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

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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 – 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.