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

Kim, Iris Q.; Marikawa, Yusuke

doi:10.1016/j.taap.2018.07.006

Cited by 10 publications

(6 citation statements)

References 74 publications

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“…They further revealed that Res repressed the transcription and suggested Res could interfere with the normal function of placenta cells. In a study by Kim and Marikawa, adverse morphogenetic effects were observed when P19C5 EBs were treated with Res at 4 μM and higher (Kim & Marikawa, 2018), which indicated that in utero exposure to such concentrations would possibly impair embryo development. So, the potential toxicity of Res is of great importance deserving careful consideration.…”

Section: Res Inhibited Cd-induced Activation Of Akt Signaling Pathwaymentioning

confidence: 99%

Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells

Wang

Liu

Jiang

et al. 2021

Birth Defects Research

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Background: Cadmium (Cd) is a common heavy metal pollutant. Prenatal exposure to Cd results in adverse effects on fetal development. Placental apoptosis, inflammation, and epigenetic disruption have been implicated in Cdinduced placental toxicity. Resveratrol (Res) is a naturally occurring polyphenol with anti-apoptotic, anti-inflammatory, and epigenetic regulatory activities. In present study, the effects of Res on placental toxicity induced by Cd were evaluated. Methods: Pregnant CD-1 mice were fed with base diet containing 0.2% Res started on gestational day 0 (GD0), and intraperitoneally injected with 4.5 mg/kg CdCl 2 or saline once on GD9. JEG-3 cells were treated with 20 μM Res for 24 hr in the absence or presence of 20 μM CdCl 2 for the second 12 hr. The fetal outcomes, the apoptosis in placenta and JEG-3 cells, the expression of inflammatory cytokines and chemokines including tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and chemokine (C-X-C motif) ligand 1 (KC), and expression of endoplasmic reticulum (ER) stress markers were evaluated. The expression and activities of DNA methyltransferase (DNMT), and the activation of Akt signaling pathway were detected. Results: Cd exposure resulted in decreased fetal weight and crown-rump length while Res ameliorated these outcomes. Res suppressed Cd-induced apoptosis in placenta and JEG-3 cells, and decreased Cd-induced expression of TNF-α, IFN-γ, MCP-1, MIP-2, and KC in placenta. Cd greatly increased ER stress in placenta in mice, which was partially ameliorated by Res treatment. Res decreased Cd-induced upregulation of DNMT activity and suppressed Cdinduced expression of DNMT3B. Res restored estradiol secretion, enhances activity and protein levels of SIRT1 and inhibited Cd-induced activation of Akt signaling pathway. Conclusion: Res ameliorated Cd-induced placental toxicity and regulated DNMT3 expression and PI3K/Akt pathway activation.

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Section: Res Inhibited Cd-induced Activation Of Akt Signaling Pathwaymentioning

confidence: 99%

Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells

Wang

Liu

Jiang

et al. 2021

Birth Defects Research

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“…Adverse morphogenetic effects were observed when EBs and COs were treated with RSV at 50um/L and higher, raising the possibility that in utero exposure to such concentrations would impair embryo development. The results of Kim et al implicates RSV had potential developmental toxicity in EBs [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol’s neural protective effects for the injured embryoid body and cerebral organoid

Wang¹,

Wei²,

Wang³

et al. 2022

BMC Pharmacol Toxicol

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Objective Resveratrol (RSV) is a polyphenol compound found in grapes, veratrum and other plants. It has been reported that RSV has anti-inflammatory, anti-oxidant, anti-cancer and other pharmacological effects. However, the impacts of RSV on development of nervous system are not understood well. The study aims to investigate RSV’s neuroprotective effect during development and to provide a health care for pregnant women and their fetuses with RSV supplementation. Methods In this study, we induced human induced pluripotent stem cells (hiPSCs) to form the embryoid bodies (EBs) and cerebral organoids (COs) with 3 dimensional (3D) culture. In the meantime, D-galactose (D-gal, 5 mg/ml) was used to make nervous injury model, and on the other hand, RSV with various doses, such as 2 μm/L, 10 μm/L, 50 μm/L, were applied to understand its neuroprotection. Therefore, the cultures were divided into control group, D-gal nervous injury group and RSV intervention groups. After that, the diameters of EBs and COs were measured regularly under a reverted microscope. In the meantime, the neural proliferation, cell apoptosis and the differentiation of germ layers were detected via immunofluorescence. Results (1) D-gal could delay the development of EBs and COs; (2) RSV could rescue the atrophy of EBs and COs caused by D-gal; (3) RSV showed its neuroprotection, through promoting the neural cell proliferation, inhibiting apoptosis and accelerating the differentiation of germ layers. Conclusion RSV has a neuroprotective effect on the development of the nervous system, suggesting RSV supplementation may be necessary during the health care of pregnancy and childhood.

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“…The functional characteristics and PCR primer sequences of the mouse genes examined are listed in Table 1 . Previous studies have shown that the expressions of these genes are dysregulated by various chemical exposures that impair the morphogenesis of mouse MEBs (Kim & Marikawa, 2018 ; Kirkwood‐Johnson et al, 2021 ; Lau & Marikawa, 2014 ; Li & Marikawa, 2015 , 2016 , 2020 ; Warkus & Marikawa, 2018 ; Yuan & Marikawa, 2017 ), and that the presence of morphological impairment in mouse MEBs correlates with the in vivo developmental toxicity of chemical exposures with a concordance of 82.9% (Warkus & Marikawa, 2017 ). The characteristics and PCR primer sequences of the human genes are described in the previous study (Marikawa et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…For MEBs made of mouse P19C5 stem cells, the morphological features, namely the size and the extent of elongation, are significantly altered by many developmentally toxic chemical exposures with a concordance of 82.9% (Warkus & Marikawa, 2017 ). The expression levels of developmental regulator genes, particularly those involved in germ layer formation and axial patterning, are also significantly altered by chemical exposures that impair MEB morphogenesis (Kim & Marikawa, 2018 ; Kirkwood‐Johnson, Katayama, & Marikawa, 2021 ; Lau & Marikawa, 2014 ; Li & Marikawa, 2015 , 2016 , 2020 ; Warkus & Marikawa, 2018 ). For MEBs made of human H9 embryonic stem cells, the expression levels of various regulator genes are altered in response to many developmentally toxic exposures with a concordance of 92.9% (Marikawa et al, 2020 ).…”

Section: Introductionmentioning

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

Cited by 10 publications

References 74 publications

Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells

Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells

Resveratrol’s neural protective effects for the injured embryoid body and cerebral organoid

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

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