalase activity (hCat). Using these mouse models we investigated the protective importance of constitutive embryonic catalase against endogenous ROS and the ROS-initiating teratogen phenytoin in embryo culture and in vivo. We hypothesized that aCat mice would be more sensitive to endogenous embryonic and phenytoin-enhanced ROS production, while hCat embryos would be less sensitive. aCat and hCat embryos respectively exhibited reduced and enhanced catalase activity compared to wild-type (WT) controls, with conversely enhanced and reduced spontaneous and phenytoin-enhanced embryopathies and DNA oxidation. Among aCat embryos exposed to phenytoin, embryopathies increased with decreasing catalase activity, and were completely blocked by addition of exogenous catalase. The alterations in phenytoin embryopathies were not due to pharmacokinetic differences, as drug concentrations in maternal and fetal tissues were similar among all strains. However, phenytoin concentrations in fetal brain exceeded those in fetal liver or maternal tissues, which may explain the predominance of cognitive deficits over structural birth defects in children exposed in utero to phenytoin. Similarly in untreated aged mice (about 18 months), female aCat mice showed a substantial loss in motor coordination compared to WT controls in the rotarod test. Following in utero exposure to phenytoin, the effect of altered embryonic catalase activity on postnatal neurodevelopment was assessed by several pre- and post-weaning tests. Catalase deficiency (aCat), independent of drug treatment, reduced performance in surface righting, negative geotaxis tests and rotarod tests. Conversely, high catalase expression (hCat) enhanced performance in the surface righting, negative geotaxis, air righting and rotarod tests. Our results provide the first evidence that the quantitatively minor amounts of antioxidative enzymes like catalase in the embryo and fetus provide important protection against the molecular damage and adverse fetal effects caused by developmental and drug-enhanced oxidative stress. Accordingly, interindividual variation in embryonic/fetal activities of catalase, and possibly other antioxidative enzymes, likely constitute an important determinant of risk for adverse developmental outcomes.

No description available.

No description available.

Thesis (Ph. D.)--Cornell University, August, 2006. / Vita. Includes bibliographical references (leaves 182-204).

Down syndrome (DS), or trisomy 21 (Ts21), is the most common genetic developmental disorder with a prevalence of about one in 700 live births. The triplication of human chromosome 21 (Hsa21) that characterizes this disorder results in a constellation of cognitive and physical alterations. The cognitive deficits range from mild to severe, and persist throughout life. Post-mortem studies of individuals with DS have revealed various neuropathologic abnormalities that are thought to underlie cognitive dysfunction, including: disruption of neurogenesis, corticogenesis, synapse formation, and myelination. However, the etiology of these alterations remains largely unknown. In order to elucidate the genetic basis of DS-phenotypes, several mouse models have been developed. The Ts65Dn, Ts1Cje, and Ts16 models, recapitulate DS-related phenotypes and have extended our knowledge of the associated pathological changes. Despite this progress, genetic dissimilarities in mouse models may confound phenotypic comparisons between mouse models and human DS. Specifically, the aforementioned models have a limited subset of triplicated Hsa-21 homologs or contain non-syntenic genes. Recently, a novel mouse model, the Dp(16)1Yey/+ (or Dp16), that has the entire Hsa-21 syntenic region of Mmu16 triplicated and no non-syntenic genes has been developed, suggesting that Dp16 may present phenotypes more closely matching the human disorder. In this study, we present the first comprehensive analysis of Dp16 embryonic, young and adult brains that includes a focus on the proliferative, inhibitory/excitatory neuronal and oligodendrocyte-lineage phenotypes using histological, immunohistochemical, and behavioral assessments. We hypothesize that due to the larger triplicated segment, the Dp16 mouse model better recapitulates DS-related neuropathologies relative to other mouse models. Despite the extended triplication, Dp16 animals lack DS-related embryonic phenotypes, however, behavioral and cellular phenotypes arise during the 2nd week following birth. The Dp16 is the first model of DS to develop postnatal phenotypes in the absence of changes to embryonic brain development, as such, Dp16 may not be a reliable model to further understand brain development in the DS fetus. However, when used in conjuncture with other models, the Dp16 will be a useful tool in understanding the contribution of aneuploidy and gene dosage to DS-phenotypes in mouse models of DS.