Synthetic α-Tocopherol, Compared with Natural α-Tocopherol, Downregulates Myelin Genes in Cerebella of Adolescent Ttpa-null Mice

Background: Vitamin E (alpha-tocopherol; alpha-T) deficiency causes spinocerebellar ataxia. alpha-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic alpha-T during early life. Objective: We assessed the effects of dietary alpha-T dose and source on tissue alpha-T accumulation and gene expression in adolescent alpha-tocopherol transfer protein-null (Ttpa(-/-)) mice. Methods: Three-week-old male Ttpa(-/-) mice (n = 7/group) were fed 1 of 4 AIN-93G-based diets for 4 wk: vitamin E deficient (VED; below alpha-T limit of detection); natural alpha-T, 600 mg/kg diet (NAT); synthetic alpha-T, 816 mg/kg diet (SYN); or high synthetic alpha-T, 1200 mg/kg diet (HSYN). Male Ttpa(+/+) littermates fed AIN-93G [75 mg synthetic alpha-T (CON)] served as controls (n = 7). At 7 wk of age, tissue alpha-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa(-/-) groups. Results: Ttpa(-/-) mice fed VED had undetectable brain alpha-T concentrations. Cerebral cortex alpha-T concentrations were greater in Ttpa(-/-) mice fed NAT (9.1 +/- 0.7 nmol/g), SYN (10.8 +/- 1.0 nmol/g), and HSYN (13.9 +/- 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa(+/+) mice fed CON (24.6 +/- 1.2 nmol/g) (P < 0.001). RRR-alpha-T was the predominant stereoisomer in brains of Ttpa(+/+) mice (similar to 40%) and Ttpa(-/-) mice fed NAT (similar to 94%). alpha-T stereoisomer composition was similar in brains of Ttpa(-/-) mice fed SYN and HSYN (2R: similar to 53%; 2S: similar to 47%). Very few of the 16,774 genes measuredwere differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). Conclusions: High-dose synthetic alpha-T compared with natural alpha-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.