Abstract
Stem cell research can lead to the development of treatments for a wide range of ailments including diabetes, heart disease, aging, neurodegenerative diseases, spinal cord injury, and cancer. OCT4 is a master regulator of self-renewal of undifferentiated embryonic stem cells. OCT4 also plays a crucial role in reprogramming of somatic cells into induced pluripotent stem (iPS) cells. Given known vivo reproductive toxicity of cobalt and nickel metals, we examined the effect of these metals on expression of several stem cell factors in embryonic Tera-1 cells, as well as stem cells. Cobalt and nickel induced a concentration-dependent increase of OCT4 and HIF-1α, but not NANOG or KLF4. OCT4 induced by cobalt and nickel was due primarily to protein stabilization because MG132 stabilized OCT4 in cells treated with either metals and because neither nickel nor cobalt significantly modulated its steady-state mRNA level. OCT4 stabilization by cobalt and nickel was mediated largely through reactive oxygen species (ROS) as co-treatment with ascorbic acid abolished OCT4 increase. Moreover, nickel and cobalt treatment increased sumoylation and mono-ubiquitination of OCT4 and K123 was crucial for mediating these modifications. Combined, our observations suggest that nickel and cobalt may exert their reproductive toxicity through perturbing OCT4 activity in the stem cell compartment.
Highlights
Cobalt [Co(II)] and Nickel [Ni(II)] are capable of crossing the placenta barrier and exerting their toxicity on the animal reproduction system, affecting embryonic development [1,2]
Equal amounts of cell lysates were blotted with antibodies to a panel of transcription factors including Octamer binding protein 4 (OCT4), NANOG, Kruppel-like factor 4 (KLF4), SALL4, and HIF-1a
OCT4 mRNA and protein are present in unfertilized oocytes, acting as an important maternal factor to regulate embryonic development [20]
Summary
Cobalt [Co(II)] and Nickel [Ni(II)] are capable of crossing the placenta barrier and exerting their toxicity on the animal reproduction system, affecting embryonic development [1,2]. Exposure of Ni(II) and Co(II) at a high concentration (100 mM) significantly reduced proliferation of inner cell mass and trophoblast cells [3]. It has been reported that there is a correlation between occupational exposure to nickel (refinery female workers) and delivery of newborns small-for-gestational-age [4] Both soluble and insoluble nickel can potentially pose threat to human health. Hypoxia improves the rate of reprogramming differentiated cells into iPS cells [10,11,12,13,14] Consistent with these findings, bovine blastocysts produced under a reduced oxygen tension exhibit significantly more inner cell mass (consisting of embryonic stem cells) than those maintained at a normal oxygen tension [15]. Our further studies reveal that ROS produced as the result of Ni(II) and Co(II) exposure is responsible for OCT4 stabilization partly via modulating post-translational modifications
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