Endocrine Disruption: Computational Perspectives on Human Sex Hormone-Binding Globulin and Phthalate Plasticizers.

Phthalates are a class of high volume production chemicals used as plasticizers for household and industrial use. Several members of this chemical family have endocrine disrupting activity. Owing to ubiquitous environmental distribution and exposure of human population at all stages of life, phthalate contamination is a continuous global public health problem. Clinical and experimental studies have indicated that several phthalates are associated with adverse effects on development and function of human and animal systems especially the reproductive system and exposures during pregnancy and early childhood are by far of utmost concern. Sex hormone-binding globulin (SHBG) is a plasma carrier protein that binds androgens and estrogens and represents a potential target for phthalate endocrine disruptor function in the body. In the present study, the binding mechanism of the nine phthalates i.e. DMP, DBP, DIBP, BBP, DNHP, DEHP, DNOP, DINP, DIDP with human SHBG was delineated by molecular docking simulation. Docking complexes of the nine phthalates displayed interactions with 15-31 amino acid residues of SHBG and a commonality of 55-95% interacting residues between natural ligand of SHBG, dihydrotestosterone, and the nine phthalate compounds was observed. The binding affinity values were more negative for long chain phthalates DEHP, DNOP, DINP, and DIDP compared to short chain phthalates such as DMP and DBP. The Dock score and Glide score values were also higher for long chain phthalates compared to short chain phthalates. Hence, overlapping of interacting amino acid residues between phthalate compounds and natural ligand, dihydrotestosterone, suggested potential disrupting activity of phthalates in the endocrine homeostasis function of SHBG, with long chain phthalates expected to be more potent than the short chain phthalates

Amino-acid residues in the binding pocket of human sex hormone-binding globulin (SHBG) involved in interactions with dimethyl phthalate (DMP), dibutyl phthalate (DBP), di-iso-butyl phthalate (DIBP), butylbenzyl phthalate (BBP).

<p>Amino-acid residues in the binding pocket of human sex hormone-binding globulin (SHBG) involved in interactions with dimethyl phthalate (DMP), dibutyl phthalate (DBP), di-iso-butyl phthalate (DIBP), butylbenzyl phthalate (BBP).</p

Nomenclature, commonly used abbreviations, and PubChem IDs of the ligands for docking study with human sex hormone-binding globulin (SHBG).

<p>Nomenclature, commonly used abbreviations, and PubChem IDs of the ligands for docking study with human sex hormone-binding globulin (SHBG).</p

Crystal structure of human sex hormone-binding globulin (SHBG) in ribbon form representation co-complexed with dihydrotestosterone (DHT) (left panel) and two dimensional representation of DHT (right panel).

<p>Crystal structure of human sex hormone-binding globulin (SHBG) in ribbon form representation co-complexed with dihydrotestosterone (DHT) (left panel) and two dimensional representation of DHT (right panel).</p

Amino-acid residues in the binding pocket of human sex hormone-binding globulin (SHBG) involved in interactions with di-iso-decyl phthalate (DIDP) and natural ligand, dihydrotestosterone (DHT).

<p>Amino-acid residues in the binding pocket of human sex hormone-binding globulin (SHBG) involved in interactions with di-iso-decyl phthalate (DIDP) and natural ligand, dihydrotestosterone (DHT).</p

Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update

Abstract Background Preterm birth (PTB), birth at <37 weeks of gestation, is a significant global public health problem. World-wide, about 15 million babies are born preterm each year resulting in more than a million deaths of children. Preterm neonates are more prone to problems and need intensive care hospitalization. Health issues may persist through early adulthood and even be carried on to the next generation. Majority (70 %) of PTBs are spontaneous with about a half without any apparent cause and the other half associated with a number of risk factors. Genetic factors are one of the significant risks for PTB. The focus of this review is on single nucleotide gene polymorphisms (SNPs) that are reported to be associated with PTB. Results A comprehensive evaluation of studies on SNPs known to confer potential risk of PTB was done by performing a targeted PubMed search for the years 2007–2015 and systematically reviewing all relevant studies. Evaluation of 92 studies identified 119 candidate genes with SNPs that had potential association with PTB. The genes were associated with functions of a wide spectrum of tissue and cell types such as endocrine, tissue remodeling, vascular, metabolic, and immune and inflammatory systems. Conclusions A number of potential functional candidate gene variants have been reported that predispose women for PTB. Understanding the complex genomic landscape of PTB needs high-throughput genome sequencing methods such as whole-exome sequencing and whole-genome sequencing approaches that will significantly enhance the understanding of PTB. Identification of high risk women, avoidance of possible risk factors, and provision of personalized health care are important to manage PTB