Tributyltin Inhibits Neural Induction of Human Induced Pluripotent Stem Cells

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.

Oxidative Stress as a Common Key Event in Developmental Neurotoxicity

“…These results suggest that changes in mitochondrial membrane permeability may be involved in the mechanism for the anesthesia-induced enhancement of mitochondrial fission in the developing brain. In addition to the in vivo studies, Mfn has been reported to mediate neural differentiation from human induced pluripotent stem cells, which are commonly used for DNT evaluation in vitro [72,73]. Several DTXs, including tributyltin and 5-fluorouracil, have been reported to induce degradation of Mfn protein and subsequently inhibit neural differentiation [72,74].…”

“…In addition to the in vivo studies, Mfn has been reported to mediate neural differentiation from human induced pluripotent stem cells, which are commonly used for DNT evaluation in vitro [72,73]. Several DTXs, including tributyltin and 5-fluorouracil, have been reported to induce degradation of Mfn protein and subsequently inhibit neural differentiation [72,74]. Thus, it would be useful to include examination of mitochondrial dynamics in the evaluation of DTXs in vivo and in vitro.…”

“…The upstream and downstream events resulting in and from abnormal ROS levels can be investigated in vitro using neuronal cells that differentiated from embryonic stem cells or induced pluripotent stem cells [72,74,92,93]. Studies using human neural stem cells, for example, have revealed that rotenone, an inhibitor of mitochondrial complex I, activates the Nrf2 pathway in response to OS and that activation of this pathway could be used as a readout to assess neurotoxicity [94].…”

Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction

“…Air pollutants such as nitrogen dioxide and particulate matter, too, have been associated with an increased risk of developing ASD [ 109 – 111 ]. Employing iPSC models, Yamada et al studied exposure of neural cells to the environmental pollutant tributyltin [ 112 ] and the organophosphate and insecticide chlorpyrifos [ 113 ], both of which have been linked to an increased risk of ASD in offspring [ 114 , 115 ]. Their data suggest that both substances lead to reduction of MFN1 and thus to mitochondrial dysfunction, which subsequently impairs neural induction [ 112 , 113 ].…”