The objective of the proposed basic research is to make clinically-relevant discoveries regarding prenatal alcohol (ethanol) exposure-induced pathology involving the brain and face. This proposal builds naturally on our CIFASD-supported basic research to date and continues to address the need for a more complete understanding of the spectrum and exposure stage-dependency of abnormalities caused by maternal alcohol use. Utilizing a well-established FASD mouse model, along with innovative technologies and approaches, and addressing 3 Specific Aims, we propose to test the overall hypothesis that alcohol induces structural abnormalities of the brain and face in mice that are consistent with and informative for those in human FASD.
The Aim 1 studies compliment and extend the clinical research proposed by Drs. Foroud and Hammond. They employ Magnetic Resonance Imaging (MRI) and dense surface modeling (DSM) for experiments that are designed to identify exposure stage-dependent correlative abnormalities of the brain and face.
The Aim 2 studies compliment and extend the Sowell group's neuroimaging-based clinical studies while following up on preliminary findings of cerebro-cortical thickness alterations in our mouse model. For this, MRI-based assessments of regional brain volumes and cerebro-cortical thickness changes, along with DTI-based investigations of fiber tract and structural connectivity alterations in adult animals are proposed.
The Aim 3 studies are directed toward further defining the histopathology and genesis of early prenatal alcohol exposure- induced regional brain dysmorphology. They will employ routine histological methods, as well as immunohistochemistry, and stereology. Specimens selected for detailed histological analyses will include those postnatal brains that had previously been imaged and analyzed for Aim 2. Additional Aim 3 studies will focus on prenatal stages and will address the novel concept that early alcohol insult yields changes in Cajal-Retzius cell populations;changes that underlie subsequent cerebro-cortical lamination defects. The proposed work is consistent with the overall purpose/goals of the CIFASD in that it will facilitate diagnosis of the full range of birth defects associated with prenatal alcohol exposure, and it will aid in elucidating biological mechanisms that contribute to alcohol teratogenesis. The results of the proposed studies promise to fill a significant FASD research void, inform human clinical research, and continue to highlight the first trimester as a critical period for alcohol-induced defects of the face and brain.

Public Health Relevance

Fetal Alcohol Spectrum Disorder (FASD) remains a major public health problem. The proposed research employs a well-established mouse model to answer FASD-related questions that are impossible to address in clinical studies. Focusing on stage of exposure-dependent facial and brain abnormalities, the results of this work promise to expand our understanding of the temporal dependence, interrelatedness, and mechanisms underlying birth defects that result from maternal alcohol use.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-CC (02))
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Gao, Peter
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Fish, E W; Wieczorek, L A; Rumple, A et al. (2018) The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice. Behav Brain Res 338:173-184
Suttie, Michael; Wozniak, Jeffrey R; Parnell, Scott E et al. (2018) Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 42:1769-1782
Boschen, Karen E; Gong, Henry; Murdaugh, Laura B et al. (2018) Knockdown of Mns1 Increases Susceptibility to Craniofacial Defects Following Gastrulation-Stage Alcohol Exposure in Mice. Alcohol Clin Exp Res 42:2136-2143
Fish, Eric W; Parnell, Scott E; Sulik, Kathleen K et al. (2017) Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL/6J mice. Birth Defects Res 109:49-54
Fish, Eric W; Murdaugh, Laura B; Sulik, Kathleen K et al. (2017) Genetic vulnerabilities to prenatal alcohol exposure: Limb defects in sonic hedgehog and GLI2 heterozygous mice. Birth Defects Res 109:860-865
Gilbert, Marcoita T; Sulik, Kathleen K; Fish, Eric W et al. (2016) Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice. Neurotoxicol Teratol 58:15-22
Fish, E W; Holloway, H T; Rumple, A et al. (2016) Acute alcohol exposure during neurulation: Behavioral and brain structural consequences in adolescent C57BL/6J mice. Behav Brain Res 311:70-80
Wieczorek, Lindsay; Fish, Eric W; O'Leary-Moore, Shonagh K et al. (2015) Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice. Alcohol 49:207-17
Parnell, Scott E; Holloway, Hunter E; Baker, Lorinda K et al. (2014) Dysmorphogenic effects of first trimester-equivalent ethanol exposure in mice: a magnetic resonance microscopy-based study. Alcohol Clin Exp Res 38:2008-14
Lipinski, Robert J; Holloway, Hunter T; O'Leary-Moore, Shonagh K et al. (2014) Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate. PLoS One 9:e102603

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