Dose-Effects of Dietary Soy on Ethanol-Impaired Molecular Pathways Mediating Cerebellar Neurodevelopment and Function in Experimental Fetal Alcohol Spectrum Disorder

Abstract

Fetal alcohol spectrum disorder (FASD) is associated with sustained impairments in motor function mediated by neurotoxic injury and dysregulated intracellular signaling through insulin and insulin-like growth factor (IGF) networks that support neuronal growth, survival, energy metabolism, and plasticity. Although neurodevelopmental abnormalities in FASD can be reduced by supplying pregnant dams with 100% soy as the sole protein source, modified approaches are needed for feasible human translation. The research goals were to characterize the effects of soy dosing on cerebellar structure and function, and the expression of insulin/IGF signaling mediators, neuronal-glial molecules, and neurotrophins in an FASD model. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% ethanol (caloric) with 0%, 10%, 30%, 50%, or 100% soy as the protein source. Ethanol and soy were withdrawn on postnatal day 1 (P1). Rotarod (RR) testing of cerebellar function was performed on P15. On P35, the offspring were sacrificed, and cerebella were harvested for image analysis and protein expression. Prenatal alcohol exposure significantly impaired RR performance, reduced brain size, and caused cerebellar hypoplasia with reduced Tau and increased glial fibrillary acidic protein (GFAP) immunoreactivity. There were no consistent residual effects of ethanol on upstream insulin/IGF signaling molecules 5 weeks after its postnatal withdrawal. Soy doses of 30% or higher nearly normalized brain weight, as well as the densities of cerebellar Purkinje and granule cell neurons in the ethanol group. Soy dose-dependent increases in RR performance were observed in controls but not in the ethanol group. Although the ethanol-mediated reductions in Tau and increases in GFAP were not prevented by dietary soy, the control and ethanol cerebella exhibited similar dose-dependent increases in neurotrophin expression. In conclusion, maternal soy intake, at doses as low as 10%, can prevent or reduce cerebellar structural and functional abnormalities associated with FASD and support the expression of neurotrophins involved in plasticity. Sustained deficits after ethanol withdrawal were associated with reduced Tau and increased GFAP, which likely compromised neuronal cytoskeletal function and contributed to persistent neuroinflammatory/oxidative stress-related injury.