To further interrogate this pathway, we used a super-repressor containing mutations at position S32 and S36 of IkBa that prevents IKKb-mediated phosphorylation. This abolished the effects of H2O2 on NF-kB activation and CTCF downregulation providing further evidence for canonical activation. The activation of NF-kB results in the induction or suppression of downstream genes depending on the presence and binding of different dimers. With low dose H2O2 exposure, we observed the induction and binding of a p65/p50 heterodimer to the CTCF promoter. The presence of a NF-kB binding site on the CTCF promoter has been previously recognized. This study with EGF induction and UV light involved both p65/p50 heterodimers, as well as p50 homodimer formation. While p65/p50 heterodimers generally activate target gene transcription, transcriptional outcomes are subject to the regulation of a dynamic balance between coactivators and corepressors. Our ChIP data indicated that the corepressor HDAC1 was BI-D1870 recruited to the CTCF gene promoter in association with p50 and p65 resulting in decreased CTCF expression. This occurred at a specific region in the CTCF promoter. Other sites failed to demonstrate significant p65/p50 binding and were used as controls. The downregulation of CTCF was mediated through NF-kB signaling, we utilized two approaches. First, we introduced an IkBa super-repressor in which mutations at IkBa phosphorylation sites render it unresponsive to canonical upstream inducers. This super-repressor robustly blocked NF-kB activity and CTCF downregulation. Secondly, we employed IkBa+/2 mice which directly induced higher basal NF-kB activity. These IkBa+/2 animals have increased activation of NF-kB in the prostate. Using a polymorphism to identify different alleles, we demonstrate that the activation of NF-kB alone leads to increased IGF2 LOI in mouse prostate and decreased CTCF expression when compared to WT. These IkBa+/2 mice also demonstrate increased prostate cancer risk with aging when utilized in genetic models. Through the use of these two approaches, the important role of the NF-kB/ CTCF pathway in controlling IGF2 imprinting was confirmed. We do not, however, discount other minor effects that H2O2 might have on IGF2 biallelic expression including altering other transcription factors. The significance of the current study lies in the elucidation of a mechanism for oxidative stress to promote altered imprinting through canonical NF-kB signaling. Inflammation plays an important role in the development of age-related cancers, but mechanistic data linking inflammation to epigenetic alterations has been lacking. It is anticipated that antagonists of inflammation that inhibit NF-kB, including the spice curcumin and diterpenes found in coffee, would modulate imprinting. Our study also suggests a pivotal role for CTCF in modulating not only imprinting, but potentially regional hypermethylation. CTCF levels have been found to decrease with aging and cancer. Finally, these observations may help explain the altered epigenetic landscape seen with aging that underlies the increased risk of cancer.