Abstract
Diethylhexyl phthalate (DEHP) is a commonly used plasticizer in the manufacture of polyvinyl chloride plastics for household and commercial use. DEHP is a ubiquitous ecocontaminant and causes developmental and reproductive problems in children and adults. After exposure, DEHP is metabolized by endogenous hydrolysis and oxidation into the primary metabolite, mono-(2-ethylhexyl) phthalate (MEHP), and the secondary metabolites, mono-(2-ethyl-5-hydroxhexyl)phthalate (5-OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (5-oxo-MEHP), mono-(2-ethyl-5-carboxypentyl) phthalate (5-cx-MEPP), and mono-[(2-carboxymethyl)hexyl] phthalate (2-cx-MMHP). Very few studies have been reported on the adverse effects of DEHP metabolites, and the available information indicates that the metabolites might also be equally or more active as compared to the parent compound. In the present study, induced fit docking was used for structural binding characterization of the above five DEHP metabolites with androgen receptor (AR) to predict the potential endocrine-disrupting effects of these metabolites in AR signaling. All the DEHP metabolites interacted with the ligand-binding pocket of AR forming amino-acid residue interactions, hydrogen bonding, and pi-pi interactions. The binding energy of DEHP with AR was similar to that of native ligand testosterone. The amino-acid residue interactions of DEHP metabolites had 91–100% similarity compared to that of testosterone. In addition, all the DEHP metabolites and testosterone showed a common hydrogen bonding interaction with amino-acid Arg-752 of AR. Taken together, the structural binding data in the present study suggested the potential for DEHP metabolites to disrupt AR signaling, which may lead to androgen-related reproductive dysfunction.
Highlights
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical prepared commercially from phthalic anhydride with an excess of 2-ethylhexanol in the presence of an acid catalyst and is the single largest plasticizer by production volume used in the world [1,2,3]
The structural binding data in the present study suggested the potential for DEHP metabolites to disrupt androgen receptor (AR) signaling, which may lead to androgen-related reproductive dysfunction
The Induced Fit Docking (IFD) approaches used in this study showed that DEHP and its metabolites docked deep in the ligand-binding domain of AR forming various interactions with a number of amino-acids
Summary
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical prepared commercially from phthalic anhydride with an excess of 2-ethylhexanol in the presence of an acid catalyst and is the single largest plasticizer by production volume used in the world [1,2,3]. Even though the production and use of DEHP are declining due to the reported adverse effects on human health, it is forecasted to constitute more than one-third of about 10 million tons of the total plasticizer market in the world in 2024 [4,5]. The main (95%) applications of DEHP are for polymer uses such as toys, footwear, shower curtains, wire and cable coating, electronic component parts, molds, Toxics 2020, 8, 115; doi:10.3390/toxics8040115 www.mdpi.com/journal/toxics. DEHP has been officially prohibited for use in the manufacture of children’s toys in the United States since 2009 and has been categorized as a Group 2B human carcinogen by the United States Environmental Protection
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