UT Southwestern researchers discover method of postponing labor in mice
DALLAS – July 28, 2003 – Researchers at UT Southwestern Medical Center at Dallas have discovered a way to inhibit a biochemical process that accompanies labor and to postpone delivery for one to two days in pregnant mice.
“Since the biochemical steps associated with labor are likely the same in both mice and humans, a similar treatment might someday help prevent pre-term labor in women,” said Dr. Carole Mendelson, professor of biochemistry and obstetrics and gynecology and senior author of the study, published online this week in Proceedings of the National Academy of Sciences.
The researchers administered the drug trichostatin A, which affects the function of receptors for progesterone, a hormone that prevents the uterus from contracting throughout most of pregnancy. The drug effectively delayed the start of labor by allowing progesterone to continue functioning. The postponement of labor was significant because mice have a gestation period of only 19 days.
In humans, progesterone and its receptors are maintained at elevated levels in the uterus throughout pregnancy and after labor begins.
“We postulated that labor is caused by a number of factors that prevent progesterone from continuing to act to maintain uterine quiescence,” Dr. Mendelson said.
In this study, the researchers analyzed a group of proteins -- called co-activators -- that allows progesterone receptors to function. They examined tissues taken from the uteruses of women in labor (undergoing Caesarean section) and those not in labor.
“We found that certain co-activators decrease very markedly in labor,” she said. “We then extended our research to animal models because we wanted to look at the changes that occur throughout pregnancy. We chose to use the mouse, which we found to manifest the same types of changes in these activators at the end of pregnancy and during labor as humans.”
Co-activators have the capacity to alter chromatin structure around progesterone-responsive genes by increasing the acetylation of histones. The genes are active when the histones are acetylated and chromatin – the genetic material of the nucleus – is open to progesterone receptors, said Dr. Mendelson.
“At the end of pregnancy and during the beginning of labor in mice and humans, there is a marked decrease in the acetylation of histones. This causes the chromatin structure to become closed, so the receptors can’t act properly,” she said.
The researchers administered trichostatin A, a histone deacetylase inhibitor, to pregnant mice late in gestation. This increased histone acetylation in the uterus and prevented pre-term labor.
“We were able to keep the chromatin ‘open’ so the progesterone receptors could continue to function,” said Dr. Mendelson.
The researcher said the discovery could be of use in preventing pre-term labor in women.
“Since pre-term birth – which can have devastating immediate and lifelong consequences – affects more than 460,000 infants in the United States each year, our findings could impact the care of pregnant women and the well-being of their babies in the future,” Dr. Mendelson said.
Other UT Southwestern researchers involved in the study included Dr. Jennifer C. Condon, postdoctoral researcher in biochemistry; Dr. Jeyasuria Pancharatnam, a postdoctoral researcher in internal medicine; and medical student Wade Wilson.
Funding was provided by the National Institutes of Health and the Texas Higher Education Coordinating Board.
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