NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

Yamada, Shigeru; Kotake, Yaichiro; Demizu, Yosuke; Kurihara, Masaaki; Sekino, Yuko; Kanda, Yasunari

doi:10.1038/srep05952

Cited by 31 publications

(21 citation statements)

References 38 publications

(41 reference statements)

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“…4A). As previously reported, 100 nM TBT had a similar inhibitory effect (24.4%; Yamada et al, 2014). Treatment with apigenin (10 μM, 48 hr) decreased G1 phase ratio (58.6% decrease) and increased G2/M phase ratio (98.1% increase) (Figs.…”

Section: Tbt Induces G2/m Cell Cycle Arrest Via Nad-idhsupporting

confidence: 83%

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

et al. 2016

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-Organotin compounds, such as tributyltin (TBT), are well-known endocrine-disrupting chemicals (EDCs). We have recently reported that TBT induces growth arrest in the human embryonic carcinoma cell line NT2/D1 at nanomolar levels by inhibiting NAD + -dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to α-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we examined whether TBT at nanomolar levels affects cell cycle progression in NT2/D1 cells. Propidium iodide staining revealed that TBT reduced the ratio of cells in the G1 phase and increased the ratio of cells in the G2/M phase. TBT also reduced cell division cycle 25C (cdc25C) and cyclin B1, which are key regulators of G2/M progression. Furthermore, apigenin, an inhibitor of NAD-IDH, mimicked the effects of TBT. The G2/M arrest induced by TBT was abolished by NAD-IDHα knockdown. Treatment with a cellpermeable α-ketoglutarate analogue recovered the effect of TBT, suggesting the involvement of NAD-IDH. Taken together, our data suggest that TBT at nanomolar levels induced G2/M cell cycle arrest via NAD-IDH in NT2/D1 cells. Thus, cell cycle analysis in embryonic cells could be used to assess cytotoxicity associated with nanomolar level exposure of EDCs.

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Section: Tbt Induces G2/m Cell Cycle Arrest Via Nad-idhsupporting

confidence: 83%

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

et al. 2016

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“…Knockdown experiments were performed using Mfn1 shRNA lentiviruses from Sigma-Aldrich (MISSION shRNA), as previously reported49. A scrambled hairpin sequence was used as a negative control.…”

Section: Methodsmentioning

confidence: 99%

Chlorpyrifos inhibits neural induction via Mfn1-mediated mitochondrial dysfunction in human induced pluripotent stem cells

Yamada

Kubo

Yamazaki

et al. 2017

Sci Rep

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Organophosphates, such as chlorpyrifos (CPF), are widely used as insecticides in agriculture. CPF is known to induce cytotoxicity, including neurodevelopmental toxicity. However, the molecular mechanisms of CPF toxicity at early fetal stage have not been fully elucidated. In this study, we examined the mechanisms of CPF-induced cytotoxicity using human induced pluripotent stem cells (iPSCs). We found that exposure to CPF at micromolar levels decreased intracellular ATP levels. As CPF suppressed energy production that is a critical function of the mitochondria, we focused on the effects of CPF on mitochondrial dynamics. CPF induced mitochondrial fragmentation via reduction of mitochondrial fusion protein mitofusin 1 (Mfn1) in iPSCs. In addition, CPF reduced the expression of several neural differentiation marker genes in iPSCs. Moreover, knockdown of Mfn1 gene in iPSCs downregulated the expression of PAX6, a key transcription factor that regulates neurogenesis, suggesting that Mfn1 mediates neural induction in iPSCs. Taken together, these results suggest that CPF induces neurotoxicity via Mfn1-mediated mitochondrial fragmentation in iPSCs. Thus, mitochondrial dysfunction in iPSCs could be used as a possible marker for cytotoxic effects by chemicals.

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“…These results suggest that IDH is a novel target of TBTC (Yamada et al 2014). IDH is a mitochondrial enzyme from the tricarboxylic acid cycle that produces NADH.…”

Section: Resultsmentioning

confidence: 81%

Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation

López‐Gallardo

Llobet²,

Emperador³

et al. 2016

Environ Health Perspect

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Background:The oxidative phosphorylation system (OXPHOS) includes nuclear chromosome (nDNA)– and mitochondrial DNA (mtDNA)–encoded polypeptides. Many rare OXPHOS disorders, such as striatal necrosis syndromes, are caused by genetic mutations. Despite important advances in sequencing procedures, causative mutations remain undetected in some patients. It is possible that etiologic factors, such as environmental toxins, are the cause of these cases. Indeed, the inhibition of a particular enzyme by a poison could imitate the biochemical effects of pathological mutations in that enzyme. Moreover, environmental factors can modify the penetrance or expressivity of pathological mutations.Objectives:We studied the interaction between mitochondrially encoded ATP synthase 6 (p.MT-ATP6) subunit and an environmental exposure that may contribute phenotypic differences between healthy individuals and patients suffering from striatal necrosis syndromes or other mitochondriopathies.Methods:We analyzed the effects of the ATP synthase inhibitor tributyltin chloride (TBTC), a widely distributed environmental factor that contaminates human food and water, on transmitochondrial cell lines with or without an ATP synthase mutation that causes striatal necrosis syndrome. Doses were selected based on TBTC concentrations previously reported in human whole blood samples.Results:TBTC modified the phenotypic effects caused by a pathological mtDNA mutation. Interestingly, wild-type cells treated with this xenobiotic showed similar bioenergetics when compared with the untreated mutated cells.Conclusions:In addition to the known genetic causes, our findings suggest that environmental exposure to TBTC might contribute to the etiology of striatal necrosis syndromes.Citation:López-Gallardo E, Llobet L, Emperador S, Montoya J, Ruiz-Pesini E. 2016. Effects of tributyltin chloride on cybrids with or without an ATP synthase pathologic mutation. Environ Health Perspect 124:1399–1405; http://dx.doi.org/10.1289/EHP182

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NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

Cited by 31 publications

References 38 publications

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

Chlorpyrifos inhibits neural induction via Mfn1-mediated mitochondrial dysfunction in human induced pluripotent stem cells

Effects of Tributyltin Chloride on Cybrids with or without an ATP Synthase Pathologic Mutation

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