Nonylphenol and Octylphenol-Induced Apoptosis in Human Embryonic Stem Cells Is Related to Fas-Fas Ligand Pathway

• Published in: Toxicological sciences 2006-12, Vol.94 (2), p.310-321
• Main Authors: Kim, Suel-Kee, Kim, Byung-Kak, Shim, Joong-Hyun, Gil, Jung-Eun, Yoon, Yong-Dal, Kim, Jong-Hoon
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - drug effects; caspase; Cell Line; Cell Survival - drug effects; Coculture Techniques; Dose-Response Relationship, Drug; Embryonic Stem Cells - drug effects; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - pathology; Environmental Pollutants - toxicity; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; fas Receptor - genetics; fas Receptor - metabolism; Fas-Fas ligand pathway; Gene Expression - drug effects; human embryonic stem cell; Humans; Mice; nonylphenol; octylphenol; Phenols - toxicity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfl114

Human embryonic stem (hES) cells have been proposed as a source of various cell types for cell replacement therapy. Besides their potential in therapeutic uses, ES cells also have other potential applications, such as in drug discovery and in vitro screening assays of various toxicants. Nonylphenol (NP) and octylphenol (OP) are common environmental contaminants, known to disrupt the reproductive and endocrine system. However, little is known about their toxicological effects on early embryonic development in humans. In this study, we used undifferentiated hES cells and the neural progenitor cells derived from them to investigate the potential toxicity of NP and OP. Our results show that the cytotoxic effects of NP and OP involve DNA fragmentation, the major characteristic of apoptosis. The NP- and OP-induced apoptosis was concomitant with the increased activity of Caspase-8 and -3. Moreover, both Fas and Fas ligand (FasL) protein expressions were markedly increased in the NP- or OP-exposed hES cells. These results suggest that NP and OP are able to trigger apoptosis in hES cells via a pathway dependent on caspase activation and Fas-FasL interaction. In particular, hES cell–derived neural progenitor cells had a higher sensitivity to the toxicants than undifferentiated hES cells, thereby suggesting that the toxic stress response may differ depending on the developmental stage. These findings offer new perspectives for understanding the fundamental mechanisms in chemical-induced apoptosis in hES cells.