Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells

Yamada, Shigeru; Asanagi, Miki; Hirata, Naoya; Itagaki, Hiroshi; Sekino, Yuko; Kanda, Yasunari

doi:10.1016/j.tiv.2016.04.013

Cited by 25 publications

(18 citation statements)

References 34 publications

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“…Consistent with this, our previous knockdown studies indicated that Mfn1 reduction was sufficient to promote mitochondrial dysfunction31. CPF-induced Mfn1 reduction might mediate mitochondrial fragmentation, decrease ATP levels, and inhibit iPSC growth.…”

Section: Discussionsupporting

confidence: 79%

“…Further studies are needed to evaluate the developmental effects of CPF on various types of iPSC-derived cells. Moreover, we show that CPF toxicity is caused by Mfn1-mediated mitochondrial dysfunction, which is involved in the cytotoxicity of organotin compounds31. Thus, mitochondrial functions influenced by Mfn1 might be a good starting point for investigating toxic mechanisms induced by exposure to other chemicals.…”

Section: Discussionmentioning

confidence: 86%

“…Regarding this apparent CPF specificity, E3 ubiquitin ligase membrane-associated RING-CH 5 (MARCH5) has been reported to selectively bind to Mfn1 dependent on its acetylation, and degrade among all mitochondrial proteins, including Mfn234. In addition, we have reported that organotin compounds induced Mfn1 degradation through MARCH5, thereby promoting mitochondrial fragmentation in iPSCs31. Thus, CPF may specifically target Mfn1 protein via MARCH5 in iPSCs without affecting mRNA levels.…”

Section: Discussionmentioning

confidence: 97%

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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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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 97%

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

Yamada

Kubo

Yamazaki

et al. 2017

Sci Rep

Self Cite

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“…Treatment groups included a vehicle control (methanol) and each of five EDCs at environmentally relevant doses [10 nM BPA (36 nM fetal serum, [35]), 5 μM DEHP (7.7μM pubertal serum, [12]), 30 μM ATR (up to 7 μM drinking water reported, [36]), 100 nM PFOA (average 94 nM ≥12 year old serum, [37]), and 25 nM TBT (0.17 – 534 adult nM serum, [38]). These concentrations are within the range those reported for human serum, for drinking water, or studies reported for mammalian oocytes and preimplantation stage embryos or pluripotent cells in vitro [22, 23, 27, 39–41]. The concentration of ATR used was ~4-fold higher than the maximum concentration reported in one study in drinking water [36], and one study of occupational human serum level (up to 245 nM [42]).…”

Section: Methodssupporting

confidence: 54%

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

Midic

Vincent

VandeVoort

et al. 2016

Reproductive Toxicology

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Endocrine disrupting chemicals (EDCs) exert significant effects on health and physiology, many traceable to effects on stem cell programming underlying development. Understanding risk of low-level, chronic EDC exposure will be enhanced by knowledge of effects on stem cells. We exposed rhesus monkey embryonic stem cells to low levels of five EDCs [bisphenol A (BPA), atrazine (ATR), tributyltin (TBT), perfluorooctanoic acid (PFOA), and di-(2-ethylhexyl) phthalate (DEHP)] for 28 days, and evaluated effects on gene expression by RNAseq transcriptome profiling. We observed little effect of BPA, and small numbers of affected genes (≤119) with other EDCs. There was substantial overlap in effects across two, three, or four treatments. Ingenuity Pathway analysis indicated suppression of cell survival genes and genes downstream of several stress response mediators, activation of cell death genes, and modulations in several genes regulating pluripotency, differentiation, and germ layer development. Potential adverse effects of these changes on development are discussed.

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“…Previous studies have shown that TBT and TPhT can accumulate in some aquatic organisms and cause cumulative poisoning or imposex [3,48], eventually leading to reproductive disorders, population decline, and potential species extinction [54,62,80]. In humans, exposure to OTs may induce cell immunotoxicity, neurotoxicity, mutagenicity, and carcinogenicity, resulting in reproductive and immunological diseases [36,73]. Because of the harmful effects of TBT and TPhT on aquatic organisms and human health, many countries and international organizations have developed water quality criteria and restricted the uses of TBT and TPhT [56].…”

Section: Introductionmentioning

confidence: 99%

Fate simulation and risk assessment of TBT and TPhT considering water level fluctuations in the TGR before and after AFS Convention implementation in China

Gao

Chen

et al. 2020

Environ Sci Eur

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Background: The Three Gorges Reservoir (TGR) is the largest freshwater reservoir in China. Previous studies showed that organotin pollution is present in the TGR. In June 2011, the AFS Convention went into effect in China. In order to explore the pollution evolution processes of tributyltin (TBT) and triphenyltin (TPhT) before and after implementation of the AFS Convention and their variations with water level fluctuations in the TGR, the characteristic parameters of the TGR and the physicochemical parameters of TBT and TPhT were used to develop a level IV multimedia fugacity model considering water level fluctuations to simulate the fate, transfer, and transport of TBT and TPhT in the TGR. Based on the simulation results, exposure concentrations of TBT and TPhT were then used to assess the ecological and health risks in the TGR region (TGRR). Results:The simulation results showed that the average concentrations of both TBT and TPhT decreased in all compartments except the sediment, whereas the total content of the system continued to increase after the AFS Convention was implemented. The concentration of TBT in the sediment was higher than that in fish, while the concentration of TPhT in fish was much greater than that in the sediment. The total contents of both TBT and TPhT were highest in the sediment phase. In addition, variations in water level of the TGR significantly affected the distribution and transport of TBT and TPhT in the TGR. Conclusions:Sediment is an important source and sink of TBT and TPhT, and the water level regulation of the TGR strengthened the two roles of sediment. Both TBT and TPhT in surface water, but especially TBT, carried significant chronic exposure risks to the aquatic community of the TGR. Intake of TPhT, mainly through eating fish, posed a potential health risk to the population in the TGRR.

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Tributyltin induces mitochondrial fission through Mfn1 degradation in human induced pluripotent stem cells

Cited by 25 publications

References 34 publications

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

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

Effects of long-term endocrine disrupting compound exposure on Macaca mulatta embryonic stem cells

Fate simulation and risk assessment of TBT and TPhT considering water level fluctuations in the TGR before and after AFS Convention implementation in China

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