Katherine M Ranard1, Matthew J Kuchan2, Richard S Bruno3, Janice M Juraska4, John W Erdman1,5. 1. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 2. Abbott Nutrition, Columbus, OH, USA. 3. Human Nutrition Program, The Ohio State University, Columbus, OH, USA. 4. Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 5. Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Abstract
BACKGROUND: Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE: We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-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 α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n = 7). At 7 wk of age, tissue α-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 α-T concentrations. Cerebral cortex α-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-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were 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 α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.
BACKGROUND:Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE: We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-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 α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n = 7). At 7 wk of age, tissue α-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 α-T concentrations. Cerebral cortex α-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-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were 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 α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.
Authors: Matthew J Kuchan; Katherine M Ranard; Priyankar Dey; Sookyoung Jeon; Geoff Y Sasaki; Karen J Schimpf; Richard S Bruno; Martha Neuringer; John W Erdman Journal: J Nutr Date: 2020-09-01 Impact factor: 4.687