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

α-Tocopherol (α-T) is a vitamin, but the reasons for the α-T requirement are controversial. Given that α-T deficiency was first identified in embryos, we studied to the premier model of vertebrate embryo development, the zebrafish embryo. We developed an α-T-deficient diet for zebrafish and used fish consuming this diet to produce α-T deficient (E-) embryos. We showed that α-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 α-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 α-T critical during early development, but the neurodevelopmental process is highly dependent on α-T trafficking by the α-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 α-T in adults but is a key regulator during embryogenesis.