Improving women's health and pregnancy outcome: understanding the aetiology of ectopic pregnancy
Lead Research Organisation:
University of Edinburgh
Department Name: Reproductive and Developmental Sciences
Abstract
About one in 80 pregnancies is ectopic. Most implant in the Fallopian tube. Ectopic pregnancy can cause potentially life-threatening abdominal bleeding and damage to the Fallopian tube affecting future child-bearing. We do not fully understand what causes a pregnancy to implant outside the womb but chlamydial infection is a major risk factor. This project aims to understand how Chlamydia, and two groups of molecules (endocannabinoids and integrins) contribute to the implantation of a pregnancy in Fallopian tube. Information from our laboratory already suggests that, in mouse, endocannabinoids contribute to the successful passage of the embryo from the Fallopian tube into the womb and that levels of endocannabinoids are different in women with ectopic pregnancy. We also hope to show in a laboratory model that abnormal production of endocannabinoids causes the embryo to get trapped in the human Fallopian tube and show how chlamydial infection causes it to implant by affecting integrin levels. We then propose to show that women with ectopic pregnancy have abnormal levels of endocannabinoids and integrins and that this is related to chlamydial infection. Improved understanding of ectopic pregnancy could significantly reduce the risks of this condition.
Technical Summary
Ectopic pregnancy (EP) remains a common cause of pregnancy-related death and is a considerable cause of morbidity. Chlamydia trachomatis (CT) infection is the major risk factor for EP yet our knowledge of the pathogenic events that lead from CT to EP is unclear.
We hypothesise EP is due to the result of:
a) embryo retention in the Fallopian tube (FT) due to smooth muscle dysfunction and,
b) changes in the phenotype/gene expression of the tubal epithelial cell that allow ectopic embryo implantation to occur.
The endocannabinoids are multifunctional proteins that have a pivotal role in embryo transport due to their effects on oviductal smooth muscle. Silencing of the endocannabinoid receptor 1 (CB1) in the mouse results in tubal embryo retention (but not tubal implantation). Attenuated CB1 expression in the human FT is associated with ectopic pregnancy. Although this provides a plausible explanation for arrest of the embryo in the FT, the exact mechanism leading from tubal embryo retention to tubal implantation has hitherto been unexplained. We propose that CT infection causes changes in the tubal epithelial cell that make the FT receptive to ectopic implantation. The integrins, particularly alpha v beta 3, have now been largely accepted as markers of receptivity to the presenting embryo in the uterus, and functional blockout of alpha v beta 3 results in reduced implantation in the mouse. However, it is not known whether integrins have a similar expression in the FT to the uterus, or are aberrantly expressed in EP.
The objectives of this project are to demonstrate that:
1) Endocannabinoids regulate smooth muscle contraction controlling passage of the embryo in the human FT in in-vitro models of tubal contractility and motility; and that CT infection results in aberrant integrin expression and embryo attachment in the human FT in an in-vitro model of tubal attachment.
2) Infection with Chlamydia in the CB1-knockout mouse causes altered tubal epithelial integrin expression and is the stimulus required for a retained embryo implant.
3) CB1 and integrin expression are different in the FT of women following EP in-vivo, and that these differences reflect CT infection.
The delineation of role of CT infection in EP has significant public health implications, particularly in relation to the introduction of national Chlamydia screening programmes. An explanation of the aetiology of tubal ectopic implantation has potential to be translated into preventative health measures that could significantly reduce morbidity/mortality due to EP.
We hypothesise EP is due to the result of:
a) embryo retention in the Fallopian tube (FT) due to smooth muscle dysfunction and,
b) changes in the phenotype/gene expression of the tubal epithelial cell that allow ectopic embryo implantation to occur.
The endocannabinoids are multifunctional proteins that have a pivotal role in embryo transport due to their effects on oviductal smooth muscle. Silencing of the endocannabinoid receptor 1 (CB1) in the mouse results in tubal embryo retention (but not tubal implantation). Attenuated CB1 expression in the human FT is associated with ectopic pregnancy. Although this provides a plausible explanation for arrest of the embryo in the FT, the exact mechanism leading from tubal embryo retention to tubal implantation has hitherto been unexplained. We propose that CT infection causes changes in the tubal epithelial cell that make the FT receptive to ectopic implantation. The integrins, particularly alpha v beta 3, have now been largely accepted as markers of receptivity to the presenting embryo in the uterus, and functional blockout of alpha v beta 3 results in reduced implantation in the mouse. However, it is not known whether integrins have a similar expression in the FT to the uterus, or are aberrantly expressed in EP.
The objectives of this project are to demonstrate that:
1) Endocannabinoids regulate smooth muscle contraction controlling passage of the embryo in the human FT in in-vitro models of tubal contractility and motility; and that CT infection results in aberrant integrin expression and embryo attachment in the human FT in an in-vitro model of tubal attachment.
2) Infection with Chlamydia in the CB1-knockout mouse causes altered tubal epithelial integrin expression and is the stimulus required for a retained embryo implant.
3) CB1 and integrin expression are different in the FT of women following EP in-vivo, and that these differences reflect CT infection.
The delineation of role of CT infection in EP has significant public health implications, particularly in relation to the introduction of national Chlamydia screening programmes. An explanation of the aetiology of tubal ectopic implantation has potential to be translated into preventative health measures that could significantly reduce morbidity/mortality due to EP.
