RESEARCH ARTICLE Disruption of Retinol (Vitamin A) Signaling by Phthalate Esters: SAR and Mechanism Studies Yanling Chen, David H. Reese* Division of Molecular Biology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. FDA, 8301 Muirkirk Rd., Laurel, MD, 20708, United States of America *
[email protected] a11111 Abstract A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production) in male rats exposed in utero to phthalate esters (PEs) are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP) were OPEN ACCESS shown to disrupt the retinol signaling pathway (RSP) in mouse pluripotent P19 embryonal Citation: Chen Y, Reese DH (2016) Disruption of carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid Retinol (Vitamin A) Signaling by Phthalate Esters: (RA), the active metabolite of retinol (vitamin A). In this new study, a total of 26 di- and SAR and Mechanism Studies. PLoS ONE 11(8): mono-esters were screened to identify additional phthalate structures that disrupt the RSP e0161167. doi:10.1371/journal.pone.0161167 and explore their mechanisms of action. The most potent PEs, those causing > 50% inhibi- Editor: Michael Schubert, Laboratoire de Biologie du tion, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same Développement de Villefranche-sur-Mer, FRANCE PEs reported to cause malformations in utero. They shared similar lipid solubility; logP val- Received: February 23, 2016 ues were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for Accepted: August 1, 2016 prolonged periods in culture.