Amphibians as a model to study endocrine disruptors: II. Estrogenic activity of environmental chemicals in vitro and in vivo

1999 ◽  
Vol 225 (1-2) ◽  
pp. 59-68 ◽  
Author(s):  
Werner Kloas ◽  
Ilka Lutz ◽  
Ralf Einspanier
Keyword(s):  
Endocrine Disruptors ◽  
Estrogenic Activity ◽  
Environmental Chemicals

Endocrine Disruptors: A Critical Review of In Vitro and In Vivo Testing Strategies for Assessing Their Toxic Hazard to Humans

2000 ◽  
Vol 28 (1) ◽  
pp. 81-118 ◽  
Author(s):  
Robert D. Combes
Keyword(s):  
Endocrine Disruptors ◽  
Human Exposure ◽  
Mechanisms Of Action ◽  
Environmental Chemicals ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Wide Range ◽  
The Us

Currently, there is much concern that a wide range of both synthetic and naturally occurring environmental chemicals can act as endocrine disruptors (EDs), and can adversely affect humans and wildlife. Many in vivo and in vitro tests have been proposed for screening EDs, and several regulatory agencies, including the US Environmental Protection Agency (EPA), have recommended tier-testing schemes. Unfortunately, most of the proposed toxicity tests have substantial problems, including non-specificity and lack of reproducibility. There is also uncertainty concerning their relevance for generating useful hazard data for risk assessment purposes, in view of the diversity of the possible ED mechanisms of action (for example, receptor binding, steroidogenesis and modulation of the homeostatic processes which regulate endogenous responses to hormones). Moreover, most of the suggested test methods have yet to be validated according to internationally accepted criteria, although the OECD and the US EPA have defined tests for validation, and an interlaboratory “prevalidation” exercise has been initiated by the OECD. All this is compounded by the lack of information regarding human exposure levels to EDs, and a lack of direct evidence for a causal link between exposure and the development of adverse human health effects. In addition, the regulatory testing of EDs has important negative implications for animal welfare, as some of the proposed in vivo tests require large group sizes of animals and stressful procedures. From a detailed analysis of the available published literature, it is concluded that it is impossible to assess the relative values of currently available in vitro and in vivo toxicity tests for EDs, or to recommend any test or test battery. Any plans for the widespread testing of EDs are therefore premature and might be unnecessary, at least for detecting possible human effects. Several recommendations are made for rectifying this unsatisfactory situation, including the postponement of screening programmes pending: a) more information on human exposure; b) further details of the mechanisms of action of EDs; and c) the development of improved tests, followed by their proper scientific validation.

scholarly journals Human Oligodendrocytes and Myelin In Vitro to Evaluate Developmental Neurotoxicity

2021 ◽  
Vol 22 (15) ◽  
pp. 7929
Author(s):  
Megan Chesnut ◽  
Thomas Hartung ◽  
Helena Hogberg ◽  
David Pamies
Keyword(s):  
Large Scale ◽  
In Vitro Models ◽  
Environmental Chemicals ◽  
Developmental Neurotoxicity ◽  
In Vivo Studies ◽  
Regulatory Guidelines ◽  
In Vitro Systems ◽  
Human Oligodendrocytes

Neurodevelopment is uniquely sensitive to toxic insults and there are concerns that environmental chemicals are contributing to widespread subclinical developmental neurotoxicity (DNT). Increased DNT evaluation is needed due to the lack of such information for most chemicals in common use, but in vivo studies recommended in regulatory guidelines are not practical for the large-scale screening of potential DNT chemicals. It is widely acknowledged that developmental neurotoxicity is a consequence of disruptions to basic processes in neurodevelopment and that testing strategies using human cell-based in vitro systems that mimic these processes could aid in prioritizing chemicals with DNT potential. Myelination is a fundamental process in neurodevelopment that should be included in a DNT testing strategy, but there are very few in vitro models of myelination. Thus, there is a need to establish an in vitro myelination assay for DNT. Here, we summarize the routes of myelin toxicity and the known models to study this particular endpoint.

