Yale Bulletin and Calendar

April 4, 2008|Volume 36, Number 24















Studies probe method to curb Parkinson’s disease and causes of infertility

Three studies led by Dr. Hugh S. Taylor of Yale School of Medicine were presented at the 2008 Society for Gynecologic Investigation (SGI) Annual Scientific Meeting held March 26-29 in San Diego, California.

One of the studies looked at a new approach for curbing Parkinson’s disease, another focused on the link between in utero exposure to a hormone that controls appetite and decreased fertility, and a third examined how synthetic estrogens affect the reproductive system.

Curbing Parkinson’s disease

The injection of uterine stem cells trigger growth of new brain cells in mice with Parkinson’s disease, reported Yale School of Medicine researchers at SGI.

“Previously, we were able to coax these multipotent stem cells to differentiate into cartilage cells,” said Taylor, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences and section chief of Reproductive Endocrinology and Infertility at Yale School of Medicine. “Now we have found that we can turn uterine stem cells into neurons that can boost dopamine levels and partially correct the problem of Parkinson’s disease.”

Parkinson’s disease is a degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech. The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, which is normally caused by the insufficient formation and action of dopamine.

The stem cells in this study were derived from human endometrial stromal cells that were cultured under conditions that induce the creation of neurons. These cells then developed axon-like projections and cell bodies with a pyramid shape typical of neurons.

“The dopamine levels in the mice increased once we transferred the stem cells into their brains,” Taylor said. “The implications of our findings are that women have a ready supply of stem cells that are easily obtained, are differentiable into other cell types, and have great potential use for other purposes.”

Other authors include Dr. Erin Wolff, who presented the abstract at SGI, Zane B. Andrews, Xiao-Bing Gao and Katherine V. Yao. This abstract was an SGI Trainee Plenary Session Selection and winner of the SGI President’s Presenter Award.

Synthetic estrogens and fertility

Researchers at Yale School of Medicine now have a clearer understanding of why synthetic estrogens such as those found in many widely-used plastics have a detrimental effect on a developing fetus and cause fertility problems, as well as vaginal and breast cancers.

Past research shows that exposure to the synthetic estrogen diethylstilbestrol (DES) alters the expression of HOXA 10, a gene necessary for uterine development, and increases the risk of cancer and pregnancy complications in female offspring.

The team led by Taylor sought to understand why a developing female fetus exposed to DES might develop uterine cancer and other problems years after exposure. Even though DES is no longer on the market, the authors chose to study its effects to gain insight into how similar synthetic estrogens might work.

The team studied DNA from the offspring of 30 pregnant mice injected with DES. They found changes in certain regions of the HOXA 10 gene. These alterations continued beyond the time of development and persisted into adulthood, indicating that exposure to DES and similar substances results in lasting genetic memory, known as “imprinting.”

“We found that HOXA 10 protein expression was shifted to the bottom portion of the uterus in the female offspring,” said Taylor. “We also found increased amounts of the enzyme responsible for changes in the DNA. Rather than just changing how much of the protein is there, DES is actually changing the structure of the HOXA 10 gene.

“These findings bring us closer to understanding the way in which DES interacts with the developing reproductive system,” said Taylor.

Pregnant women are frequently exposed to other similar substances with estrogen-like properties, such as Bisphenol-A (BPA). BPA is found in common household plastics and has recently been linked to long-term fertility problems. Like DES, these other substances may also impact female reproductive tract development and the future fertility of female fetuses.

Other authors on the abstract included Jason Bromer, who presented the abstract, and Jie Wu. This abstract was an SGI Trainee Plenary Session Selection and winner of the SGI President’s Presenter Award.

Hunger-inducing hormone and fertility

Researchers at Yale School of Medicine have found that in utero exposure to the hormone ghrelin, a molecule that controls appetite, hunger and nutrition, can result in decreased fertility and fewer offspring.

Ghrelin, the so-called “hunger hormone,” is produced in the stomach and brain, induces food intake, and operates through a brain region that controls cravings for food and other energy sources. Ghrelin decreases the HOXA 10 gene that is involved in developmental programming of the uterus. The HOXA 10 gene determines how the uterus will develop in adulthood.

“When you’re obese, ghrelin levels are lower, and based on these preliminary findings, they may result in lower fertility,” said Taylor.

The researchers bred mice designed to be deficient in ghrelin production. These mice had offspring with decreased fertility and that produced smaller litter sizes. These offspring also had lower expression of the HOXA 10 gene, which is important for proper development of the uterus in the embryo. In the adult uterus, it maintains the ability of the uterus to provide an optimal environment for proper development of the embryo.

“Obesity may have an effect on pregnancy in the next generation,” said Taylor, adding that the findings underscore the importance of nutrition, energy utilization and appropriate ghrelin levels on normal uterine development. Taylor and his team will next study the effects of lower ghrelin levels on humans.

Other authors include Amy Tetrault, who presented the abstract at SGI, Sarah Lieber, Marya Shanabrough and Tamas Horvath.

By Karen Peart


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