Exposure to certain environmental toxicants prior to puberty can increase the risk of adult reproductive disease and dysfunction. The negative impact can span generations, affecting not only the reproductive health of those directly exposed, but their descendants as well.
With new funding from the U.S. Environmental Protection Agency, a team of researchers at Vanderbilt University Medical Center aim to determine if certain preexisting inflammatory conditions may increase sensitivity to the harmful effects of environmental toxicants.
“Women with endometriosis commonly have inflammatory conditions as comorbidities, but it is not clear why,” said Kevin Osteen, Ph.D., Pierre Soupart Chair of Obstetrics and Gynecology at Vanderbilt, and principal investigator on the grant. “We suspect that these inflammatory conditions start earlier in the patient’s life and increase their likelihood of developing endometriosis or suffering infertility or adverse pregnancy outcomes.”
Osteen and Kaylon Bruner-Tran, Ph.D., a co-investigator on the grant and professor in the Department of Obstetrics and Gynecology at Vanderbilt, have been studying environmental triggers of endometriosis for several years.
They have previously reported that in utero exposure to dioxin, a chemical released into the atmosphere during combustion of fossil fuels and wood as well as waste incineration, can cause transgenerational reproductive dysfunction in mice.
“Even in the fourth generation after that first toxicant exposure, we still see an increased risk of infertility and preterm birth in mice that are able to become pregnant,” Bruner-Tran said.
Modeling Disease-Toxicant Interactions
For the new grant, which is part of the EPA’s initiative to develop alternative methods to animal testing, Osteen and Bruner-Tran will pair animal studies with in vitro analyses of human cells using organ-on-a-chip devices. Organ-on-a-chip devices are designed to more accurately recreate the cellular functions within human organ or tissue compared to traditional culture systems.
“We want to model the phenotypes we observe in animals with an organ-on-a-chip using human cells and show that the chip has fidelity to the in vivo animal studies,” Bruner-Tran said. “The organ-on-a-chip will both reduce the use of animals and enable us to do experiments involving toxicants which we could never do in humans.”
Their research aims are two-fold: to examine how preexisting inflammatory disease affects the cellular response to toxicant exposure, and vice versa, how the impact of ancestral toxicant exposure affects the cellular response to an inflammatory challenge. Osteen and Bruner-Tran have previously shown that the offspring of toxicant-exposed animals are sensitive to a number of inflammatory challenges.
“Maybe your grandparents are exposed to a toxicant, and then you’re exposed to an inflammatory challenge like an infection, and it puts you over the edge,” Osteen explained.
Identify and Intervene
“The 32-year-old woman at the clinic with endometriosis and infertility – can we identify her when she is 14?”
The long-term goal is to identify at-risk individuals earlier so that nutritional or pharmacologic interventions may be utilized to reduce the risk of endometriosis, infertility and adverse pregnancy outcomes.
“The 32-year-old woman at the clinic with endometriosis and infertility – can we identify her when she is 14, intervene, and reduce the likelihood of her arriving at the clinic as an infertility patient in the first place?”