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DURHAM, N.C. - An immature egg's internal nutrient supply is
critical to its survival, an insight that offers a new route to
understanding and treating infertility due to egg death,
according to Duke University Medical Center researchers.

As women age, their stockpile of immature eggs, called
oocytes, diminishes through cell death, eventually leading to
infertility. In studies with frog oocytes, the Duke researchers
found that the nutrient storehouse, or yolk, plays a key role
in regulating the survival of these cells. Depleting the
nutrients triggers apoptosis – programmed cell death – and
adding nutrients prolongs the life of eggs, they found. The
study offers potential for developing oocyte-protective
therapies for women undergoing chemotherapy, as well as
potential targets for improved infertility treatments, the
researchers said.

"This discovery provides a basic science underpinning for
understanding the mechanisms of oocyte death and a way to
identify potential clinical treatments," said Sally Kornbluth,
Ph.D., senior study author and an associate professor of
pharmacology and cancer biology at Duke University Medical
Center.

Adds Leta Nutt, Ph.D., lead author of the study, "Our work
provides evidence for a metabolic timer in which oocytes that
use up their energy stores are fated to die." Nutt is a
postdoctoral researcher in Duke's department of pharmacology
and cancer biology.

The results appear in the Oct. 7, 2005, issue of Cell. The
work was supported by the National Institutes of Health, the
Sidney Kimmel Foundation for Cancer Research, the V Foundation
for Cancer Research and the Triangle Community Foundation.

Oocytes are one of the few cells to rely entirely on
internal energy stores, receiving no nutrients from the body.
Human oocytes have a relatively small nutrient stockpile
compared to the frog oocytes studied by the Duke
researchers.

To explore the link between energy stores and apoptosis
(cell death), the researchers both extended the lifetime of
frog oocytes by feeding them nutrients and triggered apoptosis
by mimicking a lack of nutrients.

The oocytes lived longer when provided with the simple sugar
building blocks needed to fuel metabolism, "like fattening them
up to keep them alive," Kornbluth said. Further detective work
revealed the reason why: a molecular pathway involved in
metabolizing the sugar is directly linked to an enzyme called
caspase-2, which causes apoptosis. Caspases are enzymes that
chew up and destroy cells during the apoptosis process.

When the Duke team "fed" the simple sugars to frog eggs and
oocytes, they shut off apoptosis. Conversely, preventing eggs
from metabolizing these sugars and using the molecular pathway
quickly prompted cell death, the researchers found.

The link between an egg's energy stores and the caspase-2
enzyme is especially important because previous studies showed
that turning off caspase-2 in mice prevents oocytes from dying,
even in response to toxic agents like chemotherapy drugs, said
Seth Margolis, Ph.D., a study co-author and postdoctoral
researcher in Duke's department of pharmacology and cancer
biology. Also, female mice missing the gene to produce
caspase-2 are born with an excess number of oocytes.

"We've really demonstrated that caspase-2 is the thing
required for oocyte death, and provided a specific molecular
mechanism that can keep it shut off," Margolis said.

Collaborators on the study include Mette Jensen, Catherine
Herman and Jeffrey Rathmell of Duke, and William Dunphy of the
California Institute of Technology.