Endocrine Disruption: Structural Interactions of Androgen Receptor against Di(2-ethylhexyl) Phthalate and Its Metabolites

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.

Chemical screening, insecticidal and reprotoxic activities of Tecoma stans ethanolic leaf extract against the vector mosquito Culex pipiens

“…Also, DMEHE was identified in ethyl acetate leaf extract of Amaranthus viridis (58.52%) which exhibited an antifungal activity (Akbar et al, 2020), and a strong larvicidal activity against Spodoptera exigua (Lepidoptera) (Rachokarn et al, 2008). Pure DMEHE caused human endocrine disruption (Beg & Sheikh, 2020), cytotoxic (Krishnan et al, 2014), antibacterial (Verma et al, 2014), and antifungal (Akpuaka et al, 2012) activities. Also, DMEHE as the main di(2‐ethylhexyl) phthalate metabolite, is a known reproductive toxicant (Kalo et al, 2019).…”

Toxicological Assessment of Oral Co-Exposure to Bisphenol A (BPA) and Bis(2-ethylhexyl) Phthalate (DEHP) in Juvenile Rats at Environmentally Relevant Dose Levels: Evaluation of the Synergic, Additive or Antagonistic Effects

“…BPA and DEHP are classified as EDs that mimic, block or interfere with the endocrine system, inducing a diverse array of health issues. BPA is a weak estrogen-like compound able to link to estrogen receptor alpha [ 40 ], whereas DEHP can disrupt androgen receptor signaling [ 41 ]. Results obtained with the computational tools contributed to put into evidence that the interactions between compounds are mainly of antagonism type, and it may be in part explained with the different mechanisms at receptor level.…”

Endocrine Disruptors and Prostate Cancer

“…The data have shown that DEHP and its metabolites interacted with the ligand-binding pocket of AR, forming amino-acid residue interactions, hydrogen bonding, and pi-pi interactions. This binding energy of DEHP with AR has been shown to be similar to that of native ligand T, and the amino-acid residue interactions of DEHP metabolites had 91-100% similarity compared to that of T [136]. Therefore, considering the structural binding data, the potential role of DEHP metabolites to disrupt AR signaling has been suggested, which may lead to androgen-related reproductive dysfunction.…”

“…An interesting recent in silico docking study has characterized the bond of DEHP and its metabolites with AR to predict the potential endocrine-disrupting effects of these metabolites in AR signaling [136]. The data have shown that DEHP and its metabolites interacted with the ligand-binding pocket of AR, forming amino-acid residue interactions, hydrogen bonding, and pi-pi interactions.…”