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Abstract
BackgroundDiethylhexyl phthalate (DEHP) is widely used as a plasticizer in polyvinyl chloride products. DEHP exposure, which is widespread in the US, increases preterm birth risk; however, the mechanisms driving this relationship are unclear. Because cyclooxygenase-2 (COX-2) dependent prostaglandin synthesis is implicated in preterm birth, we evaluated effects of mono-2-ethylhexyl phthalate (MEHP), the active metabolite of DEHP, on prostaglandin E2 (PGE2) synthesis and COX expression in human placental macrophages (PM). In addition, responses in PM were compared to those in a human macrophage-like cell line, THP-1.MethodsPM and THP-1 cells were treated for 2, 4, 8, or 24 h with MEHP concentrations ranging from 10 to 180 micromolar. PGE2 concentrations were assessed in culture medium using ELISA, and COX expression was determined by western blot.ResultsTreatment of PM and THP-1 cells with 180 micromolar MEHP for 24 h significantly increased PGE2 release. Co-treatment of PMs or THP-1 cells with 180 micromolar MEHP and the non-selective COX inhibitor indomethacin reduced MEHP-stimulated PGE2 production. Similarly, co-treatment of PM and THP-1 cells with the COX-2 selective inhibitor NS-398 resulted in a significant decrease in PGE2, suggesting that MEHP-stimulated PGE2 is dependent specifically on increased COX-2 expression. Western blot analysis revealed a significant increase in COX-2 expression in PM and THP-1 cells treated with 180 micromolar MEHP, and no changes in COX-1 expression, supporting the role of COX-2 in MEHP-stimulated PGE2 synthesis.ConclusionsThe findings from this study are the first to demonstrate phthalate-stimulated PGE2 synthesis in PM and warrant future studies into COX-2-dependent prostaglandin synthesis as a mechanism of toxicant-associated preterm birth.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0046-8) contains supplementary material, which is available to authorized users.
Highlights
Diethylhexyl phthalate (DEHP) is widely used as a plasticizer in polyvinyl chloride products
The effects of 180 μM mono-2-ethylhexyl phthalate (MEHP) treatment on prostaglandin E2 (PGE2) synthesis were reproducible in THP-1 cells used to model placental macrophages (PM) behavior (Fig. 1f,g)
Co-treatment of PMs or THP-1 cells with the COX-2 selective inhibitor NS-398 resulted in significant decreases in PGE2 concentrations of 70 % and 57 %, respectively, compared with MEHP alone, suggesting that MEHP-stimulated PGE2 synthesis is dependent on COX-2 activity
Summary
Diethylhexyl phthalate (DEHP) is widely used as a plasticizer in polyvinyl chloride products. DEHP exposure, which is widespread in the US, increases preterm birth risk; the mechanisms driving this relationship are unclear. Because cyclooxygenase-2 (COX-2) dependent prostaglandin synthesis is implicated in preterm birth, we evaluated effects of mono-2-ethylhexyl phthalate (MEHP), the active metabolite of DEHP, on prostaglandin E2 (PGE2) synthesis and COX expression in human placental macrophages (PM). As many as half of preterm births are attributed to unknown causes [4]. A better understanding of contributing factors and mechanisms controlling untimely labor is necessary to prevent preterm birth and to improve maternal and fetal health. Exposure during pregnancy to some environmental toxicants, including phthalate esters, increases risk for preterm birth [6,7,8,9]
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