Molecular changes during neurodevelopment following second-trimester binge ethanol exposure in a mouse model of fetal alcohol spectrum disorder: from immediate effects to long-term adaptation.
Fetal alcohol spectrum disorder (FASD) is an umbrella term that refers to a wide range of behavioral and cognitive deficits resulting from prenatal alcohol exposure. It involves changes in brain gene expression that underlie lifelong FASD symptoms. How these changes are achieved from immediate to long-term effects, and how they are maintained, is unknown. We have used the C57BL/6J mouse to assess the dynamics of genomic alterations following binge alcohol exposure. Ethanol-exposed fetal (short-term effect) and adult (long-term effect) brains were assessed for gene expression and microRNA (miRNA) changes using Affymetrix mouse arrays. We identified 48 and 68 differentially expressed genes in short- and long-term groups, respectively. No gene was common between the 2 groups. Short-term (immediate) genes were involved in cellular compromise and apoptosis, which represent ethanol's toxic effects. Long-term genes were involved in various cellular functions, including epigenetics. Using quantitative RT-PCR, we confirmed the downregulation of long-term genes: Camk1g, Ccdc6, Egr3, Hspa5, and Xbp1. miRNA arrays identified 20 differentially expressed miRNAs, one of which (miR-302c) was confirmed. miR-302c was involved in an inverse relationship with Ccdc6. A network-based model involving altered genes illustrates the importance of cellular redox, stress and inflammation in FASD. Our results also support a critical role of apoptosis in FASD, and the potential involvement of miRNAs in the adaptation of gene expression following prenatal ethanol exposure. The ultimate molecular footprint involves inflammatory disease, neurological disease and skeletal and muscular disorders as major alterations in FASD. At the cellular level, these processes represent abnormalities in redox, stress and inflammation, with potential underpinnings to anxiety.
Molecular Genetics Unit, Department of Biology, University of Western Ontario, London, Ont., Canada.
Katarzyna
K
Mantha
Benjamin I
BI
Laufer
Shiva M
SM
Singh
D000222:Adaptation, Physiological / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D000431:Ethanol