Hindbrain and cranial nerve dysmorphogenesis result from acute maternal ethanol administration.
Acute exposure of mouse embryos to ethanol during stages of hindbrain segmentation results in excessive cell death in specific cell populations. This study details the ethanol-induced cell loss and defines the subsequent effects of this early insult on rhombomere and cranial nerve development. Ethanol at a teratogenic dosage (2.9 g/kg) or a comparable volume of vehicle was administered in each of two intraperitoneal injections to pregnant C57BL/6J mice on gestational day (GD) 8, 8 h, and GD 8, 12 h (defined hereafter as GD 8.5). Ethanol-exposed GD 9 embryos, visualized in three dimensions using laser scanning confocal microscopy of LysoTracker Red fluorescence or Nile blue sulphate vital staining, displayed excessive apoptosis in the rostral hindbrain, specifically within rhombomeres 1-3, as well as in cranial neural crest cells and ectodermal placodes. Comparably treated embryos examined on GD 10.5-11 illustrated a disproportionate reduction in the length of the rostral hindbrain. Examination of plastic histological sections of GD 9 embryos and via scanning electron microscopy on GD 10 revealed deficiencies in the hindbrain, with a phenotype including abnormal rhombomere segmentation and an extremely small fourth ventricular roofplate. Whole-mount antineurofilament immunohistochemistry on GD 10.5 and GD 11 illustrated a variety of cranial nerve abnormalities ranging from fused or absent ganglia to ectopic or disorganized fibers. In addition, a delay in the development of the glossopharyngeal (IX) nerve/ganglia complex was observed. These hindbrain and cranial nerve abnormalities are discussed in the context of the genesis of human alcohol-related birth defects and neurodevelopmental disorder.
Dunty
William C
WC
Department of Cell and Developmental Biology and the Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, NC 27599-7090, USA.
Zucker
Robert M
RM
Sulik
Kathleen K
KK
D020268:Alcohol-Induced Disorders, Nervous System / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D003391:Cranial Nerves / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D016900:Neurofilament Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012249:Rhombencephalon / Q000002:abnormalities / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors
D016900:Neurofilament Proteins; D000431:Ethanol