Human ketosteroid receptors interact with hazardous phthalate plasticizers and their metabolites: an in silico study

Abstract

Phthalic acid esters or phthalates are ubiquitous environmental pollutants known for their adverse health effects in test animals and, of late, in humans. Thus, in this molecular docking study - using Glide (Schrödinger) - the molecular interactions of 31 ligands, including 12 diphthalates, their monophthalates and phthalic acid with selected human ketosteroid receptors, i.e., androgen (hAR), progesterone (hPR) and glucocorticoid (hGR) receptors were explored and their binding affinities were compared with that of corresponding natural steroids and a known endocrine disrupting xenobiotic, bisphenol A (BPA). Mostly, diphthalates and monophthalates showed the potential for antisteroidal activity by interacting with hAR, hPR and hGR. Of them, diphenyl phthalate showed the highest G score (-7.70 kcal mol(-1) ) with hAR, and the crucial amino acid (aa) residues in the ligand binding domain (LBD) of this receptor involved in the molecular interactions were Phe 764, Leu 704, Asn 705 and Thr 877. The mono-iso-decyl phthalate showed the highest G score (-8.36) with the hPR, and the crucial aa residues in the LBD interactions were Arg 766 Gln 725 and Phe 778. The mono-iso-decyl phthalate also showed more affinity (-8.44) towards hGR than the natural ligand, and the aa residues in the LBD interactions were Gln 570 and Met 604. In addition to these, some other phthalates established comparable interactions with certain aa residues located in the LBD of these receptors, which resulted in higher G scores. Contrastingly, BPA and some natural ligands tested in this study showed lower G scores with these receptors than certain phthalates reported herein, i.e., certain phthalates are more toxic than the proven toxic BPA. Copyright © 2015 John Wiley& Sons, Ltd.

Prenatal phthalate exposure: epigenetic changes leading to lifelong impact on steroid formation

“…DEHP and MEHP were predicted to have high binding affinities for the RXRs, particularly the human RXRα (Sarath Josh et al ., ). Similar docking studies have also shown interactions between phthalates and the human androgen, progesterone, and glucocorticoid nuclear receptors (Sarath Josh et al ., ). Whether DEHP or its metabolites plays a significant role by directly or partially interacting with these nuclear receptors needs to be experimentally confirmed.…”

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

“…Phthalates act as agonists or antagonists on the NRs [ 52 ]. In silico studies observed a high affinity of some phthalates to NRs: DPhP, MBzP, MEHP, BBzP, mono-(2-propylheptyl) phthalate (MPhP) to hAR [ 225 ], DINP, DPhP, BBzP, MPhP, DnOP to hERα; MPhP, MEHP, MnHP to hERβ [ 226 ], DINP, DnDP, DEHP, DnOP, BBzP, DPhP, DDP to hPPARα; DiDP, DnDP, mono-iso-decyl phthalate (MIDP), DINP, MEHP to hPPARγ [ 227 ]. Moreover, the study by Kambia et al [ 228 ] showed that the metabolites of the phthalate substituent–terephthalate, MEHHT, also had a higher affinity to ER and AR.…”

Accessing the molecular interactions of phthalates and their primary metabolites with the human pregnane X receptor using in silico profiling

“…Final optimization and minimization were performed as described in the Schrödinger Protein Preparation Wizard (PrepWizard). The preparation protocol added hydrogen, built side chains and loops with missing atoms, optimized the H‐bonding network and performed a restrained minimization to obtain the final structure of proteins for docking studies (Sarath Josh et al ., , , ).…”

“…Therefore, screening of phthalates as a potential ligand of hPXR would provide valuable information for pharmaceutical, as well as toxicological research. Molecular docking as an efficient tool in predicting the possible interactions between target receptors and phthalates for assessing the molecular cross‐talks within human systems has been reported previously (Sarath Josh et al ., , , ); such insights would enable us to assess the receptor activating or non‐activating capacity of the ligands under study. A literature survey showed the lack of in silico studies on the hazardous phthalates and their primary metabolites by depicting the interactions with the hPXR, thereby examining the ligand interactions of hazardous phthalates would be beneficial.…”