title: Chronic prenatal ethanol exposure alters expression of central and peripheral insulin signaling molecules in adult guinea pig offspring.
abstract: Maternal ethanol consumption during pregnancy can produce a range of teratogenic outcomes in offspring. The mechanism of ethanol teratogenicity is multi-faceted, but may involve alterations in insulin and insulin-like growth factor (IGF) signaling pathways. These pathways are not only important for metabolism, but are also critically involved in neuronal survival and plasticity, and they can be altered by chronic prenatal ethanol exposure (CPEE). The objective of this study was to test the hypothesis that CPEE alters expression of insulin and IGF signaling molecules in the prefrontal cortex and liver of adult guinea pig offspring. Pregnant Dunkin-Hartley-strain guinea pigs received ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (nutritional control) throughout gestation. Fasting blood glucose concentration was measured in male and female offspring at postnatal day 150-200, followed by euthanasia, collection of prefrontal cortex and liver, and RNA extraction. IGF-1, IGF-1 receptor (IGF-1R), IGF-2, IGF-2 receptor (IGF-2R), insulin receptor substrate (IRS)-1, IRS-2, and insulin receptor (INSR) mRNA expression levels were measured in tissues using quantitative real-time PCR. The mean maternal blood ethanol concentration was 281 ± 15 mg/dL at 1 h after the second divided dose of ethanol on GD 57. CPEE resulted in increased liver weight in adult offspring, but produced no difference in fasting blood glucose concentration compared with nutritional control. In the liver, CPEE decreased mRNA expression of IGF-1, IGF-1R, and IGF-2, and increased IRS-2 mRNA expression in male offspring only compared with nutritional control. Female CPEE offspring had decreased INSR hepatic mRNA expression compared with male CPEE offspring. In the prefrontal cortex, IRS-2 mRNA expression was increased in CPEE offspring compared with nutritional control. The data demonstrate that CPEE alters both central and peripheral expression of insulin and IGF signaling molecules at the mRNA level, which may be related to metabolic dysregulation in adult offspring. Furthermore, altered insulin and IGF signaling may be a mechanism of ethanol neurobehavioral teratogenicity.
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Dobson
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Kersh
authors.initials: K
authors.lastname: Thevasundaram
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mongillo
authors.affiliation: Office of the University Veterinarian, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: Andrew
authors.initials: A
authors.lastname: Winterborn
authors.affiliation: Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8S 4K1.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Holloway
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Kingston, ON, Canada K7L 3N6; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada K7L 3N6.
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.affiliation: Department of Biomedical and Molecular Sciences, Pharmacology and Toxicology Graduate Program, Queen's University, Kingston, ON, Canada K7L 3N6; Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada K7L 3N6. Electronic address: jnr@queensu.ca.
authors.forename: James N
authors.initials: JN
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000032:analysis; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D006168:Guinea Pigs; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D007335:Insulin-Like Growth Factor II / Q000032:analysis*; D008099:Liver / Q000737:chemistry; D008297:Male; D017397:Prefrontal Cortex / Q000737:chemistry; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000032:analysis*; D017527:Receptor, IGF Type 2 / Q000032:analysis*; D011972:Receptor, Insulin / Q000032:analysis*
chemical_list: D001786:Blood Glucose; D017527:Receptor, IGF Type 2; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Chronic prenatal ethanol exposure; Fetal Alcohol Spectrum Disorder; Insulin signaling; Metabolic syndrome