title: Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs.
abstract: Fetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures including volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups - heavy binge alcohol (HBA; 2.5 g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5 g/kg/treatment ethanol and 10 mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10 mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ∼280 mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4-41; choline was administered on GD 4-148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures.
authors: Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA.
authors: Sharla M
authors: SM
authors: Birch
authors: Texas A&M Institute for Preclinical Studies (TIPS), Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA.
authors: Mark W
authors: MW
authors: Lenox
authors: Department of Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA; Texas A&M Institute for Preclinical Studies (TIPS), Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA; Department of Veterinary Integrative Biosciences, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA.
authors: Joe N
authors: JN
authors: Kornegay
authors: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Beatriz
authors: B
authors: Paniagua
authors: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Martin A
authors: MA
authors: Styner
authors: Stark Neurosciences Research Institute, IU School of Medicine, Indianapolis, IN 46202, USA; Department of Psychology, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA.
authors: Charles R
authors: CR
authors: Goodlett
authors: Department of Physiology and Pharmacology, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA.
authors: Tim A
authors: TA
authors: Cudd
authors: Department of Physiology and Pharmacology, Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX 77843, USA. Electronic address: swashburn@cvm.tamu.edu.
authors: Shannon E
authors: SE
authors: Washburn
mesh_terms: D000367:Age Factors; D000818:Animals; D063425:Binge Drinking / Q000188:drug therapy / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002794:Choline / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology* / Q000517:prevention & control; D011897:Random Allocation; D012756:Sheep
chemical_list: D018696:Neuroprotective Agents; D002794:Choline
keywords: Choline; Diagnosis; FASD; Magnetic resonance imaging; Prenatal alcohol; Volumetrics