Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor α, β, γ subtypes: an in silico approach

Abstract

This exhaustive in silico study looks into the molecular interactions of phthalates and their metabolites with human peroxisome proliferator-activated receptor (hPPAR) and retinoid X receptor (hRXR) α, β and γ subtypes--the nuclear receptor proteins function as transcription factors by regulating the expression of downstream genes. Apart from the much discussed plasticizer bisphenol A, we examined the binding affinities of 15 common diphthalates and their monophthalates, natural (linoleic acid, conjugated linoleic acid) and synthetic (bezafibrate, pioglitazone, GW 50156) ligands with hPPARs. In addition to these phthalates, specific natural (retinoic and phytanic acids) and synthetic (bexarotene, rosiglitazone) ligands were examined with hRXRs. The Maestro, Schrödinger Suite 2012 was used for the molecular docking study. In general, natural ligands of hPPAR showed less binding efficiencies than phthalic acid esters and drugs. The diphthalate di-iso-decyl phthalate showed the highest G score (-9.99) with hPPAR (γ), while its monophthalate (mono-iso-decyl phthalate) showed a comparatively less G score (-9.56). Though the PPAR modulator GW 50156 showed strong affinity with all hPPAR subtypes, its highest G score (-12.43) was with hPPARβ. Hazardous di(2-ethylhexyl)phthalate generally showed a greater preference to hRXRs than hPPARs, but its highest G score (-10.87) was with hRXRα; while its monophthalate (Mono(2-ethylhexyl)phthalate) showed a lesser G score (-8.59). The drug bexarotene showed the highest G score (-13.32) with hRXRβ. Moreover, bisphenol A showed more affinity towards hRXR. Briefly, this study gives an overview on the preference of phthalic acid esters, natural and synthetic ligands on to hPPAR and hRXR subtypes, which would lead to further in vitro mechanistic as well as in vivo preclinical and clinical studies.

Effects of Diisodecyl Phthalate on PPAR:RXR-Dependent Gene Expression Pathways in Sea Bream Hepatocytes

“…This finding is not surprising because previous studies have demonstrated that other EDCs with putative obesogenic properties such as tributyltin (TBT), 6 bisphenol A (BPA), and DEHP 57 can activate the PPAR−RXR heterodimeric complex primarily through their interaction with RXR. 55,20 Overall, the potential binding of DiDP to each partner (i.e., PPAR and RXR) of the heterodimer can result in deregulated PPAR-RXR signaling pathways, which have been already observed following DEHP exposure. 56 Gene Expression Profile of DiDP-Treated Sea Bream Hepatocytes.…”

Effects of early exposure to phthalates and bisphenols on cardiometabolic outcomes in pregnancy and childhood

“…[35] Several phthalates have been shown to be PPARγ activators, causing obesogenic effects. [34-37] PPARs form heterodimers with the retinoid X receptors (RXRs), binding together on the target DNA and thereby activating the expression of downstream genes. Therefore, RXRs have the same targets as PPARs.…”

“…Many common phthalates have been shown to bind to RXRs. [37] Likewise, oxidative stress is a potential mechanism for phthalate effects. In a prospective cohort study of pregnant women all urinary phthalates were associated with increased oxidative stress markers.…”

“…[34, 35, 37] Besides the binding to PPARs, also BPA binds to RXRs with more affinity to RXRs. [37] Likewise, oxidative stress is a potential mechanism for BPA effects.…”

“…[34, 35, 37] Besides the binding to PPARs, also BPA binds to RXRs with more affinity to RXRs. [37] Likewise, oxidative stress is a potential mechanism for BPA effects. The same Puerto Rican prospective cohort study describing the association between phthalates during pregnancy and oxidative stress markers found a significant association between urinary BPA and oxidative stress markers in pregnant women.…”