Журнал клинической и экспериментальной патологии

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Chronic Prenatal Ethanol Exposure Disrupts WNT Signaling In Adolescent Cerebella

Fusun Gundogan, Ming Tong, Mai He, William Cy Chen, Charles Kim, Quynh-Giao Nguyen, Rosa Yu and Suzanne M. de la Monte

Background: In Fetal Alcohol Spectrum Disorder (FASD), structural and functional abnormalities in the cerebellum persist through adolescence and beyond. We hypothesize that perturbations in Wnt signaling may contribute to these effects because Wnt pathways mediate neuronal morphogenesis, migration, and plasticity during development.
Objectives: We utilized an established model of FASD to assess the nature and degree to which chronic prenatal ethanol exposure impairs Wnt pathway gene expression in postnatal and adolescent cerebella. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 18% or 37% ethanol by caloric content from gestation day 6 through delivery. Offspring were sacrificed on postnatal day 3 (P3), P10, P20, or P35. Wnt pathway gene expression was examined using a targeted PCR array and duplex qRT-PCR analysis. Results: Among the 84 genes examined by targeted array, chronic prenatal ethanol exposure (37%) down-regulated just 3 genes at P10, but 33 genes at P35. Further analysis focusing on Wnt5a, Wnt5b, Fzd4, Fzd6, Axin2, Dixdc, and EP300 revealed that prenatal ethanol exposure enhanced expression of Fzd4, Fzd6, Axin2, Dixdc, and EP300 at P3 and Wnt5b at P20, but inhibited Fzd4 and EP300 at P10, and Fzd4, Fzd6, Wnt5a, and EP300 at P20. In addition, ß-catenin, Cyclin D1, and c-Myc protein expression was inhibited by ethanol exposure at P3, but not P10 or P20. To some extent responses were ethanol dose-dependent.
Conclusions: The consequences of chronic prenatal ethanol exposure on Wnt signaling in
the brain shift dramatically with developmental stage. The findings further suggest that Wnt functions such as plasticity, which are needed for adolescent brain development, should be therapeutically targeted in FASD.