title: Prenatal ethanol exposure causes glucose intolerance with increased hepatic gluconeogenesis and histone deacetylases in adult rat offspring: reversal by tauroursodeoxycholic acid.
abstract: Prenatal ethanol exposure results in increased glucose production in adult rat offspring and this may involve modulation of protein acetylation by cellular stress. We used adult male offspring of dams given ethanol during gestation days 1-7 (early), 8-14 (mid) and 15-21 (late) compared with those from control dams. A group of ethanol offspring was treated with tauroursodeoxycholic acid (TUDCA) for 3 weeks. We determined gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, hepatic free radicals, histone deacetylases (HDAC), acetylated foxo1, acetylated PEPCK, and C/EBP homologous protein as a marker of endoplasmic reticulum stress. Prenatal ethanol during either of the 3 weeks of pregnancy increased gluconeogenesis, gluconeogenic genes, oxidative and endoplasmic reticulum stresses, sirtuin-2 and HDAC3, 4, 5, and 7 in adult offspring. Conversely, prenatal ethanol reduced acetylation of foxo1 and PEPCK. Treatment of adult ethanol offspring with TUDCA reversed all these abnormalities. Thus, prenatal exposure of rats to ethanol results in long lasting oxidative and endoplasmic reticulum stresses explaining increased expression of gluconeogenic genes and HDAC proteins which, by deacetylating foxo1 and PEPCK, contribute to increased gluconeogenesis. These anomalies occurred regardless of the time of ethanol exposure during pregnancy, including early embryogenesis. As these anomalies were reversed by treatment of the adult offspring with TUDCA, this compound has therapeutic potentials in the treatment of glucose intolerance associated with prenatal ethanol exposure.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Xing-Hai
authors.initials: XH
authors.lastname: Yao
authors.forename: Hoa K
authors.initials: HK
authors.lastname: Nguyen
authors.forename: B L Grégoire
authors.initials: BL
authors.lastname: Nyomba
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000375:Aging / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D051858:Forkhead Transcription Factors; D005609:Free Radicals / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D018149:Glucose Intolerance / Q000097:blood / Q000201:enzymology / Q000473:pathology*; D005951:Glucose Tolerance Test; D006655:Histone Deacetylases / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1
chemical_list: D001786:Blood Glucose; D000431:Ethanol; D051858:Forkhead Transcription Factors; D005609:Free Radicals; D006655:Histone Deacetylases; D007328:Insulin; D009419:Nerve Tissue Proteins; D013655:Taurochenodeoxycholic Acid; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C031655:ursodoxicoltaurine
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