ReProGlo: A new stem cell-based reporter assay aimed to predict embryotoxic potential of drugs and chemicals

Uibel, Frederik; Mühleisen, Annette; Köhle, Christoph; Weimer, Marc; Stummann, Tina C.; Bremer, Susanne; Schwarz, Michael

doi:10.1016/j.reprotox.2009.12.002

Cited by 48 publications

(39 citation statements)

References 33 publications

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“…Among the fourteen assays used to examine a number of different steps in reproductive development, the ReProTect battery also includes the WEC, the mEST, and a ReProGlo assay for developmental toxicology [Schenk et al 2010]. The ReProGlo assay examines expression of a luciferase reporter gene for the Wnt/β-catenin signaling pathway in mouse embryonic stem cells [Uibel et al 2010]. Using these three assays for developmental toxicity, ten chemicals were correctly identified as either developmental toxicants, nondevelopmental toxicants, or developmental toxicants depending upon the route of application [Schenk et al 2010].…”

Section: Discussionmentioning

confidence: 99%

Alternative models in developmental toxicology

Lee¹,

Inselman²,

Kanungo

et al. 2012

Systems Biology in Reproductive Medicine

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Section: Discussionmentioning

confidence: 99%

Alternative models in developmental toxicology

Lee¹,

Inselman²,

Kanungo

et al. 2012

Systems Biology in Reproductive Medicine

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“…In addition to these highly selective CALUX HTS reporter gene assays, other assays have been established in more complex, murine embryonic stem (ES) cells by introducing reporter systems for signaling pathways controlling key differentiation pathways in embryonic development (so-called ReProGlo assays) [28]. Despite several attempts to introduce reporter genes other than that measuring wnt-pathway activation, as used in the original ReProGlo assay, none of them succeeded [Uibel et al, unpublished results].…”

Section: Establish a High Throughput Mechanistic Pathway Screen For Rmentioning

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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“…ES cell models for drug toxicity assessment [32,33,50] . For example, a stem cell-based reporter assay was developed to detect drug-induced alterations in the canonical Wnt/β-catenin signaling pathway, which is involved in the regulation of early embryonic development.…”

Section: A Series Of Secondary Assaysmentioning

confidence: 99%

“…For example, a stem cell-based reporter assay was developed to detect drug-induced alterations in the canonical Wnt/β-catenin signaling pathway, which is involved in the regulation of early embryonic development. The so-called ReProGlo assay allows simultaneous determination of cell viability and luciferase reporter activity in a high throughput 96-well microtiter format [50] . Several test chemicals were analyzed in the new assay system, and known embryo toxicants like retinoic acid and lithium chloride induced concentration-dependent increases in reporter activity.…”

Section: A Series Of Secondary Assaysmentioning

confidence: 99%

“…Indirect approaches are based on a comparison of the genome-wide activity profile of the compound with databases of the activity profiles of other compounds with known targets or activity profiles following specific genetic changes. A variety of technologies and approaches have been explored for target identification after phenotypic screening [1,44,50] . Here, we would like to describe our recent work, which took advantage of chemical probing to identify signaling pathways involved in the differentiated state of ES cells (Figure 1).…”

Section: A Series Of Secondary Assaysmentioning

confidence: 99%

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Embryonic stem cell application in drug discovery

Lou¹,

Liang²

2011

Acta Pharmacol Sin

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Embryonic stem (ES) cells and their differentiated progeny offer tremendous potential for regenerative medicine, even in the field of drug discovery. There is an urgent need for clinically relevant assays that make use of ES cells because of their rich biological utility. Attention has been focused on small molecules that allow the precise manipulation of cells in vitro, which could allow researchers to obtain homogeneous cell types for cell-based therapies and discover drugs for stimulating the regeneration of endogenous cells. Such therapeutics can act on target cells or their niches in vivo to promote cell survival, proliferation, differentiation, and homing. In the present paper, we reviewed the use of ES cell models for high-throughput/content drug screening and toxicity assessment. In addition, we examined the role of stem cells in large pharmaceutical companies' R&D and discussed a novel subject, nicheology, in stem cellrelated research fields.

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ReProGlo: A new stem cell-based reporter assay aimed to predict embryotoxic potential of drugs and chemicals

Cited by 48 publications

References 33 publications

Alternative models in developmental toxicology

Alternative models in developmental toxicology

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

Embryonic stem cell application in drug discovery

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