Advances in Understanding the Pathophysiology of Placental Disease

Techniques that allow researchers to understand the underlying mechanisms of disease include genetic analyses, RNA sequencing, and advanced proteomics and lipidomics.
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Molecular level analyses provide insight into the workings of the placenta and how its functions are disrupted during disease. | Courtesy Dr. Rissa Parker

One of the greatest joys in the horse breeding industry is the birth of a strong, healthy foal. As such, their caretakers will go to whatever means necessary to ensure a good outcome, including painstaking monitoring for signs of a problem such as early udder development or vaginal discharge. Despite their hard work, some mares still abort seemingly out of the blue or give birth to a “peanut,” a small, runty foal that struggles to gain weight and thrive. Unfortunately, any number of diseases or conditions can cause these outcomes, and it often feels like there is nothing we can do to prevent them.

Fortunately, there have been massive developments in research techniques recently that allow researchers to understand the underlying mechanisms of disease. These range from genetic analyses to RNA-sequencing and advanced proteomics and lipidomics. In brief, DNA is transcribed into messenger RNA (mRNA), which can be translated into protein. Specific proteins (enzymes) alter the use and form of lipids, and each has a slightly different role in our understanding of health and disease. Together, these techniques use the interconnected systems of genetic material and proteins to provide a more holistic understanding of normal and abnormal pregnancy and can be used to identify better ways to diagnose, treat, and even prevent pregnancy complications.

Genetic analysis provides information about a horse’s specific DNA. This remains the same throughout a horse’s life and can be passed directly to their offspring. Perhaps the best-known genetic testing in horses is the five-panel test in Quarter Horses, which includes tests for hyperkalemic periodic paralysis (HYPP), hereditary equine regional dermal asthenia (HERDA), polysaccharide storage myopathy (PSSM), and others. If a breeder knows their mare has one copy of any of these genes, they can avoid complications in their foals if they make sure they breed to a “clean” stallion, or one who does not have a copy of that gene, which makes our horses healthier overall. Additionally, there is work being done to identify the genetic basis for umbilical cord torsion, placentitis, red bag delivery, and others.

RNA-sequencing analyses can assess the amount of mRNA produced in a tissue during disease. Because mRNA expression is the first thing to change during disease, we can often see the body’s immediate response to an infectious agent, as well as how that agent causes the body’s response to change over time. Additionally, mRNA is relatively simple to measure, allowing us to monitor expression of over 32,000 genes. By monitoring this response, we can better understand what treatments are likely to help, what biomarkers may allow better diagnosis, and how to help prevent the horse from getting sick in the first place.

Lastly, proteins and lipids do the heavy lifting in tissues and are what exert the majority of the biological effects we see. Unfortunately, the technology we have in place for testing large numbers of proteins and lipids is expensive and clumsy, making it difficult to look at changes happening at a cellular level. Even so, proteins and lipids are often the best biomarkers because they remain in circulation for relatively long periods of time and reflect actual physiological changes happening in response to the disease. For example, proteomic studies have identified biomarkers for placentitis that change in blood and in amniotic fluid.

From the outside, many of these molecular techniques seem pedantic and far removed from clinical reality; however, these techniques are what allow researchers to better understand the underpinnings of disease and how to diagnose and treat it. RNA-sequencing has recently been used to identify how the mare and unborn foal act to fight both ascending and nocardioform placentitis, including how these diseases affect blood vessel development, nutrient transportation, and immune signaling. There have been other studies which have identified the key changes occurring in the placenta during early pregnancy—this work could ultimately lead to improved pregnancy diagnostic tests and better ways to assess pregnancy health.

These molecular level analyses provide keen insight into the workings of the placenta and how those functions are disrupted during disease. This issue of the Equine Disease Quarterly contains articles by Dr. Von Dollen on hydrops and Dr. Swan on leptospiral abortion. Researchers are using various molecular analyses to better understand the pathophysiology of both of these important causes of fetal loss. Although it can be difficult to see exactly how this knowledge benefits horses today, the information from these studies is what will allow researchers to develop better techniques for diagnosis, treatment, and prevention of disease. The broad view these techniques offer allows a more complete picture than any previous technology and is already making a difference in how we diagnose and treat disease. Ultimately, these techniques make major strides towards every breeder’s goal of creating pregnancies which result in strong, healthy foals.

Editor’s note: This is an excerpt from Equine Disease Quarterly, Vol. 31, Issue 2, funded by underwriters at Lloyd’s, London, brokers, and their Kentucky agents. It was written by Shavahn Loux, PhD, of the University of Kentucky’s Gluck Equine Research Center, in Lexington.


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