Pluripotent stem cell assays: Modalities and applications for predictive developmental toxicity

Piersma, Aldert H.; Baker, Nancy C.; Daston, George P.; Flick, Burkhard; Fujiwara, Michio; Knudsen, Thomas B.; Spielmann, Horst; Suzuki, Noriyuki; Tsaioun, Katya; Kojima, Hajime

doi:10.1016/j.crtox.2022.100074

Cited by 15 publications

(7 citation statements)

References 175 publications

(236 reference statements)

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“…Although essential, in vivo toxicity testing comes with challenges in predicting human responses and several ethical issues related to the suffering of animals, besides being low-throughput, costly, and labor intensive. The current golden standard for developmental toxicity testing/embryotoxicity testing accepted by regulatory bodies is described in the OECD test guideline 414 (Luconi et al 2022 ; Piersma et al 2022 ). This guideline describes how rodents, predominantly rats and rabbits are exposed to chemicals throughout a full gestation period whereafter the effects on embryonic/fetal development are assessed upon killing of the animal one day before delivery (OECD 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…In accordance with the principles of the 3Rs, i.e. replace, reduce and refine (Russell and Burch 1960 ), it is envisioned that risk assessment of chemicals in the future will rely increasingly on data from non-animal sources and therefore development of New Approach Methodologies (NAMs) with relevant predictive value for humans is key for the progression of this field within toxicology (European Chemicals Agency 2016 ; USEPA 2021 ; Escher et al 2022 ; Piersma et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

Treschow,

Valente,

Lauschke

et al. 2024

Arch Toxicol

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To meet the growing demand for developmental toxicity assessment of chemicals, New Approach Methodologies (NAMs) are needed. Previously, we developed two 3D in vitro assays based on human-induced pluripotent stem cells (hiPSC) and cardiomyocyte differentiation: the PluriBeat assay, based on assessment of beating differentiated embryoid bodies, and the PluriLum assay, a reporter gene assay based on the expression of the early cardiac marker NKX2.5; both promising assays for predicting embryotoxic effects of chemicals and drugs. In this work, we aimed to further describe the predictive power of the PluriLum assay and compare its sensitivity with PluriBeat and similar human stem cell-based assays developed by others. For this purpose, we assessed the toxicity of a panel of ten chemicals from different chemical classes, consisting of the known developmental toxicants 5-fluorouracil, all-trans retinoic acid and valproic acid, as well as the negative control compounds ascorbic acid and folic acid. In addition, the fungicides epoxiconazole and prochloraz, and three perfluoroalkyl substances (PFAS), PFOS, PFOA and GenX were tested. Generally, the PluriLum assay displayed higher sensitivity when compared to the PluriBeat assay. For several compounds the luminescence readout of the PluriLum assay showed effects not detected by the PluriBeat assay, including two PFAS compounds and the two fungicides. Overall, we find that the PluriLum assay has the potential to provide a fast and objective detection of developmental toxicants and has a level of sensitivity that is comparable to or higher than other in vitro assays also based on human stem cells and cardiomyocyte differentiation for assessment of developmental toxicity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

Treschow,

Valente,

Lauschke

et al. 2024

Arch Toxicol

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“…These efforts include the development and evaluation of new alternative methods (NAMs) of testing strategies using in vitro approaches and/or small model organisms (SMOs) such as Caenorhabditis elegans ( C. elegans) , drosophila, and zebrafish [ 11 , 12 ]. Some advantages of working with SMOs for DART studies is the ability to quickly study the direct effects of chemicals on progeny in the absence of maternal metabolism and toxicity, the vast amount of information available about their embryology, and the opportunity to work with complete embryo models instead of less complex cell culture models [ 13 ]. As attention is increasingly being focused on designing integrated approaches to DART testing and assessment using NAMs, SMO-based assays can be used as a complementary component to cell-based assays and existing mammalian DART studies in support of safety assessment, hazard identification, and regulatory decision making [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

Camacho

Welch

Sprando

et al. 2023

JDB

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Exposures to arsenic and mercury are known to pose significant threats to human health; however, the effects specific to organic vs. inorganic forms are not fully understood. Caenorhabditis elegans’ (C. elegans) transparent cuticle, along with the conservation of key genetic pathways regulating developmental and reproductive toxicology (DART)-related processes such as germ stem cell renewal and differentiation, meiosis, and embryonic tissue differentiation and growth, support this model’s potential to address the need for quicker and more dependable testing methods for DART hazard identification. Organic and inorganic forms of mercury and arsenic had different effects on reproductive-related endpoints in C. elegans, with methylmercury (meHgCl) having effects at lower concentrations than mercury chloride (HgCl2), and sodium arsenite (NaAsO2) having effects at lower concentrations than dimethylarsinic acid (DMA). Progeny to adult ratio changes and germline apoptosis were seen at concentrations that also affected gravid adult gross morphology. For both forms of arsenic tested, germline histone regulation was altered at concentrations below those that affected progeny/adult ratios, while concentrations for these two endpoints were similar for the mercury compounds. These C. elegans findings are consistent with corresponding mammalian data, where available, suggesting that small animal model test systems may help to fill critical data gaps by contributing to weight of evidence assessments.

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“…Vast collections of HTS data from ToxCast/Tox21 [https://comptox.epa.gov/dashboard] provide an open resource to examine cellular and molecular determinants of toxicity for drugs and chemicals. Pluripotent stem cell (PSC) culture is one of the most promising in vitro alternatives to pregnant animal testing for assessing developmental hazard potential of drugs and chemicals [2]. Their capacity to form most cell types in the embryo, together with their potential for self-renewal and self-organization into rudimentary tissues, has motivated the design of engineered microsystems that recapitulate various aspects of anatomical development [3][4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Engineering a Computable Epiblast for in silico Modeling of Developmental Toxicity

Barham,

Spencer,

Baker

et al. 2023

Preprint

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Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the compucell3d.org modeling environment to simulate epithelial-mesenchymal transition of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Cell fate in the model is determined by an autonomous homeobox (HOX) clock driven by morphogenetic signals (e.g., FGF, WNT, ATRA, CDX). Executing the model renders a quantitative cell-level computation of mesodermal subpopulations and consequences of perturbation based on known embryogeny. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring experimental mouse embryology, with 50% reductions in FGF4, FGF8 and BMP4 signaling resulting in 86%, 98% and 59% reductions, respectively in the posterior mesodermal population, while ATRA exposure also resulted in a 78% decrease in this population. This model enables integration of in vitro chemical bioactivity data for specific molecular targets with known embryology to test mechanistic veracity and quantitative prediction of altered development.

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Pluripotent stem cell assays: Modalities and applications for predictive developmental toxicity

Cited by 15 publications

References 175 publications

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

Engineering a Computable Epiblast for in silico Modeling of Developmental Toxicity

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