Quantitative structure‐activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals

Schmieder, Patricia K.; Ankley, Gerald T.; Mekenyan, Ovanes G.; Walker, John D.; Bradbury, Steven P.

doi:10.1897/01-345

Cited by 48 publications

(22 citation statements)

References 65 publications

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“…The issue of availability of the effective substances may also underlie the not fully linear relationship of the observed effects and doses (e.g. the effects of our lowest concentration of 0.5 μM of ZEA as well as of α-ZOL), although, the quantitative interaction receptor-effective substance (Schmieder et al 2003) should not be underestimated either. The availability of substances itself could not explain the transitions between the inhibitory and stimulatory effect -e.g.…”

Section: Resultsmentioning

confidence: 98%

Effects of zearalenone, α-zearalenol, and genistein on boar sperm motility in vitro

Krejcárková¹,

Folková²,

Šimoník³

et al. 2017

CZECH J ANIM SCI

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Krejcárková A., Folková P., Šimoník O., Šašková M., Krejčířová R., Drábek O., Rajmon R. (2017): Effects of zearalenone, α-zearalenol, and genistein on boar sperm motility in vitro. Czech J. Anim. Sci., 62, 435-445.Genistein (GEN) and zearalenone (ZEA), environmental oestrogens commonly present in feedstuff for pigs, are known for their effects on reproductive functions. The aim was to verify the in vitro effects of 0.5-20 µM concentrations of GEN, ZEA and its metabolite α-zearalenol (α-ZOL) on pig sperm motility. A dose-dependent increase of the immotile sperm amount against fast and medium-fast sperm clusters was observed with all three oestrogens from the lowest concentrations tested. Individual CASA (computer-assisted sperm analysis) parameters of motile sperms seemed to be less sensitive indicators. This should be considered especially in toxicological research on a sperm model. Background of inconsistencies in to date-published papers is discussed. The results shift the effective concentrations of ZEA, α-ZOL, and GEN to values achievable in vivo and raises the questions of risk assessment of these compounds in pig reproduction.

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Section: Resultsmentioning

confidence: 98%

Effects of zearalenone, α-zearalenol, and genistein on boar sperm motility in vitro

Krejcárková¹,

Folková²,

Šimoník³

et al. 2017

CZECH J ANIM SCI

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“…All three endocrine axes described in this report operate through homologously structured nuclear receptors that recognize and bind the appropriate hormone. Receptors for both estrogen and thyroid hormone have been shown to bind a substantial number of compounds, and research is underway to predict this binding from a quantitative analysis of chemical structure [50,51]. Chemicals may interact with other molecular components of both axes, however.…”

Section: Points Of Regulation and Potential Disruptionmentioning

confidence: 99%

Predicting chemical impacts on vertebrate endocrine systems

Nichols

Breen

Denver

et al. 2010

Enviro Toxic and Chemistry

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Animals have evolved diverse protective mechanisms for responding to toxic chemicals of both natural and anthropogenic origin. From a governmental regulatory perspective, these protective responses complicate efforts to establish acceptable levels of chemical exposure. To explore this issue, we considered vertebrate endocrine systems as potential targets for environmental contaminants. Using the hypothalamic-pituitary-thyroid (HPT), hypothalamic-pituitary-gonad (HPG), and hypothalamic-pituitary-adrenal (HPA) axes as case examples, we identified features of these systems that allow them to accommodate and recover from chemical insults. In doing so, a distinction was made between effects on adults and those on developing organisms. This distinction was required because endocrine system disruption in early life stages may alter development of organs and organ systems, resulting in permanent changes in phenotypic expression later in life. Risk assessments of chemicals that impact highly regulated systems must consider the dynamics of these systems in relation to complex environmental exposures. A largely unanswered question is whether successful accommodation to a toxic insult exerts a fitness cost on individual animals, resulting in adverse consequences for populations. Mechanistically based mathematical models of endocrine systems provide a means for better understanding accommodation and recovery. In the short term, these models can be used to design experiments and interpret study findings. Over the long term, a set of validated models could be used to extrapolate limited in vitro and in vivo testing data to a broader range of untested chemicals, species, and exposure scenarios. With appropriate modification, Tier 2 assays developed in support of the U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program could be used to assess the potential for accommodation and recovery and inform the development of mechanistically based models.

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“…12) EDCs are compounds that directly modulate steroid hormone receptor pathways (estrogens, antiestrogens, androgens, antiandrogens) and aryl hydrocarbon receptor (AhR) agonists, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds 13) and are thought to pose a number of distinct health risks to both humans and wildlife. 13,14) Some pesticides (i.e.…”

Section: Applications Of Structure-activity Relationships To Endocrinmentioning

confidence: 99%

Structure-activity relationships and pathway analysis of biological degradation processes

et al. 2006

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Quantitative (and qualitative) structure-activity relationships, (Q)SARs, have been extensively developed for use in biochemistry and toxicology. Numerous applications exist in other fields, such as the physical sciences and ecological health; however they are beyond the scope of this review. In molecular biology, knowledge about genomes, proteomes, chemical structure and relationships between these molecules have been collected and stored in public databases. 1) These two methods are utilized in different ways to understand biological systems. For example, in the development of drugs, a biological database is used to identify a drug target using data acquired via high-throughput approaches (i.e. microarray data) and then (Q)SAR analysis is used to identify small molecules that bind the drug target. However binding to a target is insufficient for full evaluation of a compound's biological activity and eventual utility as a pesticide or pharmaceutical. It is also vital to understand the compound's adsorption, distribution, metabolism, excretion and toxicity (ADME-Tox) properties. This means that (Q)SAR analysis is insufficient to understand the pharmacokinetics of compounds in a biological system. One solution to this problem is to consider drug metabolites on an individual basis, integrating the enzymes that are responsible for the degradation/metabolism of a given compound as well as its metabolites. This analysis can reveal the dynamics of xenobiotics in biological systems. For example, Ekins et al. integrated QSAR coupled to a gene network dataset to examine drug metabolism and toxicity.2) However methods to incorporate integrated (Q)SAR analysis with that of a biological database are not sufficiently advanced for wide-scale application. In this review, we give a brief overview of (Q)SAR and a publicly available biological database. We then show an example of a combined chemical and genomics analysis by using SAR and pathway analysis of the biological degradation processes of endocrine disrupting chemicals (EDCs). Structure-activity relationships Overview of structure-activity relationships(Q)SARs are mathematical relationships that link chemical structure to biological (ecological, toxicological or pharmacological) activity for a series of compounds. There are a multitude of methods available that can be used in (Q)SAR analy- (Q)SARs estimate biological activity; however these models are insufficient to fully understand and predict the ADME-Tox processes of small molecules in biological systems. By integrating (Q)SARs with biological databases, the predictive capability of these models can be significantly improved. However, the techniques and methods for integrated analysis have not yet been sufficiently developed for these combined systems. In this review, we discuss standard (Q)SAR methods and biological database construction as well as provide an example of how SAR and metabolic pathway analysis can be combined to examine the biological degradation processes of endocrine disrupting chemicals.

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Quantitative structure‐activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals

Cited by 48 publications

References 65 publications

Effects of zearalenone, α-zearalenol, and genistein on boar sperm motility in vitro

Effects of zearalenone, α-zearalenol, and genistein on boar sperm motility in vitro

Predicting chemical impacts on vertebrate endocrine systems

Structure-activity relationships and pathway analysis of biological degradation processes

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