Endocrine disruption: In silico perspectives of interactions of di-(2-ethylhexyl)phthalate and its five major metabolites with progesterone receptor

Di-(2-ethylhexyl)phthalate (DEHP) is a common endocrine disrupting compound (EDC) present in the environment as a result of industrial activity and leaching from polyvinyl products. DEHP is used as a plasticizer in medical devices and many commercial and household items. Exposure occurs through inhalation, ingestion, and skin contact. DEHP is metabolized to a primary metabolite mono-(2-ethylhexyl)phthalate (MEHP) in the body, which is further metabolized to four major secondary metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5-OH-MEHP), mono(2-ethyl-5-oxyhexyl)phthalate (5-oxo-MEHP), mono(2-ethyl-5-carboxypentyl)phthalate (5-cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2-cx-MMHP). DEHP and its metabolites are associated with developmental abnormalities and reproductive dysfunction within the human population. Progesterone receptor (PR) signaling is involved in important reproductive functions and is a potential target for endocrine disrupting activities of DEHP and its metabolites. This study used in silico approaches for structural binding analyses of DEHP and its five indicated major metabolites with PR.

Protein Data bank was searched to retrieve the crystal structure of human PR (Id: 1SQN). PubChem database was used to obtain the structures of DEHP and its five metabolites. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.

DEHP and its metabolites interacted with 19-25 residues of PR with the majority of the interacting residues overlapping (82-95?% commonality) with the native bound ligand norethindrone (NET). DEHP and each of its five metabolites formed a hydrogen bonding interaction with residue Gln-725 of PR. The binding affinity was highest for NET followed by DEHP, 5-OH-MEHP, 5-oxo-MEHP, MEHP, 5-cx-MEPP, and 2-cx-MMHP.

The high binding affinity of DEHP and its five major metabolites with PR as well as a high rate of overlap between PR interacting residues among DEHP and its metabolites and the native ligand, NET, suggested their disrupting potential in normal PR signaling, resulting in adverse reproductive effects.