| Differential effects of chronic ethanol exposure on cytochrome P450 2E1 and the hypothalamic-pituitary-adrenal axis in the maternal-fetal unit of the guinea pig. | |
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MedLine Citation:
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PMID: 20006703 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Ethanol neurobehavioural teratogenicity is a leading cause of developmental mental deficiency, in which the hippocampus is a target site of injury. The multi-faceted mechanism of ethanol teratogenicity is not completely understood. This study tested the hypothesis that chronic ethanol exposure (CEE), via chronic maternal ethanol administration, increases cytochrome P450 2E1 (CYP2E1) expression and alters hypothalamic-pituitary-adrenal (HPA) axis activity in the maternal-fetal unit during the third-trimester-equivalent of gestation. METHODS: Pregnant Dunkin-Hartley-strain guinea pigs received daily oral administration of ethanol (4 g ethanol/kg maternal body weight) or isocaloric-sucrose/pair-feeding (control) throughout gestation (term, about gestational day (GD) 68). On GD 45, 55 and 65, pregnant animals were euthanized 2h after the last daily dose. Maternal and fetal body weights and fetal hippocampal brain weight were determined. Maternal and fetal samples were collected for the determination of liver CYP2E1 enzymatic activity and plasma free cortisol and ACTH concentrations. RESULTS: CEE, with maternal blood ethanol concentration of 108-124 mg/dl at 2h after the last dose, decreased fetal hippocampal weight only at GD 65 and had no effect on fetal body weight compared with control. CYP2E1 activity increased with gestational age in the fetal liver microsomal and mitochondrial fractions. CEE increased CYP2E1 activity in the microsomal and mitochondrial fractions of maternal liver at the three gestational ages and in both hepatic subcellular fractions of the GD 65 fetus compared with control. There was a gestational-age-dependent increase in maternal and fetal plasma free cortisol concentrations, but no effect of CEE compared with control. Maternal and fetal plasma ACTH concentrations were unaffected by CEE compared with control, and were virtually unchanged during the third-trimester-equivalent that was studied. CONCLUSION: These data demonstrate that, in the pregnant guinea pig, this CEE regimen increases liver CYP2E1 activity, without affecting HPA axis function, in the maternal-fetal unit during near-term gestation. The CEE-induced increase in liver CYP2E1 activity and potential oxidative stress in the maternal-fetal unit may play a role in the pathogenesis of ethanol teratogenicity. |
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Authors:
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Amy J Hewitt; Kevin R Walker; Susan M Kobus; Margo Poklewska-Koziell; James N Reynolds; James F Brien |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-16 |
Journal Detail:
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Title: Neurotoxicology and teratology Volume: 32 ISSN: 1872-9738 ISO Abbreviation: Neurotoxicol Teratol Publication Date: 2010 Mar-Apr |
Date Detail:
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Created Date: 2010-03-15 Completed Date: 2010-06-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8709538 Medline TA: Neurotoxicol Teratol Country: United States |
Other Details:
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Languages: eng Pagination: 164-70 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2009 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol-Induced Disorders, Nervous System
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metabolism*,
physiopathology Animals Child, Preschool Cognition Disorders / chemically induced*, physiopathology Cytochrome P-450 CYP2E1 / drug effects*, metabolism Developmental Disabilities / chemically induced, metabolism, physiopathology Disease Models, Animal Drug Administration Schedule Energy Metabolism / drug effects, physiology Female Fetal Alcohol Syndrome / metabolism*, physiopathology Guinea Pigs Humans Hypothalamo-Hypophyseal System / drug effects*, physiopathology Liver / drug effects, metabolism, physiopathology Microsomes, Liver / drug effects, metabolism Mitochondria / drug effects, metabolism Oxidative Stress / drug effects, physiology Pituitary-Adrenal System / drug effects*, physiopathology Pregnancy Prenatal Exposure Delayed Effects / metabolism, physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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MOP-81185//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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EC 1.14.14.1/Cytochrome P-450 CYP2E1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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