Volatile Organic Compound Impacts on Immune Functions During Pregnancy: Molecular Mechanisms For Potential Interventions

Immune functions in the uterus, fetal membranes and placenta are critical to maintaining a healthy pregnancy. These tissues perform a delicate balancing act by maintaining antimicrobial immune defenses while promoting maternal immune tolerance of the fetus. Mounting evidence suggests that environmental toxicants can disrupt key functions of the immune system. However, critical gaps remain in our understanding of how environmental toxicants affect immune functions in gestational tissues. Filling these gaps is necessary to effectively design interventions aimed at preventing adverse pregnancy health outcomes caused by environmental exposures. Volatile organic chemicals (VOCs) like trichloroethylene (TCE) and perchloroethylene (PCE) are widespread immunotoxic environmental contaminants. VOC exposure has been shown to disrupt multiple immune processes, including host defenses against pathogenic bacteria. This has important implications for pregnancy health, as the public health burden of intrauterine infections during pregnancy is high. For example, intrauterine infections with bacteria like Group B Streptococcus (GBS) is associated with outcomes like preterm birth, stillbirth and neonatal sepsis. Studies have identified associations between VOC exposure and immune system dysfunctions, increased risk for certain infections, as well as adverse pregnancy outcomes at least partially mediated by immune cells, like fetal growth restriction. However, TCE and PCE impacts on immune functions during pregnancy are not well understood. Our preliminary data show that a TCE metabolite, S-(1,2- Dichlorovinyl)-L-cysteine (DCVC), blocks immune responses to GBS in fetal membrane explants and suppresses macrophage immune responses to bacterial toxins via downregulation of transcriptional immune pathways and cytokine release. Moreover, we showed that both DCVC and the PCE metabolite S-(1,2,2- trichlorovinyl)-L-cysteine downregulate antimicrobial and immune tolerance pathways in human placental explants ex vivo. These findings suggest that VOC metabolites exert immunosuppressive effects in gestational tissues. We now seek to define the immunotoxic effects of TCE and PCE metabolites across gestational cell types and tissues. In addition, we propose to identify molecular mechanisms underpinning these effects. In this project we will: (1) assess TCE and PCE metabolite impacts on antimicrobial functions in primary uterine decidual macrophages (a key cell type in maintaining immune defenses against intrauterine infections), (2) identify TCE and PCE metabolite impacts on microbial host defense responses to GBS in human fetal membrane explants, (3) identify transcriptomic impacts on specific immune cell types in the placentas of TCE or PCE treated pregnant rats (with or without GBS infection) and (4) determine the extent to which TCE or PCE exposure leads to increased GBS colonization of the uterus, fetal membranes and placenta in a rat model. Using TCE/PCE and GBS as model toxicant-pathogen interactions, this project will provide important insights into how environmental toxicants affect immune functions during pregnancy. Project Number: 1R01ES038132-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Sean Harris | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $795,869 | Activity Code: R01 | Study Section: Environmental Determinants of Disease Study Section [EDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11273363