Stem‐Cell‐Based
            <i>In vitro</i>
            Morphogenesis Models to Investigate Developmental Toxicity of Chemical Exposures

Marikawa, Yusuke

doi:10.1002/9781119283249.ch4

Cited by 2 publications

(2 citation statements)

References 36 publications

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“…To gain insight into the molecular mechanisms by which RDV impairs the morphogenesis of MEBs, the expression profiles of developmental regulator genes were investigated. The genes listed in Table 1 were selected for analyses, because they are essential regulators of embryonic patterning, and also because their transcriptions are dysregulated by various chemical exposures that impair the morphogenesis of mouse MEBs (Marikawa, 2018, 2022). The transcript levels of the pluripotency maintenance factors ( Pou5f1 , Nanog , Nodal ) were not significantly different between the control and RDV‐exposed (4 μM) MEBs during the course of the 4‐day culture (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Kirkwood-Johnson

Marikawa

2022

Birth Defects Research

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Background Remdesivir is an antiviral drug approved for the treatment of COVID‐19, whose developmental toxicity remains unclear. More information about the safety of remdesivir is urgently needed for people of childbearing potential, who are affected by the ongoing pandemic. Morphogenetic embryoid bodies (MEBs) are three‐dimensional (3D) aggregates of pluripotent stem cells that recapitulate embryonic body patterning in vitro, and have been used as effective embryo models to detect the developmental toxicity of chemical exposures specifically and sensitively. Methods MEBs were generated from mouse P19C5 and human H9 pluripotent stem cells, and used to examine the effects of remdesivir. The morphological effects were assessed by analyzing the morphometric parameters of MEBs after exposure to varying concentrations of remdesivir. The molecular impact of remdesivir was evaluated by measuring the transcript levels of developmental regulator genes. Results The mouse MEB morphogenesis was impaired by remdesivir at 1–8 μM. Remdesivir affected MEBs in a manner dependent on metabolic conversion, and its potency was higher than GS‐441524 and GS‐621763, presumptive anti‐COVID‐19 drugs that act similarly to remdesivir. The expressions of developmental regulator genes, particularly those involved in axial and somite patterning, were dysregulated by remdesivir. The early stage of MEB development was more vulnerable to remdesivir exposure than the later stage. The morphogenesis and gene expression profiles of human MEBs were also impaired by remdesivir at 1–8 μM. Conclusions Remdesivir impaired mouse and human MEBs at concentrations that are comparable to the therapeutic plasma levels in humans, urging further investigation into the potential impact of remdesivir on developing embryos.

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Section: Resultsmentioning

confidence: 99%

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Kirkwood-Johnson

Marikawa

2022

Birth Defects Research

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“…One of the in vitro tests to evaluate the developmental toxicity of compounds utilizes embryoid body morphogenesis of the mouse P19C5 stem cell line (reviewed in Marikawa, 2018). P19C5 cells possess developmental characteristics similar to the epiblast, the pluripotent embryonic precursor of the entire fetal body.…”

Section: Introductionmentioning

confidence: 99%

Embryoid body test with morphological and molecular endpoints implicates potential developmental toxicity of trans-resveratrol

Kim

Marikawa

2018

Toxicology and Applied Pharmacology

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Developmental toxicity of compounds, which women of reproductive age are exposed to, should be assessed to minimize the incidence of miscarriage and birth defects. The present study examined the potential developmental toxicity of resveratrol, a dietary supplement widely marketed with various health claims, using the P19C5 embryoid body (EB) morphogenesis assay, which evaluates adverse effects of chemical exposures on tissue growth and axial elongation. Resveratrol (trans isoform) impaired morphogenesis at 4 μM and higher, creating smaller and rounder EBs, whereas cis isoform, and glucuronated and sulfonated metabolites did not. Trans-resveratrol also altered expression levels of developmental regulator genes involved in embryonic patterning, such as Wnt3a, Tbx6, and Cyp26a1. To investigate the mechanisms of trans-resveratrol action, the roles of estrogen receptor, sirtuin 1 (SIRT1), and DNA replication in EB morphogenesis were examined. Neither activators of estrogen receptors (diethylstilbestrol [18 μM] and raloxifene [8 μM]) nor activator of SIRT1 (SRT1720 [2.4-3.2 μM]) caused morphological and molecular alterations that are comparable to trans-resveratrol (10 μM). By contrast, a reduction in the DNA replication rate with aphidicolin (0.4 μM) or hydroxyurea (40 μM) created smaller and rounder EBs and altered the expression levels of Wnt3a, Tbx6, and Cyp26a1 in a manner similar to trans-resveratrol. Consistently, trans-resveratrol significantly reduced the rate of EdU incorporation in P19C5 cells. These results suggest that a reduction in the DNA replication rate is one of the mechanisms by which trans-resveratrol impacts EB development. This study provides mechanistic insight for further investigations on the developmental toxicity of trans-resveratrol.

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Stem‐Cell‐Based In vitro Morphogenesis Models to Investigate Developmental Toxicity of Chemical Exposures

Cited by 2 publications

References 36 publications

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Embryoid body test with morphological and molecular endpoints implicates potential developmental toxicity of trans-resveratrol

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