Project 2: Pollutant Activation of Cell Pathways in Gestational Tissues

See all Project 2 news here.

Significance: Epidemiologic studies associate environmental chemical exposures with preterm birth. Although the placenta and extraplacental membranes play vital roles in pregnancy, the potential for environmental contaminants to contribute to preterm birth through actions on these tissues has hardly been explored. Through studies of toxicant impacts on placental and extraplacental tissues, we seek plausible toxicologic explanations for epidemiologic associations between exposure to select environmental contaminants and preterm birth.


Our work with placental and extraplacental cells in culture is accumulating evidence that supports a model by which toxicants contribute to preterm birth through increased generation of reactive oxygen species and subsequent activation of pathways relevant to labor onset, including inflammatory, cell death, and prostaglandin pathways. By showing that toxicants activate pathways associated with labor, our data provide a foundation to further explore biological explanations for environmental pollutant exposure associations with preterm birth.

Working closely with the PROTECT team, we continue to study two environmental contaminants that are common to Superfund sites, di-2-ethylhexyl phthalate (DEHP) and trichloroethylene (TCE). Although current popular models of preterm birth focus on activation of pro-inflammatory pathways in placenta and extraplacental membranes leading to production of prostaglandins that ultimately stimulate labor, recent reports suggest that oxidative stress due to increased generation of reactive oxygen species (ROS) plays an important role, also. This project builds on our exciting and novel findings that bioactive metabolites of DEHP and TCE stimulate oxidative stress, inflammatory mediators, and cell death in human placental cells – actions associated with preterm birth and low birth weight in humans and in animal models. As part of the collaborative PROTECT Center, this project interacts bidirectionally with exposure science and epidemiology studies to provide novel data on mechanisms by which environmental toxicants increase women’s risk for preterm birth.

Working with the human placental cell line HTR-8/SVneo, we have generated data that support our hypothesis that oxidative stress activates cell pathways relevant to preterm birth. Exposure of the HTR-8/SVneo human placental cells to the DEHP metabolite mono-2-ethylhexyl phthalate (MEHP) increases reactive oxygen species generation and cellular responses to reactive oxygen species, including oxidative DNA damage, activation of cell death response, and differential expression of genes sensitive to the changes in cellular reactive oxygen species, as shown in our publication (Tetz, Cheng et al., 2013). Furthermore, MEHP induces gene expression of PTGS2, an enzyme important for synthesis of prostaglandins implicated in initiation of labor (Tetz, Cheng et al., 2013). These studies provide novel data in support of MEHP stimulation of responses in placental cells that are relevant to adverse birth outcomes. Working with the TCE metabolite S-(1,2-dichlorovinyl)-l-cysteine (DCVC) and antioxidants, we showed that DCVC-stimulated ROS generation mediated increased mRNA expression and release of interleukin-6 (IL-6) in HTR-8/SVneo cells, and these responses were dependent on metabolic activation of DCVC by the enzyme beta-lyase (Hassan et al., 2016[RLC1] ). The latter study findings provide new evidence of mechanistic linkage between DCVC-stimulated ROS and increase in proinflammatory cytokine IL-6. Because abnormal activation of cytokines can disrupt trophoblast functions necessary for placental development and successful pregnancy, follow-up investigations relating these findings to physiologic outcomes are warranted.

Other studies with the model pro-oxidant tert-butylhydroperoxide have generated data that further support our model that ROS activate pathways in human placental cells in culture relevant to labor onset, including inflammatory, cell death, and prostaglandin pathways (manuscripts in preparation). Experiments with pregnant rodents are providing additional support for our over-arching hypothesis by extending in vitro results to whole animals.

 [RLC1]Hassan I, Kumar AM, Park HR, Lash LH, Loch-Caruso R. Reactive Oxygen Stimulation of Interleukin-6 Release in the Human Trophoblast Cell Line HTR-8/SVneo by the Trichlorethylene Metabolite S-(1,2-Dichloro)-l-Cysteine. Biol Reprod. 2016 Sep;95(3):66. Epub 2016 Aug 3. PubMed PMID: 27488030; PMCID: PMC5394980.

Rita Loch-Caruso, Project Leader

Professor, Environmental Health Sciences
Professor, Program in the Environment, LS&A
Associate Research Scientist, Reproductive Sciences Program
Environmental Health Sciences, School of Public Health, University of Michigan

John Meeker, Investigator

Professor, Environmental Health Sciences
Associate Dean for Research, School of Public Health, University of Michigan

Chuanwu Xi, Investigator

Associate Professor, Environmental Health Sciences
Environmental Health Sciences, School of Public Health, University of Michigan


Learn more about the team by checking out the Project 2 video!