Deciphering the enigma of the function of alpha-tocopherol as a vitamin

alpha-Tocopherol (alpha-T) is a vitamin, but the reasons for the alpha-T requirement are controversial. Given that alpha-T deficiency was first identified in embryos, we studied to the premier model of vertebrate embryo development, the zebrafish embryo. We developed an alpha-T-deficient diet for zebrafish and used fish consuming this diet to produce alpha-T deficient (E-) embryos. We showed that alpha-T deficiency causes increased lipid peroxidation, leading to metabolic dysregulation that impacts both biochemical and morphological changes at very early stages in development. These changes occur at an early developmental window, which takes place prior to an analogous time to when a human knows she is pregnant. We found that alpha-T limits the chain reaction of lipid peroxidation and protects metabolic pathways and integrated gene expression networks that control embryonic development. Importantly, not only is alpha-T critical during early development, but the neurodevelopmental process is highly dependent on alpha-T trafficking by the alpha-T transfer protein (TTPa). Data from both gene expression and evaluation of the metabolome in E- embryos suggest that the activity of the mechanistic Target of Rapamycin (mTOR) signaling pathway is dysregulated-mTOR is a master regulatory mechanism, which controls both metabolism and neurodevelopment. Our findings suggest that TTPa is needed not only for regulation of plasma alpha-T in adults but is a key regulator during embryogenesis.