The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Louise M. Winn - One of the best experts on this subject based on the ideXlab platform.
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Characterizing the effects of in utero valproic acid exposure on NF-κB signaling in CD-1 Mouse embryos during neural tube closure.
Neurotoxicology and teratology, 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Abstract Nuclear factor kappa B (NF-κB) is a heterodimer of protein subunits p65 and p50, that regulates the expression of a large number of genes related to cell growth and proliferation. The p65 subunit is activated after phosphorylation by Pim-1, while the p50 subunit is the cleaved product of its precursor molecule p105. Valproic acid (VPA), an antiepileptic drug, is a known teratogen and its exposure during pregnancy is associated with 1–2% of neural tube defects in the offspring. The current study aimed at investigating the effects of in utero VPA exposure on the key components of the NF-κB signaling pathway including p65, p50, and Pim-1 in CD-1 Mouse embryos during the critical period of neural tube closure. Here we report that p65, Pim-1 and p105/p50 mRNA were significantly (p
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Role of Cbp, p300 and Akt in valproic acid induced neural tube defects in CD-1 Mouse embryos.
Reproductive toxicology (Elmsford N.Y.), 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1-2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 Mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.
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Gestational exposure to valproic acid upregulates total Stat3 protein expression while downregulating phosphorylated Stat3 in CD‐1 Mouse embryos with neural tube defects
Birth defects research, 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Valproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for psychiatric disorders, is teratogenic causing neural tube defects (NTDs) and other defects in the exposed embryo. Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is activated via tyrosine phosphorylation. Stat3, as well as its active form (pYStat3), is expressed during neural tube closure in murine development. This study investigated the effects of in utero VPA exposure on embryonic Stat3 mRNA and protein expression during the critical period of neural tube closure in CD-1 Mouse embryos. Following the exposure of CD-1 pregnant mice to the teratogenic dose of 400 mg/kg VPA or saline on gestational day (GD) 9, embryos were harvested at 1, 3, 6, or 24 hr and on GD13. Stat3 mRNA levels remained unchanged at all time points. Total Stat3 protein levels were significantly (p < .05) increased in GD9 embryos at 1 and 6 hr post-exposure and in GD13 exposed nonexencephalic and exencephalic embryo heads. In contrast, phosphorylated Stat3 levels were significantly (p < .05) downregulated in GD9 embryos at the 3 and 6 hr time points with an overall trend of downregulation in the GD10 and GD13 groups. Total and phosphorylated Stat3 protein levels remained unchanged in nuclear extracts of the exposed nonexencephalic and exencephalic GD13 embryo heads. The reported significant downregulation of phosphorylated Stat3 levels suggests its possible role in VPA-induced NTDs in Mouse embryos.
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Benzoquinone toxicity is not prevented by sulforaphane in CD‐1 Mouse fetal liver cells
Journal of applied toxicology : JAT, 2015Co-Authors: Nicola A. Philbrook, Louise M. WinnAbstract:Benzene is an environmental pollutant known to cause leukemia in adults, and may be associated with childhood leukemia. While the mechanisms of benzene-mediated carcinogenicity have not been fully elucidated, increased reactive oxygen species (ROS) and DNA damage are implicated. Sulforaphane (SFN) induces nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to SFN-mediated protection against carcinogenesis. We exposed cultured CD-1 Mouse fetal liver cells to the benzene metabolite, benzoquinone, to determine its potential to cause DNA damage and alter DNA repair. Cells were also exposed to SFN to determine potential protective effects. Initially, cells were exposed to benzoquinone to confirm increased ROS and SFN to confirm Nrf2 induction. Subsequently, cells were treated with benzoquinone (with or without SFN) and levels of ROS, 8-hydroxy-2-deoxyguanosine (8-OHdG; marker of oxidative DNA damage), gamma histone 2A variant X (γH2AX; marker of DNA double-stranded breaks; DSBs) and transcript levels of genes involved in DNA repair were measured. Benzoquinone exposure led to a significant increase in ROS, which was not prevented by pretreatment with SFN or the antioxidative enzyme, catalase. DNA damage was increased after benzoquinone exposure, which was not prevented by SFN. Benzoquinone exposure significantly decreased the transcript levels of the critical base excision repair gene, 8-oxoguanine glycosylase (Ogg1), which was not prevented by SFN. The findings of this study demonstrate for the first time that DNA damage and altered DNA repair are a consequence of benzoquinone exposure in CD-1 Mouse fetal liver cells and that SFN conferred little protection in this model. Copyright © 2015 John Wiley & Sons, Ltd.
