A Texas study of A&M AgriLife in sheep could soon help address fertility problems in women if it can find ways to break the chain of generational transmission of polycystic ovary syndrome, PCOS – one of the most common infertility disorders.
Rodolfo Cardoso surrounded by sheep in his study on fertility in the barn Rodolfo Cardoso, dr. Sc., Is surrounded by the Texas A&M University Department of Field Laboratory for Animal Physiology with sheep included in his fertility study. (Texas A&M AgriLife photo by Laura McKenzie)
Rodolfo Cardoso, DVM, Ph.D., assistant professor and reproductive physiologist at Texas A&M College of Agriculture and Science, will lead a $ 2.4 million National Institute-funded project to investigate the multigenerational effects of prenatal exposure to androgen excess using sheep as an animal model.
Cardos is joined on this project by Dr. Renata Landers, postdoctoral researcher in the Cardos program, Jessica Sustaita, graduate student in the Cardos team and others. Vasantha Padmanabhan, a professor in the Department of Pediatrics with the University of Michigan Health System, will also serve as principal investigator on the project.
PCOS affects about 5 million women in the United States and over 100 million women worldwide. It is a complex syndrome that includes an increased risk of cardiovascular disease, dyslipidemia, hypertension, diabetes mellitus and endometrial cancer.
The findings from this sheep model will provide key biological information to improve reproductive function across generations and are of clinical relevance to women with PCOS and other hyperandrogenic fertility disorders.
A critical concern of PCOS is the vertical transmission of unwanted traits to offspring. A woman who has PCOS is very likely to pass it on to her daughters and grandchildren, Cardoso said. Sheep are very similar in that the daughters of sheep with PCOS also usually have the syndrome.
Dr. Rodolfo Cardoso takes a sonogram on a sheep in the barn to check fertility. Rodolfo Cardoso, Ph.D., uses a sonogram to check the fertility of sheep in a field physiology laboratory at Texas A&M University. (Texas A&M AgriLife photo by Laura McKenzie)
The sheep is an animal model that is very translational to humans. When we look at what happens during fetal life, the development of the sheep fetus is parallel to the development of humans. Although much of biomedical work uses rodents in research, our ability to translate our findings is much easier and clinically significant for humans when sheep are used. Other key benefits are that sheep generate only one or two fetuses, not a litter, and have a gestation process more similar to humans. “
Rodolfo Cardoso, Ph.D. DVM, assistant professor and reproductive physiologist, Department of Animal Science, Texas A&M’s College of Agriculture and Science
Approximately 70% of women with PCOS are obese or overweight with metabolic complications, he said. It is well documented that if women can lose weight and improve metabolic function, they can improve their fertility.
Also, it is known that everything that happens to a baby during fetal development can affect the health of that individual throughout its life and can be passed on to the next generation after reproduction.
“What we’re trying to respond to with this project is how to break this multigenerational cycle through dietary interventions,” Cardoso said. “The goal is to prevent animals from becoming obese and thus prevent vertical transmission of PCOS traits.”
It would take 20 or more years for people to answer the question. Changes in diet would be made with the mother while she was carrying the fetus, but then one would have to wait until that daughter grows up and gives birth to a daughter.
“With sheep, we can answer the question much faster. Within three years, we will have a daughter who reaches puberty, and soon we will have a granddaughter who will be able to investigate the effects of dietary interventions.”
He said that the mothers received androgen treatment during pregnancy. Androgen treatment mimics conditions or diseases that occur in people who raise levels of steroid hormones during pregnancy, such as PCOS and congenital adrenal hyperplasia.
Androgen levels in humans may also rise during pregnancy in other situations, for example when women who are unaware they are pregnant continue to take birth control pills or after exposure to compounds from the environment that act similarly to steroid hormones.
“We know these sheep will have PCOS and we know when their daughters will breed, they will develop PCOS. We will do a dietary intervention with these daughters and then study the grandchildren,” Cardoso said.
Above the child
In the first four years of this study, Cardoso said he would use dietary interventions or lifestyle modifications to improve pregnant women’s health, and then monitor the multigenerational impact to understand if it worked and if lifestyle interventions help.
The final year will focus on epigenetic studies, identifying the mechanisms by which prenatal androgen exposure and dietary interventions can control how specific genes are expressed.
“We know that nutrition plays an important role in intergenerational gene expression,” he said. “We know in humans that lifestyle intervention will improve PCOS. But what we don’t know is if we can minimize the risk of transmission to daughters and grandchildren. If we learn the mechanisms by which diet improves health – we can identify therapeutic goals to improve health and fertility in women with PCOS. “
Texas A&M AgriLife Communications