Established in 2010, the PROTECT Superfund Research Center integrates research, training and stakeholder engagement to provide solutions for reducing pollutant risks to pregnancy in Puerto Rico and nationwide. This project contributes to the mission of PROTECT with toxicological studies of disruption of the placenta and extraplacental membranes as potential mechanisms of preterm birth. Experiments will use explant cultures of primary human placental villous and extraplacental membranes (EPM) from healthy term deliveries as highly relevant human tissue models that allow experimental manipulation for toxicity assessment and avoid complications of inter-species differences. This proposal continues study of Superfund chemicals relevant to Puerto Rico ? di-(2-ethylhexyl) phthalate (DEHP) and trichloroethylene (TCE) ? with addition of di-(2- ethylhexyl) terephthalate (DEHTP) which is an alternative phthalate of increasing commercial use that is structurally related to DEHP. Because most adverse health effects of phthalates and TCE are attributed to metabolites, experiments will be conducted with systemically distributed metabolites of DEHP (mono-[2- ethylhexyl] phthalate and mono-[2-ethyl-carboxypropyl] phthalate), DEHTP (mono-[2-ethylhexyl] terephthalate and mono-[2-ethyl-5-carboxypentyl] terephthalate), and TCE (trichloroacetate and S-(1, 2-dichlorovinyl)-L- cysteine). Furthermore, we will assess the combined exposure of the aforementioned phthalate metabolites in a reconstituted mixture based on their relative urinary concentrations in Puerto Rican women. Because the placenta is highly perfused, these blood-borne metabolites are efficiently delivered to the placenta in exposed women. This proposal builds on current knowledge ? and past successes of this project and center ? to propose the overarching hypothesis that phthalate and TCE metabolites activate oxidative stress upstream of cytokine responses that disrupt the function of the placenta and EPM, thereby contributing to risk for preterm birth.
In Aims 1 and 2, we will use human placental villous explants to establish concentration-dependent and time-dependent relationships for the phthalate and TCE metabolites (Aim 1), and test whether oxidative stress initiates tissue function disruption by these toxicants (Aim 2). Because infection of the placenta and EPM is the leading identifiable cause of preterm birth, in Aim 3 we will probe oxidative stress as a mechanism by which toxicants modify susceptibility of EPM to Group B Streptococcus (GBS) infection. The proposed studies will expand knowledge of phthalate and TCE toxicity to placenta and EPM, providing new insights into stimulation of oxidative stress and inhibition of gestational tissue resistance to bacterial infection as biological mechanisms by which environmental contaminant exposures increase risk for preterm birth. By working with primary human tissue culture models relevant to late preterm birth ? which accounts for most of the increase in preterm births in the United States ? these findings have the potential for translation to medical and public health interventions with a significant impact on reducing preterm births.

Public Health Relevance

Preterm birth and low birth weight are expensive, dangerous and prevalent, with particular concern for high rates of these adverse pregnancy outcomes in Puerto Rico. By delivering insight into underlying mechanisms, findings from this project will contribute to strategies for integrative solutions to reduce preterm birth and low birth weight with interventions at the individual, community, clinical, and state or federal levels.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northeastern University
United States
Zip Code
Xue, Yunfei; Rajic, Ljiljana; Chen, Long et al. (2018) Electrolytic control of hydrogen peroxide release from calcium peroxide in aqueous solution. Electrochem commun 93:81-85
Taqieddin, Amir; Allshouse, Michael R; Alshawabkeh, Akram N (2018) Review-Mathematical Formulations of Electrochemically Gas-Evolving Systems. J Electrochem Soc 165:E694-E711
Yu, Xue; Feric, Zlatan; Cordero, José F et al. (2018) Potential influence of temperature and precipitation on preterm birth rate in Puerto Rico. Sci Rep 8:16106
Koman, Patricia D; Hogan, Kelly A; Sampson, Natalie et al. (2018) Examining Joint Effects of Air Pollution Exposure and Social Determinants of Health in Defining ""At-Risk"" Populations Under the Clean Air Act: Susceptibility of Pregnant Women to Hypertensive Disorders of Pregnancy. World Med Health Policy 10:7-54
Park, Hae-Ryung; Harris, Sean M; Boldenow, Erica et al. (2018) Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro. Biol Reprod 98:396-407
Torres, Norma I; Yu, Xue; Padilla, Ingrid Y et al. (2018) The influence of hydrogeological and anthropogenic variables on phthalate contamination in eogenetic karst groundwater systems. Environ Pollut 237:298-307
Ferguson, Kelly K; Yu, Youfei; Cantonwine, David E et al. (2018) Foetal ultrasound measurement imputations based on growth curves versus multiple imputation chained equation (MICE). Paediatr Perinat Epidemiol 32:469-473
Boss, Jonathan; Zhai, Jingyi; Aung, Max T et al. (2018) Associations between mixtures of urinary phthalate metabolites with gestational age at delivery: a time to event analysis using summative phthalate risk scores. Environ Health 17:56
Aker, Amira M; Ferguson, Kelly K; Rosario, Zaira Y et al. (2018) The associations between prenatal exposure to triclocarban, phenols and parabens with gestational age and birth weight in northern Puerto Rico. Environ Res 169:41-51
Johns, Lauren E; Ferguson, Kelly K; Cantonwine, David E et al. (2018) Subclinical Changes in Maternal Thyroid Function Parameters in Pregnancy and Fetal Growth. J Clin Endocrinol Metab 103:1349-1358

Showing the most recent 10 out of 163 publications