Abstract
Tributyltin (TBT), one of the organotin compounds, is a well-known environmental pollutant. In our recent study, we reported that TBT induces mitochondrial dysfunction, in human-induced pluripotent stem cells (iPSCs) through the degradation of mitofusin1 (Mfn1), which is a mitochondrial fusion factor. However, the effect of TBT toxicity on the developmental process of iPSCs was not clear. The present study examined the effect of TBT on the differentiation of iPSCs into the ectodermal, mesodermal, and endodermal germ layers. We found that exposure to nanomolar concentration of TBT (50 nM) selectively inhibited the induction of iPSCs into the ectoderm, which is the first step in neurogenesis. We further assessed the effect of TBT on neural differentiation and found that it reduced the expression of several neural differentiation marker genes, which were also downregulated by Mfn1 knockdown in iPSCs. Taken together, these results indicate that TBT induces developmental neurotoxicity via Mfn1-mediated mitochondrial dysfunction in iPSCs.
Highlights
Organotin compounds, such as tributyltin (TBT), are typical environmental contaminants and endocrine disruptive chemicals, causing various developmental defects including increased fetal mortality, decreased fetal birth weight, behavioral abnormalities, and teratogenicity in the offspring of rats[1,2]
We found that treatment with 50 nM TBT significantly reduced the gene expression of the OTX2 marker that regulates neurogenesis[22] (Fig. 1a)
To investigate the molecular mechanisms by which TBT inhibits ectodermal induction, we examined the effect of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (RGZ), which had been confirmed in our previous report, as having agonistic effects on PPARγ10
Summary
Organotin compounds, such as tributyltin (TBT), are typical environmental contaminants and endocrine disruptive chemicals, causing various developmental defects including increased fetal mortality, decreased fetal birth weight, behavioral abnormalities, and teratogenicity in the offspring of rats[1,2]. We found that TBT induced the growth inhibition of human induced pluripotent stem cells (iPSCs) through mitochondrial dysfunction, such as decreased ATP levels, depolarization of mitochondrial membrane potential (MMP) and mitochondrial fragmentation, via the degradation of mitochondrial fusion factor, mitofusin[1] (Mfn1)[11]. Embryonic fibroblasts from these knockout mice display distinct types of fragmented mitochondria, which is a phenotypical characteristic of a severe reduction in mitochondrial fusion[19] Based on these findings, we hypothesized that nanomolar TBT could affect the developmental process of iPSCs, which can differentiate into somatic cells from three developmental germ layers (ectoderm, mesoderm, endoderm)[20]. TBT reduced the expression of several neural differentiation marker genes, which were downregulated by Mfn[1] knockdown These data suggest that TBT-induced neurodevelopmental toxicity involves Mfn1-mediated mitochondrial dysfunction in human iPSCs, without affecting mesodermal and endodermal inductions
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