title: Bovine induced pluripotent stem cells are more resistant to apoptosis than testicular cells in response to mono-(2-ethylhexyl) phthalate.
abstract: Although the androgen receptor (AR) has been implicated in the promotion of apoptosis in testicular cells (TSCs), the molecular pathway underlying AR-mediated apoptosis and its sensitivity to environmental hormones in TSCs and induced pluripotent stem cells (iPSCs) remain unclear. We generated the iPSCs from bovine TSCs via the electroporation of OCT4. The established iPSCs were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4 to maintain and stabilize the expression of stemness genes and their pluripotency. Apoptosis signaling was assessed after exposure to mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate. Here, we report that iPSCs were more resistant to MEHP-induced apoptosis than were original TSCs. MEHP also repressed the expression of AR and inactivated WNT signaling, and then led to the commitment of cells to apoptosis via the cyclin dependent kinase inhibitor p21CIP1. The loss of the frizzed receptor 7 and the gain of p21CIP were responsible for the stimulatory effect of MEHP on AR-mediated apoptosis. Our results suggest that testicular iPSCs can be used to study the signaling pathways involved in the response to environmental disruptors, and to assess the toxicity of environmental endocrine disruptors in terms of the maintenance of stemness and pluripotency.
authors.affiliation: School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. chulin@cc.kmu.edu.tw.
authors.forename: Ying-Chu
authors.initials: YC
authors.lastname: Lin
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. kuoksfo@yahoo.com.tw.
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Chunyuan.Jin@nyumc.org.
authors.forename: Kenly
authors.initials: K
authors.lastname: Wuputra
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. korosakihisoka@yahoo.com.tw.
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. r991046@gap.kmu.edu.tw.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Ku
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. sal9522059@yahoo.com.tw.
authors.forename: Ya-Han
authors.initials: YH
authors.lastname: Yang
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. silviaw@hotmail.com.tw.
authors.forename: Shin-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. swang910@gmail.com.
authors.forename: Sheng-Wen
authors.initials: SW
authors.lastname: Wang
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. dechwu@yahoo.com.
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. lazzz.wu@gmail.com.
authors.forename: Chun-Chien
authors.initials: CC
authors.lastname: Wu
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. cychai@kmu.edu.tw.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. changshen.lin@gmail.com.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. changshen.lin@gmail.com.
authors.forename: Chang-Shen
authors.initials: CS
authors.lastname: Lin
authors.affiliation: School of Science and Engineering, Teikyo University, Utsunomiya, Tochigi 329-2192, Japan. kajitani@nasu.bio.teikyo-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kajitani
authors.affiliation: RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan. miyoshi@brc.riken.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan. yukionak@brc.riken.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan. hashimot@m.u-tokyo.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan. koujim@m.u-tokyo.ac.jp.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY 10987, USA. Chunyuan.Jin@nyumc.org.
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Jin
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Rd, Zhunan, Miaoli County 350, Taiwan. skhuang1@gmail.com.
authors.forename: Shau-Ku
authors.initials: SK
authors.lastname: Huang
authors.affiliation: School of Science and Engineering, Teikyo University, Utsunomiya, Tochigi 329-2192, Japan. saict1@maple.ocn.ne.jp.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Saito
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. kazu@kmu.edu.tw.
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000166:cytology* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D051157:Frizzled Receptors; D011944:Receptors, Androgen; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate