An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis

Tonk, Elisa C.M.; Pennings, Jeroen L. A.; Piersma, Aldert H.

doi:10.1016/j.reprotox.2014.10.008

Cited by 60 publications

(25 citation statements)

References 75 publications

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“…An AOP framework describing RA homeostasis and its functional interactions with other morphogenetic factors in embryogenesis could help identify such biomarkers. A first attempt toward such a framework was published by Tonk, Pennings, and Piersma () and is shown in Figure . This study also reviews data showing that RADH, CYP26 members, and a host of RA‐regulated patterning genes can be readily detected and shown to be regulated in alternative assays such as whole embryo culture, zebrafish embryo test and embryonic stem cell tests.…”

Section: Case Studies For Development Toxicity Ontologymentioning

confidence: 99%

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Building a developmental toxicity ontology

Baker

Boobis

Burgoon

et al. 2018

Birth Defects Research

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Section: Case Studies For Development Toxicity Ontologymentioning

confidence: 99%

“… Proposed AOP framework for RA‐neural tube/axial patterning pathway Note . Reproduced with permission from Tonk et al (). Reviewed in a Billings et al (), b Abu‐Abed et al (), c Pennimpede et al (), d Sandell, Lynn, Inman, McDowell, and Trainor (), and e Rhinn and Dollé ().…”

Section: Case Studies For Development Toxicity Ontologymentioning

confidence: 99%

Building a developmental toxicity ontology

Baker

Boobis

Burgoon

et al. 2018

Birth Defects Research

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“…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%

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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“…RA, a small lipophilic signaling molecule, is the main biologically active metabolite of vitamin A (retinol), playing pleiotropic functions during embryonic development . RA biosynthesis occurs in a two‐step process: first, precursor retinol (vitamin A) is oxidized to retinaldehyde by the cytosolic alcohol dehydrogenases and the retinol dehydrogenases; then, retinaldehyde is transformed to RA by members of the aldehyde dehydrogenease class known as retinaldehyde dehydrogenases (RALDH) .…”

Section: Introductionmentioning

confidence: 99%

“…RA, a small lipophilic signaling molecule, is the main biologically active metabolite of vitamin A (retinol), playing pleiotropic functions during embryonic development. 16,29,[33][34][35][36][37][38][39][40][41][42][43][44][45][46] RA biosynthesis occurs in a two-step process: first, precursor retinol (vitamin A) is oxidized to retinaldehyde by the cytosolic alcohol dehydrogenases and the retinol dehydrogenases; then, retinaldehyde is transformed to RA by members of the aldehyde dehydrogenease class known as retinaldehyde dehydrogenases (RALDH). 16,[47][48][49] The controlling actions of RA occur by regulation of the activity of the RA nuclear receptor family, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), to govern the expression of target genes binding to retinoic acid response elements (RAREs) present in the regulatory sequences of these RA-regulated genes.…”

Section: Introductionmentioning

confidence: 99%

Cyp1B1 expression patterns in the developing chick inner ear

Cardeña-Núñez

Sánchez-Guardado

Hidalgo‐Sánchez

2019

Developmental Dynamics

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Background Retinoic acid (RA) plays an important role in organogenesis as a paracrine signal through transcriptional regulation of an increasing number of known downstream target genes, regulating cell proliferation, and differentiation. During the development of the inner ear, RA directly governs the morphogenesis and specification processes mainly by means of RA‐synthesizing retinaldehyde dehydrogenase (RALDH) enzymes. Interestingly, CYP1B1, a cytochrome P450 enzyme, is able to mediate the oxidative metabolisms also leading to RA generation, its expression patterns being associated with many known sites of RA activity. Results This study describes for the first time the presence of CYP1B1 in the developing chick inner ear as a RALDH‐independent RA‐signaling mechanism. In our in situ hybridization analysis, Cyp1B1 expression was first observed in a domain located in the ventromedial wall of the otic anlagen, being included within the rostralmost aspect of an Fgf10‐positive pan‐sensory domain. As development proceeds, all identified Fgf10‐positive areas were Cyp1B1 stained, with all sensory patches being Cyp1B1 positive at stage HH34, except the macula neglecta. Conclusions Cyp1B1 expression suggested a possible contribution of CYP1B1 action in the specification of the lateral‐to‐medial and dorsal‐to‐ventral axes of the developing chick inner ear.

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An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis

Cited by 60 publications

References 75 publications

Building a developmental toxicity ontology

Building a developmental toxicity ontology

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

Cyp1B1 expression patterns in the developing chick inner ear

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