In research that could have key ramifications for women of childbearing age, the findings of a study by Oregon State University scientists have shown that embryos produced by vitamin E-deficient zebrafish have malformed brains and nervous systems. “This is totally amazing—the brain is absolutely physically distorted by not having enough vitamin E,” said research lead Maret Traber, PhD, a professor in the OSU College of Public Health and Human Sciences, and the Ava Helen Pauling Professor at Oregon State’s Linus Pauling Institute. Traber, and colleagues have published their findings in Scientific Reports, in a paper titled, “Vitamin E is necessary for zebrafish nervous system development.”

Discovered in 1922, Vitamin E (VitE) was found to be essential for fertilized rat eggs to culminate in live births. “Vitamin E (VitE) is necessary during embryo development and prevents fetal resorption in VitE-deficient rats,” the authors explained. Vitamin E has many biologic roles, and in human diets is commonly attained through consuming oils, such as olive oil. It is found in high levels in foods including hazelnuts, sunflower seeds and avocados.

Vitamin E is a group of eight compounds—four tocopherols and four tocotrienols—that are distinguished by their chemical structure. The term vitamin E generally refers to alpha-tocopherol, which is found in foods associated with a European diet, as well as in dietary supplements. Gamma-tocopherol, on the other hand, is the type of vitamin E most commonly found in a typical American diet.

Olive oil is a common food that’s high in vitamin E, a micronutrient that’s often deficient in the average American diet. [Photo courtesy of U.S. Department of Agriculture]
“Plants make eight different forms of vitamin E, and you absorb them all, but the liver only puts alpha-tocopherol back into the bloodstream,” said Traber. “All of the other forms are metabolized and excreted. I’ve been concerned about women and pregnancy because of reports that women with low vitamin E in their plasma have increased risk of miscarriage.”

 

The zebrafish lifecycle can progress from fertilized egg to a swimming fish in about five days, so the animals are a useful model for studying the development and genetics of vertebrates. Zebrafish share a remarkable similarity to humans at the molecular, genetic and cellular levels, which means that the findings of studies carried out in zebrafish may be immediately relevant to humans. Embryonic zebrafish are of special interest because they develop quickly, are transparent and are easy to care for.

It’s already known that vitamin E is necessary during embryo development, and deficiency can result in embryonic lethality, the authors wrote. “We have previously shown that VitE deficiency dysregulates whole animal phospholipid metabolism, energy status and antioxidant systems using VitE deficient zebrafish (Danio rerio) embryos.” Studies have also shown that vitamin E-deficient vertebrates exhibit neurodevelopmental defects. In contrast, the researchers noted, “VitE supplementation confers protective effects against oxidative stress-induced neural tube defects (NTD) in mice and in human diabetic embryopathy.”

The researchers hypothesized that vitamin E-deficient zebrafish would experience nervous system disruption during embryogenesis. To investigate the role of VitE in supporting neurodevelopment in zebrafish embryos, they studied the development of and gene transcription in embryos spawned from adult zebrafish that were fed diets either containing, or lacking vitamin E. “Why does an embryo need vitamin E? We’ve been chasing that for a long time,” said Traber, a leading authority on vitamin E who has been researching the micronutrient for three decades. “With this newest study we actually started taking pictures so we could visualize: Where is the brain? Where is the brain forming? How does vitamin E fit into this picture?”

In an embryo, a brain primordium and the neural tube appear early and will form the nervous system and innervate all organs and body structures. The reported studies found that without vitamin E, the zebrafish embryos showed neural tube defects and brain defects. “They were kind of like folic acid-deficient neural tube defects, and now we have pictures to show the neural tube defects and brain defects and that vitamin E is right on the closing edges of the cells that are forming the brain,” Traber said.

In healthy organisms, neural crest cells drive the creation of facial bones and cartilage and innervate the body, building the peripheral nervous system. “Acting as stem cells, the crest cells are important for the brain and spinal cord and also go on to be the cells of about 10 different organ systems including the heart and liver,” Traber said. “By having those cells get into trouble with vitamin E deficiency, basically the entire embryo formation is dysregulated. It is no wonder we see embryo death with vitamin E deficiency.”

Traber likens it to the children’s game KerPlunk, in which kids take turns pulling out the straws that support several dozen marbles in a vertical tube. When the wrong straw is pulled out, everything collapses; vitamin E is the straw whose extraction brings down the house on embryo development, especially with the brain and nervous system.

“Now we’re at the point where we’re so close being able to say exactly what’s wrong when there isn’t enough vitamin E but at the same time we’re very far away because we haven’t found what are the genes that are changing,” Traver added. “What we know is the vitamin E-deficient embryos lived to 24 hours and then started dying off. At six hours there was no difference, by 12 hours you see the differences but they weren’t killing the animals, and at 24 hours there were dramatic changes that were about to cause the tipping point of total catastrophe.”

And while the authors acknowledged that “Little is known about VitE trafficking in the brain,” they concluded, “These experiments represent a major step in determining the molecular basis of VitE in the developing vertebrate nervous system … Our findings support the hypothesis that VitE is necessary in the midbrain-hindbrain boundary to support formation of the ventricular shape, size and constriction.” This may be a result of two different VitE functions, they commented, “First, VitE is a potent lipophilic antioxidant that is a necessary antioxidant to protect the polyunsaturated fatty acid-rich membranes of nervous tissue. Second, VitE enhances membrane fluidity and repair.”

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