Cause of infertility found through mice

By Dan Shah

Studies on mice performed by researchers at the University have revealed that the absence of a specific protein may contribute to infertility.

The researchers, funded by the National Institute of Health, have concluded that without this protein, an embryo cannot be implanted and pregnancy cannot occur. The protein, CCAAT/Enhancer Binding Protein beta, also known as C/EBPb, is triggered by steroid hormones in female mice during pregnancy.

After four years of steroid hormone research using GeneChip technology, the group of researchers scanned several thousand genes in the mice and found several genes regulated by steroid hormones.

“For pregnancy, we are specifically interested at the time of the implantation when the embryo attaches (to the wall of the uterus),” said Indrani Bagchi, a professor of veterinary biosciences.

Initial studies focused on a particular gene that was rapidly induced by steroid hormones during pregnancy, suggesting an important function, said Milan K. Bagchi, a professor of molecular and integrative physiology. The gene is responsible for releasing the protein C/EBPb during pregnancy.

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The group of researchers next began testing mice lacking the protein.

“We then collaborated with Peter Johnson (from the National Cancer Institute’s Laboratory of Protein Dynamics and Signaling) who provided us with the mice,” Milan Bagchi said.

The mice proved the researchers’ preliminary conclusion about the protein, and they found that the uterus in the mouse was unable to support pregnancy. They also found that the protein has a very important role in transporting nutrients to the embryo from the mother.

“(The protein’s) function is very critical to supporting the embryo,” Milan Bagchi said. “During pregnancy, right after the embryo attaches to the wall, stromal cells (connective tissue cells) begin to change into decidual cells. The function of decidual cells is to provide nutrients to the embryo from the mother’s blood vessels. In absence of C/EBPb, the stromal cells could not turn into decidual cells. It’s a very programmed process in reproduction.”

This realization is especially important, said Raju Mantena, a graduate student in veterinary biosciences, because this protein is one of the mediators of steroid hormones in the reproductive process. Few mediators are currently known.

The protein tends to disappear after the cells are transformed and decidualization takes place around day 8 or 9, further showing that the protein plays a role in the process, Mantena said.

The researchers want to further their study of the molecular level of pregnancy to see what other genes play a role and find other ways to regulate pregnancy.

“The GeneChip technology helps us study at a molecular level,” said Milan Bagchi. “There is a certain amount of information that is lacking and we believe that C/EBPb is not the only (protein playing a critical role). Our hope is that with this type of technology, we can find other pathways to regulate pregnancy.”

Indrani Bagchi said that the group wants to research the hierarchy of different molecules in the reproductive process to better understand the importance of different genes during pregnancy.

The existence of this protein in humans and its regulation by estrogen and the menstrual cycle is already known, Mantena said.

Milan Bagchi hopes the findings can translate into the human system, which would have important benefits.

“We can now proceed to see what kind of role (this protein) plays in humans,” said Milan Bagchi. “It is known that it is expressed in humans when the uterus is getting ready for implantation.”

Indrani Bagchi and Milan Bagchi believe that if the current findings were applicable to humans, the protein would serve as an important marker for predicting the reproductive system’s willingness to accept an embryo. This is especially important in practices such as in vitro fertilization, which is only about 25 percent successful, Milan Bagchi said.

In the process, the uterus is not always willing to accept an embryo and the researchers are hoping that the presence of the protein, which has increased levels at some points during the menstrual cycle, could act as a marker to how successful the operation could be.