scholarly journals Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures

2020 ◽  
Vol 118 (1) ◽  
pp. e2020551118
Author(s):  
Vanessa Delfosse ◽  
Tiphaine Huet ◽  
Deborah Harrus ◽  
Meritxell Granell ◽  
Maxime Bourguet ◽  
...  
Keyword(s):  
Low Dose ◽  
Endocrine Disrupting Chemicals ◽  
Pregnane X Receptor ◽  
Binding Pocket ◽  
Synergistic Activation ◽  
Endocrine Disrupting ◽  
Xenobiotic Response ◽  
Binding Mechanisms ◽  
Shed Light

Humans are chronically exposed to mixtures of xenobiotics referred to as endocrine-disrupting chemicals (EDCs). A vast body of literature links exposure to these chemicals with increased incidences of reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, chemicals have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects. Our previous work shed light on a mechanism by which a binary mixture of xenobiotics activates PXR in a synergistic fashion. Structural analysis revealed that mutual stabilization of the compounds within the ligand-binding pocket of PXR accounts for the enhancement of their binding affinity. In order to identify and characterize additional active mixtures, we combined a set of cell-based, biophysical, structural, and in vivo approaches. Our study reveals features that confirm the binding promiscuity of this receptor and its ability to accommodate bipartite ligands. We reveal previously unidentified binding mechanisms involving dynamic structural transitions and covalent coupling and report four binary mixtures eliciting graded synergistic activities. Last, we demonstrate that the robust activity obtained with two synergizing PXR ligands can be enhanced further in the presence of RXR environmental ligands. Our study reveals insights as to how low-dose EDC mixtures may alter physiology through interaction with RXR–PXR and potentially several other nuclear receptor heterodimers.

scholarly journals In Vivo Testing System for Determining the Estrogenic Activity of Endocrine-Disrupting Chemicals(EDCs) in Goldfish (Carassius auratus).

2001 ◽  
Vol 47 (2) ◽  
pp. 213-218 ◽  
Author(s):  
Hiroshi Ishibashi ◽  
Katsuyasu Tachibana ◽  
Mutsuyosi Tsuchimoto ◽  
Kiyoshi Soyano ◽  
Yasuhiro Ishibashi ◽  
...  
Keyword(s):  
Carassius Auratus ◽  
Estrogenic Activity ◽  
Endocrine Disrupting Chemicals ◽  
Testing System ◽  
Goldfish Carassius Auratus ◽  
Endocrine Disrupting ◽  
In Vivo Testing

scholarly journals Endocrine Disrupting Chemicals, Phthalic Acid and Nonylphenol, Activate Pregnane X Receptor-Mediated Transcription

2000 ◽  
Vol 14 (3) ◽  
pp. 421-428 ◽  
Author(s):  
Hisashi Masuyama ◽  
Yuji Hiramatsu ◽  
Mamoru Kunitomi ◽  
Takafumi Kudo ◽  
Paul N. MacDonald
Keyword(s):  
Gene Expression ◽  
Bisphenol A ◽  
Nuclear Receptor ◽  
Phthalic Acid ◽  
Steroid Hormone ◽  
Endocrine Disrupting Chemicals ◽  
Pregnane X Receptor ◽  
Specific Gene ◽  
Hormone Metabolism ◽  
Endocrine Disrupting

Abstract Recently, Pregnane X receptor (PXR), a new member of the nuclear receptor superfamily, was shown to mediate the effects of several steroid hormones, such as progesterone, glucocorticoid, pregnenolone, and xenobiotics on cytochrome P450 3A genes (CYP3A) through the specific DNA sequence for CYP3A, suggesting that PXR may play a role in steroid hormone metabolism. In this paper, we demonstrated that phthalic acid and nonylphenol, endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated transcription at concentrations comparable to those at which they activate estrogen receptor-mediated transcription using a transient reporter gene expression assay in COS-7 cells. However, bisphenol A, another EDC, had no effect on PXR-mediated transcription, although this chemical significantly enhanced ER-mediated transcription. In the yeast two-hybrid protein interaction assay, PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol. Thus, EDC-occupied PXR may regulate its specific gene expression through the receptor-coactivator interaction. In contrast, these EDCs had no effect on the interaction between PXR and suppressor for gal 1, a component of proteasome. Finally, the expression of CYP3A1 mRNA in the liver of rats exposed to phthalic acid or nonylphenol markedly increased compared with that in rats treated with estradiol, bisphenol A, or ethanol as assessed by competitive RT-PCR. These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR.

