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

Abstract

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.

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

“…Accumulating studies have revealed that NP toxicity induces oxidative stress through the generation of ROS and stimulates apoptosis in a variety of cell types, including human embryonic stem cells, TM4 SCs and testicular SCs (Choi et al 2014;Gong et al 2009;Kim et al 2006;Kuo et al 2012;Zhang et al 2014). NP activates endoplasmic reticulum stress response, Fas/FasL, MAPKs, Akt and JNK signaling pathways, resulting in changes in cell survival, cell cycle progression and apoptosis (Choi et al 2014;Duan et al 2016c;Lepretti et al 2015;Liu et al 2015;Yao et al 2005).…”

Mouse and Human Embryonic Stem Cells: Can They Improve Human Health by Preventing Disease?

“…hESC were used recently to evaluate the ability of nonylphenol and octophenyl, two environmental contaminates that disrupt the reproductive and endocrine systems, to induce apoptosis [47]. Using a variety of methods, this study found that these test chemicals did induce apoptosis in hESC via a Fas-Fas ligand pathway in which caspase 8 and 3 activation increased following exposure to the test chemicals.…”

Actions of endocrine-disrupting chemicals on stem/progenitor cells during development and disease

“…It has also been postulated that hES cells could be used for reproductive toxicity screening in vitro (Krtolica & Giritharan 2010) as well as for drug discovery to minimize unexpected toxicity when entering a clinical trial (Jensen et al 2009). Using undifferentiated hES cells in an in vitro screening assay, Kim et al (2006) reported that exposure to the organic compounds such as nonylphenol (NP) and octylphenol (OP) decreased expression of Oct4 and Nanog in a dose-dependent manner. As Oct4 and Nanog are transcription factors required for maintaining stem cell pluripotency and self-renewal, it is likely that NP and OP decrease hES pluripotency.…”

“…As Oct4 and Nanog are transcription factors required for maintaining stem cell pluripotency and self-renewal, it is likely that NP and OP decrease hES pluripotency. Furthermore, NP and OP were cytotoxic, inducing DNA fragmentation and hES cell death through Fas-Fas ligand interactions and caspase-3 and -8 activity (Kim et al 2006). Interestingly, hES cellderived neural progenitor cells showed greater sensitivity to NP and OP exposure, possibly through the downregulation of ATP-binding cassette transporters known to pump out toxicants (Kim et al 2006).…”