Tennessee Valley Research Agent Orange Effects on Pregnancy and Fetal Outcomes

Led by Dr. Jennifer Gaddy, associate professor of medicine at Vanderbilt University Medical Center (VUMC) and research scientist at TVHS, the Gaddy Laboratory biomedical research team has received a  VA Merit Award and supplemental funding from the Toxic Exposure Research Program to investigate how TCDD allows bacteria in the reproductive tract to affect pregnancy outcomes.

“There hasn’t been enough basic research on how these chemicals affect reproduction and pregnancy… and so, I’m throwing everything I got at it,” Gaddy said. 

To study the effects of TCDD, Gaddy exposed de-identified placental tissue from VUMC to TCDD and then introduced an infection to observe the response.

Placental macrophages are immune cells that defend the reproductive tract from inflammatory insults like infections and germs. However, Gaddy discovered that TCDD alters these immune functions and can result in placental macrophage cell death. This can cause people to be more prone to having various bacterial infections, which is one of the leading causes of preterm birth.  

“[TCDD] paralyzes the host immune system to where it doesn't recognize or combat the infection well, and we think that ultimately is one of the drivers of why we get these adverse pregnancy outcomes from those exposed to Agent Orange,” Gaddy said. 

TCDD is a dioxin molecule and contaminant of Agent Orange, a chemical herbicide and defoliant developed through combustion and commonly known for its use in herbicidal warfare in Vietnam. Chemicals in Agent Orange are present in forest fires, large manufacturing facilities, incinerators, and the water and soil surrounding these locations. The TCDD toxin is a forever chemical that accumulates in the environment and does not break down over time. 

“Since we're seeing more environmental exposures and more people are being exposed to these forever chemicals, we're going to see more adverse effects,” Gaddy said. “We're going to need chemotherapeutics and diagnostic biomarkers to fight that.” 

Most human exposures to the dioxin molecule occur from contaminated food. Of the foods most associated with high TCDD contamination, 16 of these are consumed in disproportionally high quantities by pregnant people, enhancing the risk of exposure in this population.

“We have multiple entities interested in funding this type of research on pregnancy and adverse pregnancy outcomes, like the National Institute of Health. The main reason is because places in the United States, like Tennessee, have been rated failing for maternal mortality and birth outcomes,” Gaddy said.

Gaddy hopes to determine why the immune system does not recognize TCDD and create measurable indicators of these symptoms and issues developed by TCDD, known as biomarkers. Biomarkers can determine disease processes early in illnesses and ultimately lead to correct diagnosis and drug targets.

“The most powerful thing we're doing is biomarker discovery. We hope to establish in the literature immune biomarkers that precede preterm birth as a consequence of infection,” Gaddy said. “And then determine if we can deploy therapy for Veterans who were exposed to environmental toxins to help them sustain their pregnancy.”

Gaddy plans to reapply for the VA Merit Award to continue researching TCDD, specifically focusing on the persistent transgenerational effects found in mice colonies from findings by Dr. Kevin Osteen, professor of obstetrics and gynecology at VUMC and research scientist at TVHS. 

Osteen discovered that infections were not predictive of preterm birth in mice, meaning most mice exposed to a low dose of the bacteria mimic lipopolysaccharide (LPS) delivered at normal rates. However, 100% of mice exposed to Agent Orange delivered preterm when subjected to the low dose of LPS. This discovery led to the idea that TCDD changes the host’s immune system, not only the reproductive tract. 

“Agent Orange exposures affects other than just one generation, and so we're really interested in understanding that immunology is the primary exposure in this iteration of the grant,” Gaddy said. 

TCDD does not alter DNA but rather creates an epigenetic change in a host that controls gene activity and impacts how it is regulated. Osteen also discovered men exposed to TCDD can have adverse effects on the pregnancies of their partners since the placenta is a largely paternal-driven organ system. 

In addition to pregnancy outcomes, this research gives insight into how toxins can affect other inflammatory conditions and the development of organ systems. 

“TCDD is not so common in middle Tennessee, but just understanding the mechanism by which it occurs is really important for us to understand how prior exposure might cause illness not only in pregnant women but also in men,” said Dr. Stokes Peebles, chief of staff of research and development at TVHS. “In men, the macrophages are also very important in the host defense against pneumonia, certain skin and gastrointestinal infections, and others.”

Osteen emphasizes the importance of lifestyle management and is currently researching how dietary intervention can decrease the risk of inflammation and preterm birth outcomes correlated to TCDD, along with the effects of receiving anti-inflammatory drugs before initiating pregnancy.

Gaddy recently received the Burroughs Wellcome Fund (BWF) 2024 Next Gen Pregnancy Research Grant. The grant offers $500,000 over the next five years to examine how the Group B Streptococcus bacteria invade the reproductive tract to attack the fetus.

The BWF grant will support Gaddy’s research at Vanderbilt to examine how the CovR protein regulator develops to aid bacteria in resisting the metal intoxication from immune cells during pregnancy. 

“If we can understand how the regulator is working, we can drug and target it,” Gaddy said. “We work with very talented chemists that help make synthetic molecules to attack bacterial and host proteins,” Gaddy said. 

Veterans who have a health condition caused by exposure to the herbicide Agent Orange during service may be eligible for VA disability compensation. For more information on Agent Orange diseases and illnesses and PACT ACT information, visit here.