Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin

Abstract

Endocrine disruption is a phenomenon when a man-made or natural compound interferes with normal hormone function in human or animal body systems. Endocrine-disrupting compounds (EDCs) have assumed considerable importance as a result of industrial activity, mass production of synthetic chemicals and environmental pollution. Phthalate plasticizers are a group of chemicals used widely and diversely in industry especially in the plastic industry, and many of the phthalate compounds have endocrine-disrupting properties. Increasing evidence indicates that steroid nuclear receptors and steroid binding proteins are the main targets of endocrine disruption. Corticosteroid-binding globulin (CBG) is a steroid binding protein that binds and transports cortisol in the blood circulation and is a potential target for endocrine disruption. An imbalance of cortisol in the body leads to many health problems. Induced fit docking of nine important and environmentally relevant phthalate plasticizers (DMP, BBP, DBP, DIBP, DnHP, DEHP, DINP, DnOP, DIDP) showed interactions with 10-19 amino acid residues of CBG. Comparison of the interacting residues of CBG with phthalate ligands and cortisol showed an overlapping of the majority (53-82%) of residues for each phthalate. Five of nine phthalate compounds and cortisol shared a hydrogen bonding interaction with the Arg-252 residue of CBG. Long-chain phthalates, such as DEHP, DINP, DnOP and DIDP displayed a higher binding affinity and formed a number of interactions with CBG in comparison to short-chain phthalates. The similarity in structural binding characteristics of phthalate compounds and native ligand cortisol suggested potential competitive conflicts in CBG-cortisol binding function and possible disruption of cortisol and progesterone homeostasis.

Sea Anemones Responding to Sex Hormones, Oxybenzone, and Benzyl Butyl Phthalate: Transcriptional Profiling and in Silico Modelling Provide Clues to Decipher Endocrine Disruption in Cnidarians

“…Five GOIs ( 17βHSD14, 17βHSD12, NPC2, PTCH3, SMO ) that have sterol binding pockets were used in silico modelling. In silico modelling has previously demonstrated phthalates and steroids without an aromatic A-ring are capable of binding to sterol-binding proteins ( Sheikh and Beg, 2017 ; Khalturin et al, 2018 ). Patched genes have multiple functionally redundant homologs that cannot discriminate between ligands ( Carpenter et al, 1998 ; Zhulyn et al, 2015 ; Hu and Song, 2019 ).…”

Structural binding perspectives of common plasticizers and a flame retardant, BDE‐153, against thyroxine‐binding globulin: potential for endocrine disruption

“…Therefore, in view of their wide‐ranging applications along with the leach out propensity, environmental contamination occurs, and both humans and animals are extensively exposed to plasticizers. Recent studies have reported the potential interference of plasticizers with various endocrine pathways resulting in signaling disruption (Sheikh, 2016; Sheikh et al, 2016; Sheikh & Beg, 2017, 2019).…”

Experimental cryptorchidism enhances testicular susceptibility to dibutyl phthalate or acrylamide in Sprague-Dawley rats

“…7 The potential mechanisms underlying phthalate toxicity remain unclear but endocrine disruption is a possibility. 8 In particular, exposure to dibutyl phthalate (DBP) has been reported to be associated with reduced levels of testosterone and reduced anogenital distance (AGD) in newborns, a sexually dimorphic landmark indicative of altered fetal androgen levels. 9,10 Perinatal exposure of rats to some phthalates, including DBP, results in a range of reproductive tract defects in male offspring, including reduced AGD, CPT, multinucleated gonocytes, and reduced semen quality.…”