We observed that Ni and Co significantly increased expression of OCT4 in a time- and concentration-dependent manner. Ni- or Co-induced OCT4 expression is primarily due to protein stabilization. Our further studies reveal that ROS produced as the result of Ni and Co exposure is responsible for OCT4 stabilization partly via AZ 960 modulating post-translational modifications. OCT4 is a master regulator of proliferation and self-renewal of embryonic stem cells. OCT4 mRNA and protein are present in unfertilized oocytes, acting as an important maternal factor to regulate embryonic development. The inner cell mass and trophoblast layer regulated by OCT4 are crucial because both contribute to the normal development of healthy embryos. Given its importance, OCT4 expression is tightly controlled and any perturbations of its expression are expected to have an adverse effect on cell proliferation and differentiation. Nickel and cobalt are both belong to group VII in the periodic chart, thus having similar chemical properties. Cobalt also shares similar features with nickel on iron regulation. An earlier in vivo study showed Ni reduced mouse embryo implantation frequency significantly when it was injected to mice during the pre-implantation stage. The size and weight of mouse litters were reduced in the treated groups as compared with that of control group. In a separate study, it has been shown that Ni treated mice exhibit a high rate of embryo resorption, abnormal fetuses, and stillborn. Nickel exposure also causes a significant reduction in the trophoblast area and inner cell mass. At least impart, to altered expression and activity of OCT4. It has been shown that nickel and cobalt toxicity and carcinogenicity are mediated through ROS production. Using the electron paramagnetic resonance spin trapping approach, Hanna et al. have shown that various Co complexes generate ROS from the reaction of hydrogen peroxide under physiological conditions. Moreover, it has been suggested that depletion of glutathione may be a possible mechanism of oxidative stress induced by nickel. Many stem cell transcription factors function as onco-proteins, thus promoting cell proliferation and facilitating malignant transformation when their expression and activities are deregulated. Given that OCT4 controls expression of many transcription factors including NANOG, SALL4, Myc and SOX2, it is tempting to speculate that Co or Ni carcinogenesis in the stem cell compartment may be partly due to an enhanced activities of OCT4 and its downstream targets. OCT4 has two distinct DNA binding domains, POU domain and homeobox which independently bind half-sites of the canonical octamer motif. This flexibility allows OCT4 to form heterodimers with other transcription factors, as well as to form homodimers. Posttranslational modifications are known to impact on protein conformation. In fact, it has been shown that OCT4 protein stability and transcriptional activities are subjected to the regulation by post-translational modifications including phosphoylation, sumoylation and poly-ubiquitination. Our current studies strongly suggest that embryonic toxicity caused by nickel or cobalt exposure is likely due.