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

doi:10.1371/journal.pone.0147013

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 journal › Article › peer-review

20 Scopus citations

Abstract

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 language	English
Article number	e0147013
Journal	PLoS ONE
Volume	11
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0147013
State	Published - 11 Jan 2016
Externally published	Yes

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

abstract = "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.",

author = "Wang, {Ximi K.} and Monica Agarwal and Nataliya Parobchak and Alex Rosen and Vetrano, {Anna M.} and Aarthi Srinivasan and Bingbing Wang and Todd Rosen",

note = "Funding Information: M.A. is a recipient of 2014 Summer Research Fellowship Program of Rutgers Robert Wood Johnson Medical School. Publisher Copyright: Copyright {\textcopyright} 2016 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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AU - Wang, Ximi K.

AU - Agarwal, Monica

AU - Parobchak, Nataliya

AU - Rosen, Alex

AU - Vetrano, Anna M.

AU - Srinivasan, Aarthi

AU - Wang, Bingbing

AU - Rosen, Todd

N1 - Funding Information: M.A. is a recipient of 2014 Summer Research Fellowship Program of Rutgers Robert Wood Johnson Medical School. Publisher Copyright: Copyright © 2016 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016/1/11

Y1 - 2016/1/11

N2 - 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.

AB - 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.

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

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