D A Whitehouse - One of the best experts on this subject based on the ideXlab platform.
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Teratogenic effects of benomyl in the Wistar rat and CD-1 Mouse, with emphasis on the route of administration.
Toxicology and Applied Pharmacology, 2004Co-Authors: Robert J Kavlock, Neil Chernoff, Jacqueline A Gray, L. Earl Gray, D A WhitehouseAbstract:Abstract Benomyl, a systemic fungicide whose molecular basis of action is inhibition of tubulin polymerization, was administered during organogenesis via the dietary and gavage routes to pregnant Wistar rats, and via the gavage route to pregnant CD-1 mice. Benomyl was fetotoxic and teratogenic in both species via the po route of administration, producing a broad spectrum of malformations at a dose of 62.5 mg/kg/day in the rat and 100 mg/kg/day in the Mouse. Via the dietary route of administration, benomyl produced fetotoxicity, but no teratogenic effects. The fetotoxic potential of benomyl from dietary exposure was approximately an order of magnitude less effective than from gavage exposure. Benomyl did not affect postnatal growth, viability, or locomotor activity at subteratogenic doses. The most sensitive indicator of perinatal exposure to benomyl via the po route of administration was a permanent reduction in testes and accessory sex gland weight noted in male offspring of dams receiving 31.2 mg/kg/day benomyl during gestation and lactation. No effects on any parameters were evident in rats receiving 15.6 mg/kg/day by po gavage. The relevance of the two routes of administration for risk extrapolation is discussed.
Sidra Shafique - One of the best experts on this subject based on the ideXlab platform.
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Characterizing the effects of in utero valproic acid exposure on NF-κB signaling in CD-1 Mouse embryos during neural tube closure.
Neurotoxicology and teratology, 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Abstract Nuclear factor kappa B (NF-κB) is a heterodimer of protein subunits p65 and p50, that regulates the expression of a large number of genes related to cell growth and proliferation. The p65 subunit is activated after phosphorylation by Pim-1, while the p50 subunit is the cleaved product of its precursor molecule p105. Valproic acid (VPA), an antiepileptic drug, is a known teratogen and its exposure during pregnancy is associated with 1–2% of neural tube defects in the offspring. The current study aimed at investigating the effects of in utero VPA exposure on the key components of the NF-κB signaling pathway including p65, p50, and Pim-1 in CD-1 Mouse embryos during the critical period of neural tube closure. Here we report that p65, Pim-1 and p105/p50 mRNA were significantly (p
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Role of Cbp, p300 and Akt in valproic acid induced neural tube defects in CD-1 Mouse embryos.
Reproductive toxicology (Elmsford N.Y.), 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1-2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 Mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.
