title: Chlorpyrifos inhibits neural induction via Mfn1-mediated mitochondrial dysfunction in human induced pluripotent stem cells.
abstract: 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.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.|Pharmacological Evaluation Institute of Japan (PEIJ), Kanagawa, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kubo
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Yamazaki
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D002460:Cell Line; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000071841:PAX6 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D033681:Mitochondrial Membrane Transport Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human; D004390:Chlorpyrifos