Mono-(2-ethylhexyl) phthalate promotes pro-labor gene expression in the human placenta

Ximi K. Wang, Monica Agarwal, Nataliya Parobchak, Alex Rosen, Anna M. Vetrano, Aarthi Srinivasan, Bingbing Wang, Todd Rosen

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Women exposed to phthalates during pregnancy are at increased risk for delivering preterm, but the mechanism behind this relationship is unknown. Placental corticotropin releasing hormone (CRH) and cyclooxygenase-2 (COX-2) are key mediators of parturition and are regulated by the non-canonical NF-kB (RelB/p52) signaling pathway. In this study, we demonstrate that one of the major phthalate metabolites, mono-(2-ethylhexyl)-phthalate (MEHP), increased CRH and COX-2 mRNA and protein abundance in a dose-dependent manner in primary cultures of cytotrophoblast. This was coupled with an increase in nuclear import of RelB/p52 and its association with the CRH and COX-2 promoters. Silencing of NFkB inducing kinase, a central signaling component of the non-canonical NF-kB pathway, blocked MEHP-induced upregulation of CRH and COX-2. These results suggest a potential mechanism mediated by RelB/p52 by which phthalates could prematurely induce pro-labor gene activity and lead to preterm birth.

Original languageEnglish
Article numbere0147013
JournalPLoS ONE
Issue number1
StatePublished - 11 Jan 2016
Externally publishedYes


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