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Common Nutrients Fed To Pregnant Mice Altered Their Offspring’s Coat Color And Disease Susceptibility

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Duke Health News 919-660-1306

DURHAM, N.C. – A startling scientific discovery about
nutrition demonstrates that we are more than what we eat: we
are likely what our mothers ate, too, according to scientists
at the Duke Comprehensive Cancer Center.

In a study of nutrition's effects on development, the
scientists showed they could change the coat color of baby mice
simply by feeding their mothers four common nutritional
supplements before and during pregnancy and lactation.
Moreover, these four supplements lowered the offspring's
susceptibility to obesity, diabetes and cancer.

Results of the study are published in and featured on the
cover of the Aug. 1, 2003, issue of Molecular and Cellular
Biology.

"We have long known that maternal nutrition profoundly
impacts disease susceptibility in their offspring, but we never
understood the cause-and-effect link," said Randy Jirtle,
Ph.D., professor of radiation oncology at Duke and senior
investigator of the study. "For the first time ever, we have
shown precisely how nutritional supplementation to the mother
can permanently alter gene expression in her offspring without
altering the genes themselves."

In the Duke experiments, pregnant mice that received dietary
supplements with vitamin B12, folic acid, choline and betaine
(from sugar beets) gave birth to babies predominantly with
brown coats. In contrast, pregnant mice that did not receive
the nutritional supplements gave birth predominantly to mice
with yellow coats. The non-supplemented mothers were not
deficient in these nutrients.

A study of the cellular differences between the groups of
baby mice showed that the extra nutrients reduced the
expression of a specific gene, called Agouti, to cause the coat
color change. Yet the Agouti gene itself remained
unchanged.

Just how the babies' coat colors changed without their
Agouti gene being altered is the most exciting part of their
research, said Jirtle. The mechanism that enabled this
permanent color change – called "DNA methylation" -- could
potentially affect dozens of other genes that make humans and
animals susceptible to cancer, obesity, diabetes, and even
autism, he said.

"Our study demonstrates how early environmental factors can
alter gene expression without mutating the gene itself," said
Rob Waterland, Ph.D., a research fellow in the Jirtle
laboratory and lead author of the study. "The implications for
humans are huge because methylation is a common event in the
human genome, and it is clearly a malleable effect that is
subject to subtle changes in utero."

During DNA methylation, a quartet of atoms -- called a
methyl group – attaches to a gene at a specific point and
alters its function. Methylation leaves the gene itself
unchanged. Instead, the methyl group conveys a message to
silence the gene or reduce its expression inside a given cell.
Such an effect is referred to as "epigenetic" because it occurs
over and above the gene sequence without altering any of the
letters of the four-unit genetic code.

In the treated mice, one or several of the four nutrients
caused the Agouti gene to become methylated, thereby reducing
its expression – and potentially that of other genes, as well.
Moreover, the methylation occurred early during gestation, as
evidenced by its widespread manifestation throughout cells in
the liver, brain, kidney and tail.

"Our data suggest these changes occur early in embryonic
development, before one would even be aware of the pregnancy,"
said Jirtle. "Any environmental condition that impacts these
windows in early development can result in developmental
changes that are life-long, some of them beneficial and others
detrimental."

If such epigenetic alterations occur in the developing sperm
or eggs, they could even be passed on to the next generation,
potentially becoming a permanent change in the family line,
added Jirtle. In fact, data gathered by Swedish researcher
Gunnar Kaati and colleagues indicates just such a
multi-generational effect. In that study of nutrition in the
late 1800s, boys who reached adolescence (when sperm are
reaching maturity) during years of bountiful crop yield
produced a lineage of grandchildren with a significantly higher
rate of diabetes. No cause-and-effect link was established, but
Jirtle suspects epigenetic alterations could underlie this
observation.

Humans and other animals are susceptible to epigenetic
changes because of an evolutionary trait in which "junk"
remnants of viral infections, called "transposons," inserted
themselves randomly within the human and animal genomes.
Transposons use the gene replication machinery to reproduce
themselves. Cells use methylation as a means to inactivate
these junk transposons and prevent their replication. Yet if
the transposons have inserted themselves in or near a
functional gene, the gene can be inadvertently methylated, too,
thereby reducing its expression.

The scientists demonstrated that such inadvertent
methylation occurred at the Agouti gene when the mice were fed
the nutrients. The four nutrients encourage methylation because
they possess chemicals that donate methyl groups within cells.
Thus, they are primed to methylate susceptible sites in the
genome. In fact, more than 40 percent of the human genome is
comprised of transposons that are likely to be methylated, so
any genes positioned near them could be at risk for inadvertent
methylation.

"We used a model system to test the hypothesis that early
nutrition can affect phenotype through methylation changes,"
said Jirtle. "Our data confirmed the hypothesis and
demonstrated that seemingly innocuous nutrients could have
unintended effects, either negative or positive, on our genetic
expression."

For example, methylation that occurs near or within a tumor
suppressor gene can silence its anti-cancer activity, said
Jirtle. Similarly, methylation may have silenced genes other
than Agouti in the present study – genes that weren't analyzed
for potential methylation. And, the scientists do not know
which of the four nutrients alone or in combination caused
methylation of the Agouti gene.

Herein lies the uncertainty of nutrition's epigenetic
effects on cells, said Jirtle. Folic acid is a staple of
prenatal vitamins, used to prevent neural tube defects like
spina bifida. Yet excess folic acid could methylate a gene and
silence its expression in a detrimental manner, as well. The
data simply don't exist to show each nutrient's cellular
effects.

Moreover, methylating a single gene can have multiple
effects. For example, the Agouti gene regulates more than just
coat color. Mice that over-express the Agouti protein tend to
be obese and susceptible to diabetes because the protein also
binds with a receptor in the hypothalamus and interferes with
the signal to stop eating. Methylating the Agouti gene in mice,
therefore, also reduces their susceptibility to obesity,
diabetes and cancer.

Hence, the researchers stress the importance of
understanding the molecular effects of nutrition on cells, not
just the outward manifestations of it.

"Diet, nutritional supplements and other seemingly innocuous
compounds can alter the development in utero to such an extent
that it changes the offspring's characteristics for life, and
potentially that of future generations," said Waterland.
"Nutritional epigenetics could, for example, explain the
differences between genetically identical twins, or the
disparities in the incidence of stroke between the South and
the North. The possibilities are endless."

The study was funded by grants from the National Institute
of Environmental and Health Sciences, the National Cancer
Institute and by a Dannon Institute fellowship to Robert
Waterland.

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