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Int. J. Mol. Sci. 2014, 15(3), 5011-5031; doi:10.3390/ijms15035011
Article

Bovine Induced Pluripotent Stem Cells Are More Resistant to Apoptosis than Testicular Cells in Response to Mono-(2-ethylhexyl) Phthalate

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1 School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan 2 Cancer Center, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan 3 College of Medicine, Kaohsiung Medical University and Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan 4 Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan 5 Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY 10987, USA 6 School of Science and Engineering, Teikyo University, Utsunomiya, Tochigi 329-2192, Japan 7 RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan 8 Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan 9 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Rd, Zhunan, Miaoli County 350, Taiwan 10 Saito Laboratory of Cell Technology, Yaita, Tochigi 329-2192, Japan
* Authors to whom correspondence should be addressed.
Received: 25 January 2014 / Revised: 4 March 2014 / Accepted: 6 March 2014 / Published: 20 March 2014
(This article belongs to the Section Molecular Pathology)
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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.
Keywords: bovine iPSCs; testicular cells; OCT4; electroporation; endocrine disruptor; frizzled receptor; WNT signal; androgen receptor bovine iPSCs; testicular cells; OCT4; electroporation; endocrine disruptor; frizzled receptor; WNT signal; androgen receptor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Lin, Y.-C.; Kuo, K.-K.; Wuputra, K.; Lin, S.-H.; Ku, C.-C.; Yang, Y.-H.; Wang, S.-W.; Wang, S.-W.; Wu, D.-C.; Wu, C.-C.; Chai, C.-Y.; Lin, C.-L.; Lin, C.-S.; Kajitani, M.; Miyoshi, H.; Nakamura, Y.; Hashimoto, S.; Matsushima, K.; Jin, C.; Huang, S.-K.; Saito, S.; Yokoyama, K.K. Bovine Induced Pluripotent Stem Cells Are More Resistant to Apoptosis than Testicular Cells in Response to Mono-(2-ethylhexyl) Phthalate. Int. J. Mol. Sci. 2014, 15, 5011-5031.

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