Estrogenic Activities of 517 Chemicals by Yeast Two-Hybrid Assay
01 Aug 2000-Journal of Health Science (The Pharmaceutical Society of Japan)-Vol. 46, Iss: 4, pp 282-298
TL;DR: A simple and rapid screening method using the yeast two-hybrid system based on the ligand-dependent interaction of nuclear hormone receptors with coactivators to test the estrogenic activity of chemicals.
Abstract: One of the urgent tasks in understanding endocrine disruptors (EDs) is to compile a list of suspected substances among the huge number of chemicals by using the screening test method. We developed a simple and rapid screening method using the yeast two-hybrid system based on the ligand-dependent interaction of nuclear hormone receptors with coactivators. To date, we have tested the estrogenic activity of more than 500 chemicals including natural substances, medicines, pesticides, and industrial chemicals. 64 compounds were evaluated as positive, and most of these demonstrated a common structure; phenol with a hydrophobic moiety at the para-position without bulky groups at the ortho-position. These results are expected to facilitate further risk assessment of chemicals.
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TL;DR: It is suggested that MBP has high toxicity for early life stages of the medaka, and that the estrogenic activity of MBP was about 250-fold higher than that of BPA to male medaka.
68 citations
TL;DR: The development and use of an EDA approach to identify endocrine-disrupting chemicals in a multi-contaminated river sediment revealed that ER and PXR activities were mainly due to polar to mid-polar compounds, while dioxin-like and anti-androgenic activities were in the less polar fractions.
Abstract: Effect-directed analysis (EDA)-based strategies have been increasingly used in order to identify the causative link between adverse (eco-)toxic effects and chemical contaminants. In this study, we report the development and use of an EDA approach to identify endocrine-disrupting chemicals (EDCs) in a multi-contaminated river sediment. The battery of in vitro reporter cell-based bioassays, measuring estrogenic, (anti)androgenic, dioxin-like, and pregnane X receptor (PXR)-like activities, revealed multi-contamination profiles. To isolate active compounds of a wide polarity range, we established a multi-step fractionation procedure combining: (1) a primary fractionation step using normal phase-based solid-phase extraction (SPE), validated with a mixture of 12 non-polar to polar standard EDCs; (2) a secondary fractionation using reversed-phase-based high-performance liquid chromatography (RP-HPLC) calibrated with 33 standard EDCs; and (3) a purification step using a recombinant estrogen receptor (ER) affinity column. In vitro SPE and HPLC profiles revealed that ER and PXR activities were mainly due to polar to mid-polar compounds, while dioxin-like and anti-androgenic activities were in the less polar fractions. The overall procedure allowed final isolation and identification of new environmental PXR (e.g., di-iso-octylphthalate) and ER (e.g., 2,4-di-tert-butylphenol and 2,6-di-tert-butyl-α-methoxy-p-cresol) ligands by using gas chromatography coupled with mass spectrometry with full-scan mode acquisition in mid-polar fractions. In vitro biological activity of these chemicals was further confirmed using commercial standards, with di-iso-octylphthalate identified for the first time as a potent hPXR environmental agonist.
67 citations
Cites background from "Estrogenic Activities of 517 Chemic..."
..., BHT or 2,6-di-tert-butyl-para-cresol) and p-cresol, which are structurally closed, were described as human ER ligands [38, 39]....
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TL;DR: The endocrine disruption potential of BPA replacement compounds in the market was assessed to assist their safety evaluations and revealed hydrophobic contacts and hydrogen bonds as the main interactions between ER and the estrogenic compounds.
Abstract: Bisphenol A (BPA) replacement compounds are released to the environment and cause widespread human exposure. However, a lack of thorough safety evaluations on the BPA replacement compounds has raised public concerns. We assessed the endocrine disruption potential of BPA replacement compounds in the market to assist their safety evaluations. A literature search was conducted to ascertain the BPA replacement compounds in use. Available experimental estrogenic activity data of these compounds were extracted from the Estrogenic Activity Database (EADB) to assess their estrogenic potential. An in silico model was developed to predict the estrogenic activity of compounds lacking experimental data. Molecular dynamics (MD) simulations were performed to understand the mechanisms by which the estrogenic compounds bind to and activate the estrogen receptor (ER). Forty-five BPA replacement compounds were identified in the literature. Seven were more estrogenic and five less estrogenic than BPA, while six were nonestrogenic in EADB. A two-tier in silico model was developed based on molecular docking to predict the estrogenic activity of the 27 compounds lacking data. Eleven were predicted as ER binders and 16 as nonbinders. MD simulations revealed hydrophobic contacts and hydrogen bonds as the main interactions between ER and the estrogenic compounds.
65 citations
TL;DR: Structure–activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae‐based Lac‐Z reporter assay and the hydrogen‐bonding ability of hydroxy group in the 3‐position on 17β‐estradiol was observed to be essential for gene activation.
Abstract: Structure–activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae-based Lac-Z reporter assay. Relative gene activation was compared to 17β-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17β-estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen-bonding ability of the phenolic ring mimicking the A-ring, (2) a hydrophobic centre similar in size and shape to the B- and C-rings, and (3) a hydrogen-bond donor mimicking the 17β-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17β-hydroxyl groups of 17β-estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen-bonding ability of hydroxy group in the 3-position on 17β-estradiol was observed to be essential for gene activation. Compounds with a 4-hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B-ring of 17β-estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4-hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B- and C-ring of 17β-estradiol, or have a high hydrogen-bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4′-diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen-to-oxygen distance close to that exhibited by the 3- and 17-hydroxyl groups of 17β-estradiol. © 2002 by Wiley Periodicals, Inc. Environ Toxicol 17: 14–23, 2002
64 citations
01 Nov 2010
TL;DR: The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects infonnation for these toxic substances described therein and begins with a public health statement that describes a substance's relevant toxicological properties.
Abstract: DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. A Toxicological Profile for Ethylbenzene, Draft for Public Comment was released in October 2007. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary. For information regarding the update status of previously released profiles, contact ATSDR at: FOREWORD This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects infonnation for these toxic substances described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. The focus of the profiles is on health and toxicologic infonnation; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is infonnation concerning levels of significant human exposure and, where known, significant health effects. The adequacy of infonnation to detennine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic infonnation and epidemiologic evaluations on a toxic substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects; (B) A determination of whether adequate infonnation on the health effects of each substance is available or in the process of development to detennine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and (C) Where appropriate, identification of toxicologic testing needed to identifY the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the Federal, State, and local levels; …
64 citations
References
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Book•
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01 Jan 1996
TL;DR: The cause of disruptions in animal breeding cycles, accompanied by increases in birth defects, sexual abnormalities and reproductive failure, is traced to the pervasive presence in the environment of chemicals that mimic hormones and trick the reproductive system.
Abstract: For years, scientists have noticed disruptions in animal breeding cycles, accompanied by increases in birth defects, sexual abnormalities and reproductive failure. Humans are not immune either, with sperm counts dropping by as much as 50% in recent decades and with women seeing a rise in hormone-related cancers, endometriosis and other disorders. This book traces the cause of these aberrations and diseases to the pervasive presence in the environment of chemicals that mimic hormones and trick the reproductive system. The conclusions are as obvious as they are inescapable - unless we make vital changes in the way we manufacture and employ the artefacts of our "good life", there will be no life at all.
917 citations