A multi-institutional study benchmarking the zebrafish developmental assay for prediction of embryotoxic plasma concentrations from rat embryo–fetal development studies

Cassar, Steven; Beekhuijzen, Manon; Beyer, Bruce K.; Chapin, Robert E.; M, Dorau; Hoberman, Alan M.; Krupp, Eckart; Leconte, Isabelle; Stedman, Donald B.; Stethem, Christine; Oetelaar, Daphne van den; Tornesi, Belén

doi:10.1016/j.reprotox.2019.02.004

Cited by 32 publications

(19 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the teratogenic effect of any substance depends on the ability of that substance to cross the placental barrier. In addition, some compounds found to be toxic in a rat embryotoxicity study were also found to cause deformities in zebrafish [ 44 ]. For these reasons, the use of ZO essential oil should be concerned in pregnant women.…”

Section: Discussionmentioning

confidence: 99%

Phytochemical and Safety Evaluations of Zingiber ottensii Valeton Essential Oil in Zebrafish Embryos and Rats

Thitinarongwate

Mektrirat

Nimlamool

et al. 2021

Toxics

View full text Add to dashboard Cite

Zingiber ottensii Valeton (ZO) exhibits pharmacological activity and has long been used in traditional medicine. However, reports about its safety profiles are limited. The present study aimed to evaluate the phytochemical profile and the toxic effects of ZO essential oil on the development of zebrafish and acute oral toxicity in rats. The essential oil was isolated from ZO rhizomes, and phytochemicals were analyzed using a gas chromatography–mass spectrometer (GC–MS). The embryotoxic and teratogenic effects of ZO essential oil were evaluated in zebrafish embryos and larvae and the acute oral toxicity was determined in rats. GC–MS results showed the essential oil contained zerumbone as a major phytoconstituent (24.73%). The zebrafish embryotoxicity of ZO essential oil appeared to be concentration- and time-dependent manner, with a moderate LC50 (1.003 µg/mL). Teratogenicity in zebrafish embryos also included morphological defects, decreased hatchability, and reduced heart rate. In rats, ZO essential oil (2000 mg/kg, p.o.) resulted in no mortality or significant toxicities. These findings suggest that ZO has embryotoxic and teratogenic effects in zebrafish embryos but does not result in death or acute oral toxicity in rats. Further long-term toxicity studies are needed to confirm the safety of products developed from ZO essential oil.

show abstract

Section: Discussionmentioning

confidence: 99%

Phytochemical and Safety Evaluations of Zingiber ottensii Valeton Essential Oil in Zebrafish Embryos and Rats

Thitinarongwate

Mektrirat

Nimlamool

et al. 2021

Toxics

View full text Add to dashboard Cite

show abstract

“…Analyses of these data does not require expertise in D. discoideum developmental morphology. This is important because one of the problematic aspects of current zebrafish developmental toxicity research has been to unify and harmonize the guidelines for testing procedures and scoring systems ( Beekhuijzen et al , 2015 ; Cassar et al , 2019 ). Furthermore, scoring systems can still require expert analysis ( Brannen et al , 2010 ; Panzica-Kelly et al , 2010 ; Weigt et al , 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…The initial dose range for characterizing the effects of the test compounds on cell growth was based on an “anchoring” starting dose which was selected by converting the rat LD 50 mg/kg value for each compound to a molar concentration. The rat LD 50 was selected from either intravenous or intraperitoneal administered treatment as the direct absorption of chemicals into the bloodstream is intuitively most similar to adding compounds directly to D. discoideum growth media ( Cassar et al , 2019 ). Once this dose was identified, a dose range above and below the anchor dose concentration was tested.…”

Section: Methodsmentioning

confidence: 99%

Dictyostelium discoideum: An Alternative Nonanimal Model for Developmental Toxicity Testing

Baines

Wolton

Thompson

2021

Toxicological Sciences

View full text Add to dashboard Cite

A critical aspect of toxicity evaluation is developmental and reproductive toxicity (DART) testing. Traditionally, DART testing has been conducted in vivo in mammalian model systems. New legislation aimed at reducing animal use and the prohibitive costs associated with DART testing, together with a need to understand the genetic pathways underlying developmental toxicity means there is a growing demand for alternative model systems for toxicity evaluation. Here we explore the potential of the eukaryotic social amoeba Dictyostelium discoideum, which is already widely used as a simple model system for cell and developmental biology, as a potential non-animal model for DART testing. We developed assays for high-throughput screening of toxicity during D. discoideum growth and development. This allowed the toxicity of a broad range of test compounds to be characterized, which revealed that D. discoideum can broadly predict mammalian toxicity. In addition, we show that this system can be used to perform functional genomic screens to compare the molecular modes of action of different compounds. For example, genome wide screens for mutations that affect lithium and valproic acid (VPA) toxicity allowed common and unique biological targets and molecular processes mediating their toxicity to be identified. These studies illustrate that D. discoideum could represent a predictive non-animal model for DART testing due to its amenability to high throughput approaches and molecular genetic tractability.

show abstract

“…Exposure-based assessment using the Daston list is a valuable strategy to validate individual in vitro assays for teratogenicity screening [10], and was employed to evaluate the HESCA-CSR platform in the present study. The Daston list was also applied to evaluate the morphology-based assay using the mouse P19C5 gastrulation model [22], the zebrafish development assay [59], and also another assay platform of human ES cells, which measures changes in specific metabolite levels as an indication of teratogenicity [38,60]. Exposurebased assessment of more assay platforms should delineate their applicability and limitation, and help assemble the most effective combination of assays to detect a wide range of teratogenic exposures.…”

Section: Discussionmentioning

confidence: 99%

Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells

Marikawa

Chen

Menor

et al. 2020

Reproductive Toxicology

View full text Add to dashboard Cite

Pluripotent stem cells recapitulate many aspects of embryogenesis in vitro. Here, we established a novel culture system to differentiate human embryonic stem cell aggregates (HESCA), and evaluated its utility for teratogenicity assessment. Culture of HESCA with modulators of developmental signals induced morphogenetic and molecular changes associated with differentiation of the paraxial mesoderm and neuroectoderm. To examine impact of teratogenic exposures on HESCA differentiation, 18 compounds were tested, for which adequate information on in vivo plasma concentrations is available. HESCA treated with each compound were examined for gross morphology and transcript levels of 15 embryogenesis regulator genes. Significant alterations in the transcript levels were observed for 94% (15/16) of the teratogenic exposures within 5-fold margin, whereas no alteration was observed for 92% (11/12) of the non-teratogenic exposures. Our study demonstrates that transcriptional changes in HESCA serve as predictive indicator of teratogenicity in a manner comparable to in vivo exposure levels.

show abstract

A multi-institutional study benchmarking the zebrafish developmental assay for prediction of embryotoxic plasma concentrations from rat embryo–fetal development studies

Cited by 32 publications

References 39 publications

Phytochemical and Safety Evaluations of Zingiber ottensii Valeton Essential Oil in Zebrafish Embryos and Rats

Phytochemical and Safety Evaluations of Zingiber ottensii Valeton Essential Oil in Zebrafish Embryos and Rats

Dictyostelium discoideum: An Alternative Nonanimal Model for Developmental Toxicity Testing

Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells

Contact Info

Product

Resources

About