Validation of the Rat Limb Bud Micromass Test in the International ECVAM Validation Study on Three <i>In Vitro</i> Embryotoxicity Tests

Spielmann, Horst; Genschow, Elke; Brown, Nigel A.; Piersma, Aldert H.; Verhoef, Aart; Spanjersberg, Marielle Q I; Huuskonen, Hannele; Paillard, F.; Seiler, A.

doi:10.1177/026119290403200306

Cited by 42 publications

(23 citation statements)

References 17 publications

(41 reference statements)

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“…By 2002, three well-established alternative embryotoxicity tests had already been validated, i.e., the mouse embryonic stem cell test, the whole rat embryo culture and the limb bud assay (Genschow et al, 2004; Piersma et al, 2004; Spielmann et al, 2004). This decade-long validation process represented a radical departure from other validation studies ongoing at that time.…”

Section: Systemic Biology and Toxicologymentioning

confidence: 99%

3S - Systematic, systemic, and systems biology and toxicology

Smirnova

Kleinstreuer²,

Corvi

et al. 2018

ALTEX

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A biological system is more than the sum of its parts - it accomplishes many functions via synergy. Deconstructing the system down to the molecular mechanism level necessitates the complement of reconstructing functions on all levels, i.e., in our conceptualization of biology and its perturbations, our experimental models and computer modelling. Toxicology contains the somewhat arbitrary subclass "systemic toxicities"; however, there is no relevant toxic insult or general disease that is not systemic. At least inflammation and repair are involved that require coordinated signaling mechanisms across the organism. However, the more body components involved, the greater the challenge to reca-pitulate such toxicities using non-animal models. Here, the shortcomings of current systemic testing and the development of alternative approaches are summarized. We argue that we need a systematic approach to integrating existing knowledge as exemplified by systematic reviews and other evidence-based approaches. Such knowledge can guide us in modelling these systems using bioengineering and virtual computer models, i.e., via systems biology or systems toxicology approaches. Experimental multi-organ-on-chip and microphysiological systems (MPS) provide a more physiological view of the organism, facilitating more comprehensive coverage of systemic toxicities, i.e., the perturbation on organism level, without using substitute organisms (animals). The next challenge is to establish disease models, i.e., micropathophysiological systems (MPPS), to expand their utility to encompass biomedicine. Combining computational and experimental systems approaches and the chal-lenges of validating them are discussed. The suggested 3S approach promises to leverage 21st century technology and systematic thinking to achieve a paradigm change in studying systemic effects.

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Section: Systemic Biology and Toxicologymentioning

confidence: 99%

3S - Systematic, systemic, and systems biology and toxicology

Smirnova

Kleinstreuer²,

Corvi

et al. 2018

ALTEX

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“…Schematic overview of the EST culture method evaluated for pharmaceuticals (1,2). To reduce the number of animals needed for developmental toxicity testing and screening, a range of in vitro test systems have been developed over the past decades, including the whole embryo culture (WEC), the micromass test and the zebra fish embryo test (3)(4)(5)(6). However, these systems all require the use of test animals, and are therefore not completely animal free alternatives.…”

Section: Definition Of the Estmentioning

confidence: 99%

Innovative approaches in the embryonic stem cell test (EST)

Theunissen

Piersma²

2012

Front Biosci

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The embryonic stem cell test (EST) is a high-throughput in vitro screening assay for developmental toxicity free of animal use. The EST uses the ability of murine embryonic stem cells to differentiate into the mesodermal cardiac lineage in combination with two cytotoxicity test systems. Validation of the EST showed that the test system is very promising as an alternative method to animal testing, however to optimize predictability and increase knowledge on the applicability domain of the EST, improvements to the method were proposed and studied. In this review we discuss the first definition of the EST followed by the innovative approaches which have been proposed to increase the predictivity of the EST, including implementation of molecular endpoints in the EST, such as omics technologies and the addition of alternative differentiation models to the testing paradigm, such as neural and osteoblast differentiation and the use of human stem cells. These efforts to improve the EST increase the value of embryonic stem cells used as in vitro systems to predict developmental toxicity.

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“…The ZET is one of the most recent in vitro alternative assays for developmental toxicity testing and is often used in addition to the EST, MM and WEC (Busquet et al 2014;Genschow et al, 2004;Hill et al, 2005;Lee et al, 2012;Piersma et al, 2004;Spielmann et al, 2004). Zebrafish (Danio rerio) embryos have proven to be an adequate developmental model due to their transparency 1 | 23 Figure 5.…”

Section: The Zebrafish Embryo Toxicity Test (Zet)mentioning

confidence: 99%

“…Such late developmental effects may in theory be better reflected by the zebrafish embryotoxicity test (ZET). The ZET is one of the most recent in vitro alternative assays for developmental toxicity testing and is often used in addition to the validated embryonic stem cell test (EST), the rat limb bud micromass test (MM) and the rat postimplantation whole embryo culture (WEC) (Busquet et al, 2014Hill et al, 2005;Lee et al, 2012;Piersma et al, 2004;Spielmann et al, 2004). The use of zebrafish embryos as developmental toxicity in vitro model is facilitated by the transparency of the organism throughout embryonic development and a rapid embryonic growth (Panzica-Kelly et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Studying the role of estrogen receptor alpha in the developmental toxicity of diethylstilbestrol using alternative testing strategies

Adam¹

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Table of Contents Chapter 1 General Introduction Chapter 2 Estrogen receptor alpha (ERα)-mediated coregulator binding and gene expression discriminates the toxic ERα agonist diethylstilbestrol (DES) from the endogenous ERα agonist 17β-estradiol (E2) Chapter 3 The in vivo developmental toxicity of diethylstilbestrol (DES) in rat evaluated by an alternative testing strategy Chapter 4 Assessment of the in vitro developmental toxicity of diethylstilbestrol and estradiol in the zebrafish embryotoxicity test Chapter 5 Physiologically based kinetic modelling-facilitated comparison of internal female dose levels of diethylstilbestrol and 17βestradiol, to study a potential role of kinetics in the differences in their developmental toxicity Chapter 6 General Discussion

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Validation of the Rat Limb Bud Micromass Test in the International ECVAM Validation Study on Three In Vitro Embryotoxicity Tests

Cited by 42 publications

References 17 publications

3S - Systematic, systemic, and systems biology and toxicology

3S - Systematic, systemic, and systems biology and toxicology

Innovative approaches in the embryonic stem cell test (EST)

Studying the role of estrogen receptor alpha in the developmental toxicity of diethylstilbestrol using alternative testing strategies

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