Evaluation of Estrogenic Activity of Wastewater: Comparison Among In Vitro ERα Reporter Gene Assay, In Vivo Vitellogenin Induction, and Chemical Analysis

2015 ◽  
Vol 49 (10) ◽  
pp. 6319-6326 ◽  
Author(s):  
Masaru Ihara ◽  
Tomokazu Kitamura ◽  
Vimal Kumar ◽  
Chang-Beom Park ◽  
Mariko O. Ihara ◽  
...  
Keyword(s):  
Chemical Analysis ◽  
Reporter Gene ◽  
Estrogenic Activity ◽  
Reporter Gene Assay ◽  
Gene Assay

scholarly journals Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jianan Zhang ◽  
Morgan E. Walker ◽  
Katherine Z. Sanidad ◽  
Hongna Zhang ◽  
Yanshan Liang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Metabolic Activation ◽  
Consumer Products ◽  
Environmental Chemicals ◽  
Intestinal Microbes ◽  
Targeted Inhibition

AbstractEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

scholarly journals ADME/Tox Properties and Biochemical Interactions of Silybin Congeners: In silico Study

2017 ◽  
Vol 12 (2) ◽  
pp. 1934578X1701200 ◽  
Author(s):  
Antonia Diukendjieva ◽  
Merilin Al Sharif ◽  
Petko Alov ◽  
Tania Pencheva ◽  
Ivanka Tsakovska ◽  
...  
Keyword(s):  
In Silico ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Toxic Effects ◽  
Active Constituent ◽  
Main Component

Silymarin, the active constituent of Silybum marianum (milk thistle), and its main component, silybin, are products with well-known hepatoprotective, cytoprotective, antioxidant, and chemopreventative properties. Despite substantial in vitro and in vivo investigations of these flavonolignans, their mechanisms of action and potential toxic effects are not fully defined. In this study we explored important ADME/Tox properties and biochemical interactions of selected flavonolignans using in silico methods. A quantitative structure–activity relationship (QSAR) model based on data from a parallel artificial membrane permeability assay (PAMPA) was used to estimate bioavailability after oral administration. Toxic effects and metabolic transformations were predicted using the knowledge-based expert systems Derek Nexus and Meteor Nexus (Lhasa Ltd). Potential estrogenic activity of the studied silybin congeners was outlined. To address further the stereospecificity of this effect the stereoisomeric forms of silybin were docked into the ligand-binding domain of the human estrogen receptor alpha (ERα) (MOE software, CCG). According to our results both stereoisomers can be accommodated into the ERα active site, but different poses and interactions were observed for silybin A and silybin B.

255 THE ESTROGENIC EVALUATION OF PARABENS USING RAT UTERINE CALBINDIN-D9k

2010 ◽  
Vol 22 (1) ◽  
pp. 285
Author(s):  
T. T. B. Vo ◽  
E. B. Jeung
Keyword(s):  
Gene Expression ◽  
Adverse Effects ◽  
Treated Group ◽  
Environmental Chemicals ◽  
Female Rats ◽  
Protein Levels ◽  
Calbindin D9k ◽  
The Difference

In the current study, calbindin-D9k (CaBP-9k), a potent biomarker for screening estrogen-like environmental chemicals in vivo and in vitro, was adopted to examine the potential estrogen-like property of the following parabens: propyl-, isopropyl-, butyl-, and isobutyl-paraben. Immature female rats were administered for 3 days from postnatal day 14 to 16 with 17?-ethinylestradiol (EE, 1 mg/kg of body weight (BW) per day) or parabens (62.5, 250, and 1000 mg/kg of BW per day). In uterotrophic assays, significantly increased uterus weights were detected in the EE-treated group and in the groups treated with the greatest dose of isopropyl-, butyl- and isobutyl-paraben. In addition, these parabens induced uterine CaBP-9k mRNA and protein levels, whereas co-treatment of parabens and fulvestrant (Faslodex, formerly known as ICI 182, 780), a pure estrogen receptor (ER) antagonist, completely reversed the paraben-induced gene expression and increased uterine weights. To investigate the ER-mediated mechanism(s) by which parabens exert their effects, the expression level of ERα and progesterone receptor (PR) was analyzed. Exposure to EE or parabens caused a dramatic decrease in expression of both ER? mRNA and protein levels, whereas co-treatment with fulvestrant reversed these effects. These data showed the difference of CaBP-9k and ER? expression, suggesting that CaBP-9k might not express via ER? pathway. In the effect of parabens on CaBP-9k expression through PR mediation, a significantly increased expression of uterine PR gene, a well-known ER regulating gene, at both transcriptional and translational levels was indicated in the greatest dose of isopropyl- and butyl-paraben. These parabens induced PR gene expression that was completely blocked by fulvestrant. This result indicates that CaBP-9k expression might involve PR mediates in the estrogenic effect of paraben in immature rat uteri. Taken together, parabens exhibited an estrogen-like property in vivo, which might be mediated by a PR and/or ER? signaling pathway. In addition, our results expanded the current understanding of the potential adverse effects of parabens associated with their estrogen-like activities. Further investigation is needed to elucidate in greater detail the adverse effects of parabens in humans and wildlife.

