Preterm birth is expensive, dangerous and prevalent. In Puerto Rico, the preterm birth rate is the highest of any jurisdiction in the U.S. and below only Malawi globally. 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 actions on placental and extraplacental tissues, we will identify toxicologic explanations for epidemiologic associations between exposure to select environmental contaminants and preterm birth. Working closely with the PROTECT team, we will continue study of 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. 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. Moreover, working with a model pro-oxidant that generates intracellular ROS, we have identified a key cell signaling pathway important in these responses. In pregnant rats, TCE exerted effects consistent with the responses observed in vitro with a TCE metabolite. An important objective of our proposed experiments is to measure oxidative stress and inflammatory response biomarkers in pregnant rats exposed to DEHP and TCE, and associate these biomarkers with adverse birth outcomes using histology to assess placental pathology, and using immunoassay, mRNA analysis, and IHC to assess placenta, maternal blood, and amniotic fluid. In addition, we will define the ROS-sensitive mechanisms that link DEHP and TCE to downstream events associated with preterm birth in experiments conducted with various in vitro models, including a human placental cell line, primary human placental trophoblasts, primary placental macrophages, and transwell cultures of human extraplacental membranes exposed in vitro to DEHP and TCE metabolites. In an aim new to this project, we will define toxicant-microbial interactions for infection of human extraplacental membranes in vitro. This project will provide novel data on mechanisms by which environmental toxicants increase women's risk for preterm birth. As part of this collaborative Center, our project will interact bidirectionally with exposure science and epidemiology studies.

Public Health Relevance

This project will provide novel mechanistic insights into how environmental chemical exposures contribute to preterm birth. Along with collaborations in the PROTECT Center, these findings will better define environmental contaminant risks to pregnancy that will be communicated to protective public health agencies, the medical community and the public for development of strategies to reduce risks for preterm birth within and beyond Puerto Rico. Reducing preterm birth rates will have significant benefits for individuals and society because preterm birth is a major contributing factor for infant death and complications from preterm birth can develop into long-term health conditions that severely impact quality of life.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Northeastern University
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Watkins, Deborah J; Ferguson, Kelly K; Anzalota Del Toro, Liza V et al. (2015) Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. Int J Hyg Environ Health 218:212-9
Yu, Xue; Ghasemizadeh, Reza; Padilla, Ingrid et al. (2015) Spatiotemporal changes of CVOC concentrations in karst aquifers: analysis of three decades of data from Puerto Rico. Sci Total Environ 511:10-Jan
Ferguson, Kelly K; McElrath, Thomas F; Chen, Yin-Hsiu et al. (2015) Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. Am J Obstet Gynecol 212:208.e1-8
Boldenow, Erica; Hogan, Kelly A; Chames, Mark C et al. (2015) Role of cytokine signaling in group B Streptococcus-stimulated expression of human beta defensin-2 in human extraplacental membranes. Am J Reprod Immunol 73:263-72
Rajic, Ljiljana; Fallahpour, Noushin; Yuan, Songhu et al. (2014) Electrochemical transformation of trichloroethylene in aqueous solution by electrode polarity reversal. Water Res 67:267-75
Ferguson, Kelly K; Cantonwine, David E; Rivera-González, Luis O et al. (2014) Urinary phthalate metabolite associations with biomarkers of inflammation and oxidative stress across pregnancy in Puerto Rico. Environ Sci Technol 48:7018-25
Ferguson, Kelly K; McElrath, Thomas F; Ko, Yi-An et al. (2014) Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Environ Int 70:118-24
Korir, Michelle L; Knupp, David; LeMerise, Kathryn et al. (2014) Association and virulence gene expression vary among serotype III group B streptococcus isolates following exposure to decidual and lung epithelial cells. Infect Immun 82:4587-95
Yao, Yuanyuan; Wang, Poguang; Giese, Roger (2014) Evaporative derivatization of phenols with 2-sulfobenzoic anhydride for detection by matrix-assisted laser desorption/ionization mass spectrometry. Rapid Commun Mass Spectrom 28:653-61
Fortenberry, Gamola Z; Meeker, John D; Sánchez, Brisa N et al. (2014) Paraoxonase I polymorphisms and attention/hyperactivity in school-age children from Mexico City, Mexico. Environ Res 132:342-9

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