In vitro and in silico hormonal activity studies of di‐(2‐ethylhexyl)terephthalate, a di‐(2‐ethylhexyl)phthalate substitute used in medical devices, and its metabolites

Kambia, Nicolas; Séverin, Isabelle; Farce, Amaury; Moreau, Emmanuel; Dahbi, Laurence; Duval, Claire; Dine, T.; Sautou, V.; Chagnon, Marie‐Christine

doi:10.1002/jat.3792

Cited by 32 publications

(34 citation statements)

References 48 publications

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“…In silico studies observed a high affinity of some phthalates to NRs: DPhP, MBzP, MEHP, BBzP, mono-(2-propylheptyl) phthalate (MPhP) to hAR [ 225 ], DINP, DPhP, BBzP, MPhP, DnOP to hERα; MPhP, MEHP, MnHP to hERβ [ 226 ], DINP, DnDP, DEHP, DnOP, BBzP, DPhP, DDP to hPPARα; DiDP, DnDP, mono-iso-decyl phthalate (MIDP), DINP, MEHP to hPPARγ [ 227 ]. Moreover, the study by Kambia et al [ 228 ] showed that the metabolites of the phthalate substituent–terephthalate, MEHHT, also had a higher affinity to ER and AR.…”

Section: Intracellular Signaling Mechanisms Of Phthalates’ Action mentioning

confidence: 99%

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Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Hlisníková

Petrovičová

Kolena

et al. 2020

IJERPH

146

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The production of plastic products, which requires phthalate plasticizers, has resulted in the problems for human health, especially that of reproductive health. Phthalate exposure can induce reproductive disorders at various regulatory levels. The aim of this review was to compile the evidence concerning the association between phthalates and reproductive diseases, phthalates-induced reproductive disorders, and their possible endocrine and intracellular mechanisms. Phthalates may induce alterations in puberty, the development of testicular dysgenesis syndrome, cancer, and fertility disorders in both males and females. At the hormonal level, phthalates can modify the release of hypothalamic, pituitary, and peripheral hormones. At the intracellular level, phthalates can interfere with nuclear receptors, membrane receptors, intracellular signaling pathways, and modulate gene expression associated with reproduction. To understand and to treat the adverse effects of phthalates on human health, it is essential to expand the current knowledge concerning their mechanism of action in the organism.

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Section: Intracellular Signaling Mechanisms Of Phthalates’ Action mentioning

confidence: 99%

“…This mechanism of action is called active antagonism and is shown in Figure 2 [ 233 ]. On the other side, phthalates can stimulate the activity of some NR [ 228 ]. ER and PPAR are not ligand-specific receptors.…”

Section: Intracellular Signaling Mechanisms Of Phthalates’ Action mentioning

confidence: 99%

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Hlisníková

Petrovičová

Kolena

et al. 2020

IJERPH

146

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“…This study demonstrated that DEHT and its metabolites exhibit much weaker effects on hormonal activities than DEHP. However, special attention must be paid to the 5-hydroxy metabolite of mono-(ethylhexyl)terephthalate (5-OH-MEHT) due to co-stimulation of estrogen alpha and human androgen receptors and an increase in estrogen synthesis [12].…”

Section: Introductionmentioning

confidence: 99%

Comparative Effects of Di-(2-ethylhexyl)phthalate and Di-(2-ethylhexyl)terephthalate Metabolites on Thyroid Receptors: In Vitro and In Silico Studies

et al. 2021

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Plasticizers added to polyvinylchloride (PVC) used in medical devices can be released into patients’ biological fluids. Di-(2-ethylhexyl)phthalate (DEHP), a well-known reprotoxic and endocrine disruptor, must be replaced by alternative compounds. Di-(2-ethylhexyl) terephthalate (DEHT) is an interesting candidate due to its lower migration from PVC and its lack of reprotoxicity. However, there is still a lack of data to support the safety of its human metabolites with regard to their hormonal properties in the thyroid system. The effects of DEHT metabolites on thyroid/hormone receptors (TRs) were compared in vitro and in silico to those of DEHP. The oxidized metabolites of DEHT had no effect on T3 receptors whereas 5-hydroxy-mono-(ethylhexyl)phthalate (5-OH-MEHP) appeared to be primarily an agonist for TRs above 0.2 µg/mL with a synergistic effect on T3. Monoesters (MEHP and mono-(2-ethylhexyl)terephthalate, MEHT) were also active on T3 receptors. In vitro, MEHP was a partial agonist between 10 and 20 µg/mL. MEHT was an antagonist at non-cytotoxic concentrations (2–5 µg/mL) in a concentration-dependent manner. The results obtained with docking were consistent with those of the T-screen and provide additional information on the preferential affinity of monoesters and 5-OH-MEHP for TRs. This study highlights a lack of interactions between oxidized metabolites and TRs, confirming the interest of DEHT.

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“…In a recent study [34], using luciferase assays for analyzing the androgenic or antiandrogenic activity of DEHP and its important metabolites, it was shown that in contrast to the antiandrogenic activity of DEHP, the primary and secondary metabolites did not show any activity with AR. Whereas, in another recent study [35], using similar luciferase assays, neither DEHP nor its major primary and secondary metabolites showed any antagonistic activity against AR. This is in contrast to the structural binding results in the present study in which DEHP and its metabolites interacted with AR and were predicted to exert antagonistic effects.…”

Section: Discussionmentioning

confidence: 82%

“…Very few studies have been reported on the potential adverse effects of endogenous DEHP metabolites on human body functions. Available in vitro and structural studies on selective DEHP metabolites with androgen receptor (AR) have reported conflicting results [33][34][35][36]. Widespread environmental distribution, commercial use, and human exposure of DEHP warrant a thorough toxicological investigation of its endogenous metabolites.…”

Section: Introductionmentioning

confidence: 99%

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

Beg

Sheikh

2020

Toxics

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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.

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In vitro and in silico hormonal activity studies of di‐(2‐ethylhexyl)terephthalate, a di‐(2‐ethylhexyl)phthalate substitute used in medical devices, and its metabolites

Cited by 32 publications

References 48 publications

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Effects and Mechanisms of Phthalates’ Action on Reproductive Processes and Reproductive Health: A Literature Review

Comparative Effects of Di-(2-ethylhexyl)phthalate and Di-(2-ethylhexyl)terephthalate Metabolites on Thyroid Receptors: In Vitro and In Silico Studies

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

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