Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway

Abstract

Nonylphenol (NP), a representative endocrine disruptor, interferes with reproductive function in aquatic organisms and animals. Although many previous studies have focused on apoptotic cell death by NP, the fundamental mechanism of NP on apoptosis remains poorly understood. Here, we investigated the molecular mechanism on NP-induced apoptotic cell death in mouse TM4 Sertoli cells. To evaluate NP treatment on cell viability, formazan and lactate dehydrogenase (LDH) assays were performed. Results indicate that NP reduced cell viability and increased the release of LDH in dose- and time-dependent manners. The reduction of cell viability by NP treatment appeared to involve necrosis as well as apoptosis based on nuclear fragmentation, an increase in the sub G1 population, and the detection of poly(ADP ribose) polymerase and caspase-3 cleavage. Additionally, the anti-apoptotic protein Bcl-2 diminished, whereas the pro-apoptotic protein Bax increased in a time-dependent manner. Note that NP-induced apoptotic cell death was enhanced by the generation of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) signaling. Pretreatment with N-acetylcysteine, an antioxidant, attenuated NP-induced apoptotic cell death. Moreover, NP caused a transient activation of the MAPK pathway. In particular, NP-induced cell death was significantly suppressed by U0126, a specific inhibitor of ERK. Taken together, our results suggest that NP induces apoptosis in mouse TM4 Sertoli cells via ROS generation and ERK activation.

Mitogen-activated protein kinase and Akt pathways are involved in 4-n-nonyphenol induced apoptosis in mouse Sertoli TM4 cells

“…Interestingly, Choi et al (2013) have been confirmed that 4-NP reduced TM4 cell viability and induced apoptotic cell death, which was mediated via ROS generation and activation of the ERK signaling pathway in TM4 cells. Apparently, in their study, the concentrations of 4-NP (0, 5, 10, 15, 20 or 50 g/mL), equivalent to 0, 22.70, 45.40, 68.10, 90.81 and 227.03 M, were much higher than those in the environment and diet exposure as mentioned above.…”

“…High levels of specific EDCs are known to cause endocrine, reproductive, or neurological problems. Studies found that cells treated with 200 M NP exhibited a one hundred percent mortality or apoptosis response (Choi et al, 2013;Kuo et al, 2010). Health impacts of low-level exposure to EDCs are not as well known.…”

BPA-induced apoptosis of rat Sertoli cells through Fas/FasL and JNKs/p38 MAPK pathways

“…The MAPKs can be grouped into three main families: ERKs (extracellular-signal-regulated kinases), JNKs (Jun amino-terminal kinases), and p38/SAPKs (stress-activated protein kinases) [15,16] Lee et al find that 1,3-dinitrobenzene induces apoptosis via the JNK/MAPK pathway, whereas nonylphenol causes apoptosis via the ERK pathway [17,18]. Furthermore, BPA reduces Sertoli cells TF secretion through the ERK pathway which may impair spermatogenesis [19].…”

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

“…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). Importantly, our previous study outlined that NP treatment triggers Sertoli cell (SC) autophagy, probably through the ROS-mediated AMPK-mTOR pathway (Duan et al 2016c).…”

“…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).…”