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Gestational exposure to valproic acid upregulates total Stat3 protein expression while downregulating phosphorylated Stat3 in CD‐1 Mouse embryos with neural tube defects
Birth defects research, 2020Co-Authors: Sidra Shafique, Louise M. WinnAbstract:Valproic acid (VPA), a widely prescribed antiepileptic drug and an effective treatment for psychiatric disorders, is teratogenic causing neural tube defects (NTDs) and other defects in the exposed embryo. Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that is activated via tyrosine phosphorylation. Stat3, as well as its active form (pYStat3), is expressed during neural tube closure in murine development. This study investigated the effects of in utero VPA exposure on embryonic Stat3 mRNA and protein expression during the critical period of neural tube closure in CD-1 Mouse embryos. Following the exposure of CD-1 pregnant mice to the teratogenic dose of 400 mg/kg VPA or saline on gestational day (GD) 9, embryos were harvested at 1, 3, 6, or 24 hr and on GD13. Stat3 mRNA levels remained unchanged at all time points. Total Stat3 protein levels were significantly (p < .05) increased in GD9 embryos at 1 and 6 hr post-exposure and in GD13 exposed nonexencephalic and exencephalic embryo heads. In contrast, phosphorylated Stat3 levels were significantly (p < .05) downregulated in GD9 embryos at the 3 and 6 hr time points with an overall trend of downregulation in the GD10 and GD13 groups. Total and phosphorylated Stat3 protein levels remained unchanged in nuclear extracts of the exposed nonexencephalic and exencephalic GD13 embryo heads. The reported significant downregulation of phosphorylated Stat3 levels suggests its possible role in VPA-induced NTDs in Mouse embryos.
Robert J Kavlock - One of the best experts on this subject based on the ideXlab platform.
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Teratogenic effects of benomyl in the Wistar rat and CD-1 Mouse, with emphasis on the route of administration.
Toxicology and Applied Pharmacology, 2004Co-Authors: Robert J Kavlock, Neil Chernoff, Jacqueline A Gray, L. Earl Gray, D A WhitehouseAbstract:Abstract Benomyl, a systemic fungicide whose molecular basis of action is inhibition of tubulin polymerization, was administered during organogenesis via the dietary and gavage routes to pregnant Wistar rats, and via the gavage route to pregnant CD-1 mice. Benomyl was fetotoxic and teratogenic in both species via the po route of administration, producing a broad spectrum of malformations at a dose of 62.5 mg/kg/day in the rat and 100 mg/kg/day in the Mouse. Via the dietary route of administration, benomyl produced fetotoxicity, but no teratogenic effects. The fetotoxic potential of benomyl from dietary exposure was approximately an order of magnitude less effective than from gavage exposure. Benomyl did not affect postnatal growth, viability, or locomotor activity at subteratogenic doses. The most sensitive indicator of perinatal exposure to benomyl via the po route of administration was a permanent reduction in testes and accessory sex gland weight noted in male offspring of dams receiving 31.2 mg/kg/day benomyl during gestation and lactation. No effects on any parameters were evident in rats receiving 15.6 mg/kg/day by po gavage. The relevance of the two routes of administration for risk extrapolation is discussed.
Richard E. Brown - One of the best experts on this subject based on the ideXlab platform.
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Effects of chronic and acute methylphenidate hydrochloride (Ritalin) administration on locomotor activity, ultrasonic vocalizations, and neuromotor development in 3- to 11-day-old CD-1 Mouse pups.
Developmental psychobiology, 2001Co-Authors: Marsha R. Penner, Melanie P. Mcfadyen, Normand Carrey, Richard E. BrownAbstract:The present study examined the effects of chronic and acute treatment with methylphenidate hydrochloride (Ritalin) on isolation-induced ultrasonic vocalizations, spontaneous locomotor activity, and neuromotor coordination in 3- to 11-day-old CD-1 Mouse pups. In Experiment 1, 3- to 11-day-old pups received daily injections of saline, 5 mg/kg or 20 mg/kg of methylphenidate hydrochloride, or no injection and were tested on postnatal Days 3, 5, 7, 9, and 11. Both doses of methylphenidate resulted in significant increases in locomotor activity at all ages, but had no significant effect on body weight, neuromotor development, or emission of ultrasonic vocalizations. In Experiment 2, pups were given a single dose of methylphenidate (5 or 20 mg/kg), saline, or no injection on one of postnatal Days 5, 7, 9, or 11. This acute methylphenidate treatment increased locomotor activity, but had no significant effects on ultrasonic vocalizations or neuromotor coordination. These results indicate that short-term, chronic methylphenidate treatment elevates locomotor responses, but has no immediate effects on anxietylike responses or on the development of neuromotor behavior of CD-1 mice in the first 11 days of life.