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UNC researcher gives Falk Lecture

By Robin Arnette
November 2010

Steven Zeisel, M.D., Ph.D.
Zeisel is a Kenan Distinguished University Professor in Nutrition at the University of North Carolina at Chapel Hill Gillings School of Global Public Health. He is also Director of the UNC Nutrition Research Institute in Kannapolis, N.C. (Photo courtesy of Steve McCaw)

NIEHS/NTP Director Linda Birnbaum, Ph.D., presenting Dr. Zeisel with a gift.
Director Birnbaum thanked Zeisel for a wonderful seminar by presenting him with a gift of appreciation on behalf of the Institute. (Photo courtesy of Steve McCaw)

David Miller, Ph.D.
Acting NIEHS Scientific Director and head of the Intracellular Regulation Group David Miller, Ph.D., was especially interested in Zeisel's liver studies. The liver is one of the organs Miller uses to study xenobiotic transport. (Photo courtesy of Steve McCaw)

family of Hans L. Falk pose with Dr. Birbaum, and Dr. Zeisel
The family of Hans L. Falk, for whom this lecture series is named, posed with the Institute director and seminar speaker. From left to right are Stephen Falk, Birnbaum, Gabrielle Falk, Zeisel, and Raymond Falk. (Photo courtesy of Steve McCaw)

Nutrition research performed over the past several decades highlights how diet and chemical exposures influence the requirement of choline in human development. One of the scientists whose work played a prominent role in these studies is Steven Zeisel, M.D., Ph.D. Zeisel talked about his work during the annual Hans L. Falk Memorial Lecture Oct. 4 at NIEHS.

Setting the stage for his seminar, Zeisel (http://www.sph.unc.edu/?option=com_profiles&profileAction=ProfDetail&pid=704212990) Exit NIEHS explained that metabolic variation - the amount that humans differ from each other in metabolism - was vital to understanding why some people respond to a particular dose of a nutrient, while others don't.

"We originally thought that all people were the same when it came to metabolism," Zeisel said, "but the new view from the last decade or so is that changes in our genetic code lead to metabolic changes."

Humans differ in the requirement for choline

According to Zeisel, humans need choline and get some of it by eating choline-rich foods, such as beef liver and eggs, but the nutrient is also made in the liver by phosphatidylethanolamine N-methyltransferase (PEMT). To determine if choline was truly necessary, Zeisel and his team fed volunteers bread that contained the recommended amount of choline, in the form of phosphatidylcholine, for 10 days. Afterward, the researchers gave the participants bread with trace amounts of choline and watched them for 42 days.

"If they got sick, we stopped immediately and gave them the choline bread back. If they didn't get sick, we let them continue the study," Zeisel added. "During the choline-depleted phase, blood choline levels dropped, which was expected, but we also saw the development of a fatty liver."

It turns out, Zeisel continued, that phosphatidylcholine makes up the outer membrane of a particle that transports fat and cholesterol out of the liver. If a person can't make the particle, the fat accumulates. When Zeisel added choline back into their diet, the fat in their livers decreased.

Zeisel determined that 80 percent of men and postmenopausal women developed organ damage when deprived of choline, but only 44 percent of premenopausal women developed damage. He postulated that estrogen provided protection to young women. Zeisel strengthened his argument when he found that PEMT contained estrogen response elements in its promoter and was induced by estrogen.

Further studies revealed that the reason 44 percent of women were still getting sick was due to a misspelling that caused a mutation in the set of genes that adjusted the requirement for choline. This mutation affected their liver cells' ability to respond to estrogen and, as a result, the women needed choline in their diet.

Rodent studies reveal more about choline

Work with several collaborators concluded that pregnant rats who received four times the amount of choline during the five days of gestation (Day 11-17), when the hippocampus or memory center of the brain develops, gave birth to pups that exhibited elevated memory performance. These rats performed exceptionally well on memory tests - remembering where food was placed - at 2.5, 14, and 26 months after birth and throughout adulthood, compared to rats with no extra choline during development.

Zeisel ended his talk by discussing an environmental agent that interfered with choline. He and his team applied a high dose of diethanolamine (DEA), an additive in sunscreens and shampoos, to the skin of pregnant rodents for five days. Doing so lowered choline concentrations in the mothers' livers. DEA also reduced the amount of hippocampal cell division by half and increased the level of cell death in the pups in utero.

"DEA is about one or two percent of sunscreens and shampoos, and consumers are probably only getting 10 percent of the exposure in our study," Zeisel urged, "but we don't know what effect these low exposures would have on women who use these products for nine months or a lifetime. The European Union has banned DEA in sunscreens and shampoos."

NIEHS/NTP Director Linda Birnbaum, Ph.D., hosted this year's Falk Lecture and presented Zeisel with a gift of appreciation following the seminar.



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