mice with a genetic predisposition toward preterm birth also experience mild
inflammation, preterm birth rates soar. But when those mice are treated with a
combination of rapamycin and progesterone preterm birth rates plummet,
according to a new study led by scientists at Cincinnati Children’s.
These findings, published online Aug. 27, 2013,
in the Journal of Clinical Investigation,
provide evidence that gene-environment interactions are a major contributor to
preterm birth and that treatments to prevent preterm birth are possible.
The study was led
by Sudhansu K. Dey, PhD, director of Reproductive Sciences at Cincinnati Children’s,
first author Jeeyeon Cha, an MD / PhD graduate student in the Dey lab, and
Yasushi Hirota, MD / PhD, a former postdoctoral fellow in the Dey lab and now a faculty
member at the University of Tokyo.
“The results are
clinically relevant because aspects of the molecular signatures observed in the
mouse studies are consistent with those observed in tissue samples of women who
had undergone preterm birth,” Dey says.
A recent report
from the World Health Organization states that while more than 60 percent of
preterm births occur in developing countries, the U.S. is among 10 nations with
the highest numbers of preterm birth. Dey and colleagues suggest that different
factors may be driving preterm birth in developing and developed countries. Infection
and inflammation may affect developing countries more, while chronic diseases
such as diabetes and hypertension, and the increased use of assisted
reproductive technologies in older women may increase prematurity rates in
To conduct their
research, the investigators generated a mouse model of preterm delivery in
which the Trp53 gene was inactivated
in the uterus. Trp53 encodes the p53 protein,
which helps regulate cell growth and replication.
deletion caused the mice to have a 50 percent preterm birth rate. This occurs
because the mice exhibit increased signaling by mammalian target of rapamycin
complex 1 (mTORC1) and cyclooxygenase-2 (COX2). The signaling generates fatty
acids called prostaglandins that can prematurely trigger uterine contractions. Research
also shows that human women who have experienced preterm birth have shown
similar increases in mTORC1 and COX2 signaling.
In this study, Trp53-deficient female mice were
subjected to mild inflammation with LPS (endotoxin), which resulted in a 100
percent preterm birth rate. The team
then observed that a combination of rapamycin (an mTORC1 inhibitor) and
progesterone, an ovarian hormone necessary for pregnancy success, was effective
at preventing preterm birth with no apparent adverse effects on maternal or
is used by some at-risk women to prevent preterm birth. Although further
investigation is required, the new findings suggest that adding low doses of an
mTORC1 inhibitor may further reduce incidence rates.