title: Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters.
abstract: The androgen receptor (AR) has a critical role in promoting androgen-dependent and -independent apoptosis in testicular cells. However, the molecular mechanisms that underlie the ligand-independent apoptosis, including the activity of AR in testicular stem cells, are not completely understood. In the present study, we generated induced pluripotent stem cells (iPSCs) from bovine testicular cells by electroporation of octamer-binding transcription factor 4 (OCT4). The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4, which maintained and stabilized the expression of stemness genes and pluripotency. The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters, including di (2-ethyhexyl) phthalates, di (n-butyl) phthalate, and butyl benzyl phthalate. Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of BAX/BCL-2, thereby favoring apoptosis. Phthalate esters also increased the expression of cyclin-dependent kinase inhibitor 1 (p21(Cip1)) in a p53-dependent manner and enhanced the transcriptional activity of p53. The forced expression of AR and knockdown of p21(Cip1) led to the rescue of the phthalate-mediated apoptosis. Overall, this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency, as well as for identifying the iPSC signaling pathway(s) that are deregulated by these chemicals.
authors.affiliation: 1] Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan [2] Department of Internal Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan [3] Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: S-W
authors.initials: SW
authors.lastname: Wang
authors.forename: S S-W
authors.initials: SS
authors.lastname: Wang
authors.forename: D-C
authors.initials: DC
authors.lastname: Wu
authors.forename: Y-C
authors.initials: YC
authors.lastname: Lin
authors.forename: C-C
authors.initials: CC
authors.lastname: Ku
authors.forename: C-C
authors.initials: CC
authors.lastname: Wu
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chai
authors.forename: J-N
authors.initials: JN
authors.lastname: Lee
authors.forename: E-M
authors.initials: EM
authors.lastname: Tsai
authors.forename: C-Ls
authors.initials: CL
authors.lastname: Lin
authors.forename: R-C
authors.initials: RC
authors.lastname: Yang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Ko
authors.forename: H-S
authors.initials: HS
authors.lastname: Yu
authors.forename: C
authors.initials: C
authors.lastname: Huo
authors.forename: C-P
authors.initials: CP
authors.lastname: Chuu
authors.forename: Y
authors.initials: Y
authors.lastname: Murayama
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
authors.forename: C
authors.initials: C
authors.lastname: Jin
authors.forename: R
authors.initials: R
authors.lastname: Eckner
authors.forename: C-S
authors.initials: CS
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Saito
authors.forename: K K
authors.initials: KK
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002417:Cattle; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010795:Phthalic Acids / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000166:cytology*; D016159:Tumor Suppressor Protein p53
chemical_list: D010795:Phthalic Acids; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; C027561:butylbenzyl phthalate