# Project 2 - Toxicant-Stimulated Disruption of Gestational Tissues with Implications for Adverse Pregnancy Outcomes

> **NIH NIH P42** · NORTHEASTERN UNIVERSITY · 2021 · $223,101

## Abstract

SUMMARY 
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 – whi...

## Key facts

- **NIH application ID:** 10128463
- **Project number:** 5P42ES017198-11
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Sean M Harris
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $223,101
- **Award type:** 5
- **Project period:** 2010-04-12 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128463

## Citation

> US National Institutes of Health, RePORTER application 10128463, Project 2 - Toxicant-Stimulated Disruption of Gestational Tissues with Implications for Adverse Pregnancy Outcomes (5P42ES017198-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128463. Licensed CC0.

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