scholarly journals Determination of the Estrogenic Activity of Coffee Extract Solutions Prepared from Capsule Coffee Using the BG1Luc4E2 Assay

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 464-464
Author(s):  
Junichi Sakaki ◽  
Melissa Melough ◽  
Cathy Yang ◽  
Anthony Provatas ◽  
Christopher Perkins ◽  
...  
Keyword(s):  
Estrogenic Activity ◽  
Rank Correlation ◽  
Positive Control ◽  
In Vivo Models ◽  
Spearman’S Rank Correlation ◽  
Estrogenic Potential ◽  
Spearman’S Rank Correlation Coefficient ◽  
Estrogenic Chemicals

Abstract Objectives Estrogenic chemicals (ECs) possess estrogenic activity (EA) which can have harmful effects on the reproductive system. Coffee is known to have estrogenic potency due to its natural phytoestrogens, but coffee prepared from plastic capsules (capsule coffee) may increase exposure to ECs and consequently increase EA, potentially increasing risk to reproductive health. The objective of this study was to determine the EA of capsule coffee extract solutions in vitro. Methods Six varieties of capsule coffee and two varieties of coffee prepared from whole beans using a stainless-steel French press were first brewed then concentrated and extracted. The BG1Luc4E2 assay was then conducted to determine the EA of the coffee extracts. The normalized EA (% RME2) of the coffee extracts was determined as the relative estrogenic potency compared to the maximum normalized EA of the positive control 17β-estradiol (set to 100 % RME2). EA was determined if at least one data point on the concentration-response curve was above 15% RME2 and confirmed via inhibition with the estrogen receptor antagonist ICI 182,780. The correlation between the EA estimated by the BG1Luc4E2 assay and the estrogenic potential (EEQ) was determined with Spearman's rank correlation coefficient. Results All eight coffee extract solutions tested positive for EA and results were confirmed by their complete inhibition with ICI. The level of EA for the six capsule coffee extracts ranged from 48 to 56 % RME2, while the level of EA for the two coffee varieties prepared from whole beans were 40 and 42 % RME2. There was a significant correlation between EA and EEQ was (ρ = 0.8857, P = 0.0333). Conclusions These results indicate that the EAs of capsule coffees were higher than that of coffee prepared from a plastic-free method and that the EA measured in an in vitro model was correlated with the calculated estrogenic potential of the coffee extract's EC contents. Future studies are warranted in in vivo models as well as in humans as tests of estrogenic potency in vitro do not necessarily predict the effects in living organisms. Funding Sources This study was supported by the National Institutes of Health.

scholarly journals The Xenoestrogen Bisphenol A Inhibits Postembryonic Vertebrate Development by Antagonizing Gene Regulation by Thyroid Hormone

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2964-2973 ◽  
Author(s):  
Rachel A. Heimeier ◽  
Biswajit Das ◽  
Daniel R. Buchholz ◽  
Yun-Bo Shi
Keyword(s):  
Bisphenol A ◽  
Estrogenic Activity ◽  
Sex Differentiation ◽  
Inhibitory Effect ◽  
Vertebrate Development ◽  
Developmental Context ◽  
Mammalian Embryos ◽  
Intestinal Remodeling

Bisphenol A (BPA), a chemical widely used to manufacture plastics, is estrogenic and capable of disrupting sex differentiation. However, recent in vitro studies have shown that BPA can also antagonize T3 activation of the T3 receptor. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. This study proposed to identify critical T3 pathways that may be disrupted by BPA based on molecular analysis in vivo. Because amphibian metamorphosis requires T3 and encompasses the postembryonic period in mammals when T3 action is most critical, we used this unique model for studying the effect of BPA on T3-dependent vertebrate development at both the morphological and molecular levels. After 4 d of exposure, BPA inhibited T3-induced intestinal remodeling in premetamorphic Xenopus laevis tadpoles. Importantly, microarray analysis revealed that BPA antagonized the regulation of most T3-response genes, thereby explaining the inhibitory effect of BPA on metamorphosis. Surprisingly, most of the genes affected by BPA in the presence of T3 were T3-response genes, suggesting that BPA predominantly affected T3-signaling pathways during metamorphosis. Our finding that this endocrine disruptor, well known for its estrogenic activity in vitro, functions to inhibit T3 pathways to affect vertebrate development in vivo and thus not only provides a mechanism for the likely deleterious effects of BPA on human development but also demonstrates the importance of studying endocrine disruption in a developmental context in vivo.

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