Human sex hormone-binding globulin as a potential target of alternate plasticizers: an in silico study

Abstract

BackgroundCurrently, alternate plasticizers are used to replace phthalate plasticizers in children’s toys, medical equipments and food packaging, due to the adverse effects of phthalate compounds on human health and laws prohibiting their use. Current information regarding the safety and potential adverse effects of alternate plasticizers is limited and recent studies have found alternate plasticizers to display similar characteristics to those observed in phthalate plasticizers. This study was undertaken to evaluate and predict the potential endocrine disrupting activity of the three most commonly used alternate plasticizers: di(2-ethylhexyl)terephthalate (DEHT), tris(2-ethylhexyl)trimellitate (TOTM), and diisononyl hexahydrophthalate (DINCH) against human sex hormone-binding globulin (SHBG) using in silico approaches.Materials and methodsThe crystal structure of human SHBG (Id: 1D2S) was retrieved from Protein Data Bank. PubChem database was searched for the structures of alternate plasticizers, DEHT, TOTM, and DINCH. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.ResultsInduced Fit Docking of three alternate plasticizer compounds indicated that each of the three compounds fitted well into the steroid binding pocket of SHBG. Docking displays showed interactions of alternate plasticizers with 25–30 amino-acid residues of SHBG; 18–20 amino residues overlapped between the natural ligand, DHT, and the three compounds (commonality of 82–91 %). The hydrogen-bonding interaction of the amino-acid residue, Asn-82, of SHBG was also present in displays of DHT and all the three alternate phthalates. The binding affinity of all the three alternate phthalates was higher than DHT; maximum in DINCH followed by TOTM and DEHT.ConclusionOur results suggested that the three alternate plasticizers have potential to engage the important interacting residues of SHBG and thus interfere in its steroid homeostatic function.

Potential Health Risk of Endocrine Disruptors in Construction Sector and Plastics Industry: A New Paradigm in Occupational Health

“…There is a significant lack of data on endocrine potency of these replacement phthalates. This highlights a need for further investigation especially as in silico results show they interfere with human sex hormone-binding globulin [ 66 ] and increase insulin resistance [ 67 ]. In 2002, the plasticizer 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the European market as a substitute for DEHP.…”

Sex Differences in the Association of Urinary Concentrations of Phthalates Metabolites with Self-Reported Diabetes and Cardiovascular Diseases in Shanghai Adults

“…SHBG is hormone-related biomarker that has been reported to affect free-circulating hormone levels and represents a potential target for the phthalates endocrine disruptor function in the human body [ 56 ]. Phthalates have been suggested to have a potential disrupting activity in the endocrine homeostasis function of SHBG [ 57 , 58 , 59 ].…”

Association between Urinary Metabolites and the Exposure of Intensive Care Newborns to Plasticizers of Medical Devices Used for Their Care Management

“…To date, no endocrine disruption effect has been assessed with DINP metabolites, but recent data shows that the parent plasticizer (DINP) exhibits a binding affinity with SHBG in the in silico study of Sheikh et al [ 27 ], with a docking complex that forms 86% of interactions. Moreover, DINP exposure led to significant transcriptional changes even at low-exposure concentrations, suggesting a great endocrine disruption potency when tested in zebrafish in the work of Lee et al [ 35 ].…”

“…Children’s exposure to DINCH should be investigated carefully as the total exposure may be close to the tolerable daily intake according to the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) public report [ 26 ]. Moreover, Sheick et al [ 27 ] recently observed that DINCH showed high binding affinity with sex hormone binging globulin (SHBG), suggesting that the alternate plasticizer has potential to strongly inhibit the steroid binding function of SHBG. Therefore, it cannot be excluded that DINCH can cause a potential disruption effect on the androgen and estrogen homeostasis of SHBG and thus interfere with steroid signaling functions.…”