A high throughput screening system for predicting chemically-induced reproductive organ deformities

Burg, Bart van der; Pieterse, Bart; Buist, Harrie; Lewin, Geertje; Linden, Sander C. van der; Man, Hai-Yen; Rorije, Emiel; Piersma, Aldert H.; Mangelsdorf, Inge; Wolterbeek, André; Kroese, E. Dinant; Vugt-Lussenburg, Barbara van

doi:10.1016/j.reprotox.2014.11.011

Cited by 25 publications

(26 citation statements)

References 56 publications

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“…This is different from the ToxCast test panel that includes a wider range of mechanisms with multiple tests per mechanistic endpoint [21]. Results suggest that it may not be needed to include a range of assays for each endpoint to make good predictions of in vivo activity of chemicals, as was shown for the estrogen receptor reporter gene assays [20]. This is consistent with the earlier notion that transactivation of ERs in one assay, ER subtype or species can be extrapolated to other species or subtypes of ERs for the purpose of chemical screening in the current practice of risk assessment relying on relatively uninformative animal data [29].…”

Section: Establish a High Throughput Mechanistic Pathway Screen For Rmentioning

confidence: 95%

“…The first approach in simplification of the testing battery was directed towards inclusion of integrative medium throughput assays that can be run in a routine laboratory environment, avoiding assays with differentiated (primary) tissues as present in the ReProTect battery. This can then be combined with more high throughput assays (see next section) thereby enhancing throughput and further simplifying test procedures [20]. The next step would be to validate this battery and select the most promising assays needed to give proper predictions of reproductive toxicity of chemicals.…”

Section: Establish Sensitive Parameters and A Medium Throughput In VImentioning

confidence: 99%

“…A systematic approach has been taken developing the screening panel using very sensitive and selective reporter genes, covering a wide range of receptors and signaling pathways that potentially are involved in reproductive toxicity [20]. The approach taken aimed to provide several advantages on top of a low rate of false positivity.…”

Section: Establish a High Throughput Mechanistic Pathway Screen For Rmentioning

confidence: 99%

“…To this end, in a next feasibility study sets of chemicals were selected that can induce either sex organ (SO) deformities or neural tube deformities (NTD). On the one hand these were used to study the different adverse outcome pathways involved in neural tube defects [45], while on the other hand these sets of chemicals were used to further validate and specify the application domains of the different elements in the high throughput CALUX test battery [20]. Analysis of the results of the CALUX high throughput panel shows that it is very suitable to identify not only endocrine active compounds, but also can predict chemically induced SO deformations with over 80% accuracy [20].…”

Section: Mechanistic Validation and Linkage To Adverse Outcome Pathwaysmentioning

confidence: 99%

“…On the one hand these were used to study the different adverse outcome pathways involved in neural tube defects [45], while on the other hand these sets of chemicals were used to further validate and specify the application domains of the different elements in the high throughput CALUX test battery [20]. Analysis of the results of the CALUX high throughput panel shows that it is very suitable to identify not only endocrine active compounds, but also can predict chemically induced SO deformations with over 80% accuracy [20]. This is consistent with the study of Lewin et al [41], showing a clear correlation between the in vivo reproductive aberrations and activity in the reporter gene assay on estrogenic activity.…”

Section: Mechanistic Validation and Linkage To Adverse Outcome Pathwaysmentioning

confidence: 99%

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The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

Burg

Wedebye

Dietrich

et al. 2015

Reproductive Toxicology

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a b s t r a c tThere is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible.

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Section: Establish a High Throughput Mechanistic Pathway Screen For Rmentioning

confidence: 95%

Section: Establish Sensitive Parameters and A Medium Throughput In VImentioning

confidence: 99%

Section: Establish a High Throughput Mechanistic Pathway Screen For Rmentioning

confidence: 99%

Section: Mechanistic Validation and Linkage To Adverse Outcome Pathwaysmentioning

confidence: 99%

Section: Mechanistic Validation and Linkage To Adverse Outcome Pathwaysmentioning

confidence: 99%

See 3 more Smart Citations

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

Burg

Wedebye

Dietrich

et al. 2015

Reproductive Toxicology

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View full text Add to dashboard Cite

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A Family of Water‐Immiscible, Dipolar Aprotic, Diamide Solvents from Succinic Acid

et al. 2020

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Three dipolar aprotic solvents were designed to possess high dipolarity and low toxicity: N,N,N′,N′‐tetrabutylsuccindiamide (TBSA), N,N′‐diethyl‐N,N′‐dibutylsuccindiamide (EBSA), and N,N′‐dimethyl‐N,N′‐dibutylsuccindiamide (MBSA). They were synthesized catalytically by using a K60 silica catalyst in a solventless system. Their water immiscibility stands out as an unusual and useful property for dipolar aprotic solvents. They were tested in a model Heck reaction, metal–organic framework syntheses, and a selection of polymer solubility experiments in which their performances were found to be comparable to traditional solvents. Furthermore, MBSA was found to be suitable for the production of an industrially relevant membrane from polyethersulfone. An integrated approach involving in silico analysis based on available experimental information, prediction model outcomes and read across data, as well as a panel of in vitro reporter gene assays covering a broad range of toxicological endpoints was used to assess toxicity. These in silico and in vitro tests suggested no alarming indications of toxicity in the new solvents.

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Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

et al. 2015

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The in vitro test battery of the European research consortium ESNATS (‘novel stem cell-based test systems’) has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow-up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1658-7) contains supplementary material, which is available to authorized users.

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A high throughput screening system for predicting chemically-induced reproductive organ deformities

Cited by 25 publications

References 56 publications

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals

A Family of Water‐Immiscible, Dipolar Aprotic, Diamide Solvents from Succinic Acid

Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

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