scholarly journals Assessment and Molecular Actions of Endocrine-Disrupting Chemicals That Interfere with Estrogen Receptor Pathways

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Gwenneg Kerdivel ◽  
Denis Habauzit ◽  
Farzad Pakdel
Keyword(s):  
Synergistic Effects ◽  
Animal Health ◽  
Endocrine Disrupting Chemicals ◽  
Estrogen Signaling ◽  
Synthetic Chemicals ◽  
Endocrine Disrupting ◽  
And Function ◽  
Analytical Tools

In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel ofin vivoandin vitrobioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens.

scholarly journals Membrane filtration in water recycling: removal of natural hormones

2003 ◽  
Vol 3 (3) ◽  
pp. 155-160 ◽  
Author(s):  
L.D. Nghiem ◽  
A.I. Schäfer ◽  
T.D. Waite
Keyword(s):  
Membrane Filtration ◽  
Endocrine Disrupting Chemicals ◽  
In Vivo Studies ◽  
Water Recycling ◽  
Endocrine Disrupting ◽  
Adsorptive Behavior ◽  
Stirred Cell ◽  
Natural Hormones

Recent detections of endocrine-disrupting chemicals (EDCs) in effluent are of great concern to sections of the community associated with the issue of water recycling. In vitro and in vivo studies by many researchers have confirmed the impacts of EDCs on trout at the common concentration encountered in sewage effluent. Amongst many types of EDCs the impacts of steroid estrogens such as estrone, estradiol (natural hormones) and ethinylestradiol (a synthetic hormone) are prominent as they have far higher endocrine-disrupting potency than other synthetic EDCs. Given the continuous developments in membrane technology, tertiary treatment using membrane processes has been identified as a promising technology to provide a safeguard to water recycling practice and to protect the environment. This paper investigates retention and adsorptive behavior of the natural hormones estrone and estradiol by two commercial low-pressure nanofiltration membranes TFC-SR2 and TFC-S, using dead end stirred cell systems. The removal phenomena of estradiol are similar to that of estrone. pH has been found to significantly influence the adsorption of estrone and estradiol by the membranes, presumably due to hydrogen bonding. This adsorption is critical in the risk of possible release of such hormones to the product waters. Total adsorbed amounts were calculated for standard membrane elements and are indeed important.

Developing a Laboratory Animal Model for Perinatal Endocrine Disruption: The Hamster Chronicles

2002 ◽  
Vol 227 (9) ◽  
pp. 709-723 ◽  
Author(s):  
William J. Hendry ◽  
Daniel M. Sheehan ◽  
Shafiq A. Khan ◽  
Jeffrey V. May
Keyword(s):  
Endocrine Disruption ◽  
Reproductive Tract ◽  
Developmental Toxicity ◽  
Endocrine Disrupting Chemicals ◽  
Experimental System ◽  
Endocrine Disrupting ◽  
Considerable Concern ◽  
Insight Into ◽  
Future Plans

At the biomedical, regulatory, and public level, considerable concern surrounds the concept that inappropriate exposure to endocrine-disrupting chemicals, especially during the prenatal and/or neonatal period, may disrupt normal reproductive tract development and adult function. The intent of this review was to 1. Describe some unique advantages of the hamster for perinatal endocrine disruptor (ED) studies, 2. Summarize the morphological and molecular consequences of exposure to the established perinatal ED, diethylstilbestrol, in the female and male hamster, 3. Present some new, histomorphological insight into the process of neonatal diethylstilbestrol-induced disruption in the hamster uterus, and 4. Introduce recent efforts and future plans to evaluate the potency and mechanism of action of other putative EDs in the hamster experimental system. Taken together, the findings indicate that the hamster represents a unique and sensitive in vivo system to probe the phenomenon of endocrine disruption. The spectrum of candidate endpoints includes developmental toxicity, neoplasia, and more subtle endpoints of reproductive dysfunction.

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