Toxic effects of trichloroethylene and its metabolite on placental cells at the maternal-fetal interface

PROJECT SUMMARY/ABSTRACT Adverse birth outcomes are prevalent conditions that increase the risk of morbidity and mortality during infancy and the development of chronic metabolic diseases in adulthood. Despite being multifactorial in nature, the causes of adverse birth outcomes, particularly concerning placental dysfunction, are not well understood. Maternal exposure to environmental contaminants is believed to contribute to these outcomes. As a reproductive toxicologist, Dr. Elkin's research seeks to understand the role that maternal exposure to environmental contaminants play in contributing to adverse birth outcomes involving placental dysfunction, and to identify mechanisms by which these aberrant effects can be mitigated or prevented. This Transition to Independent Environmental Health Research (TIEHR) Care Award will provide Dr. Elkin the opportunity to increase training and experience to meet: 1) research development goals, including utilization of single-nucleus technologies and establishment of an in vitro model to represent the syncytial barrier at the maternal-fetal interface, and 2) professional development goals, including science communication, mentoring, and management skills. In humans, maternal exposure to the industrial solvent trichloroethylene is associated with increased risk of low birth weight and restricted fetal growth, conditions linked to placental dysfunction. For the research component of this project, Dr. Elkin will investigate the biological mechanisms of the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) contributing to restricted fetal growth by identifying molecular factors underpinning disruption of placental function at the maternal-fetal interface. At the maternal- fetal interface, several different cell types of trophoblast lineage have critical functions. Previously, Dr. Elkin extensively characterized the effects of DCVC on HTR-8/SVneo cells, which model invasive extravillous trophoblasts. Nevertheless, toxic effects on other important cell types at the maternal-fetal interface have not been explored. Recently, Dr. Elkin's colleagues published promising preliminary data showing that DCVC caused aberrant apoptosis, oxidative stress and inflammation in differentiated BeWo cells, a cell line that models the interhaemal barrier of multinucleated syncytiotrophoblasts separating maternal and fetal circulations. Using an in vitro approach, Dr. Elkin's project will expand on compelling preliminary data by: (1) identifying other placental cell types vulnerable to DCVC at the maternal fetal interface using single-nucleus RNA-sequencing (2) examining DCVC effects on mitochondrial energetics of differentiated syncytiotrophoblasts and (3) determining if DCVC affects placental villous barrier function. The proposed research will address the NIEHS goal of “advancing scientific understanding of the role that early exposure to environmental contaminants play in impacting disease risk later in life.” The findings will inform various stakeholders including lawmakers tasked with protecting the public and clinicians developing therapeutic interventions to combat elevated risk of untoward complications, ultimately improving maternal/fetal outcomes.