There is mounting evidence that oxidative stress may impact not only the genome, but epigenetic elements as well. The regulatory factors linking inflammation to epigenetics have not been well defined. One candidate is CTCF, a regulatory protein with 11 highly conserved zinc finger domains that plays an important role in transcription, but recent data suggest a role in modulating the epigenome. The presence of CTCF prevents DNA methylation of CG-enriched regions in vitro. Our laboratory has previously found that during aging, CTCF is decreased in the prostate associated with a loss of the normal imprint at IGF2. The IGF2-H19 locus is a well-characterized epigenetic target with important implications in cancer development. In the present study, we establish a novel mechanistic link ALK5 Inhibitor II between oxidative stress and IGF2 imprinting through NF-kB-mediated repression of CTCF expression and binding to the H19-ICR region. This NFkB/CTCF response occurs in both human prostate cells in vitro and in prostate tissues from mice that have higher basal NF-kB activity. Imprinting of the IGF2 gene is driven primarily by the binding of the insulator CTCF to the H19 ICR in both the human and the mouse. Exposure to H2O2 results in IGF2 LOI in both cell lines tested. This LOI was calculated as a percentage of the expressed allele and was likely underrepresented given the multiple 11p15 copies seen in these cell lines. LOI was confirmed in a mouse prostate containing multiple cell types. This biallelic expression was associated with reproducible CTCF loss of binding and expression consistent with known models. The regulation of CTCF is complex and poorly studied. However, CTCF downregulation has been observed after cell exposure to UV radiation. CTCF is a dynamic protein whose loss of binding leads to hypermethylation of CpG-enriched regions. An increase in DNA methylation across the H19-ICR consistent with this previous observation was observed. Regional hypermethylation at this CTCF binding site is in contrast to previous observations that oxidative stress globally decreases methylation in mouse models deficient in CuZnSOD, a result of DNA adducts inhibiting DNA methyltransferase. The increase in methylation at the H19-ICR region occurred after CTCF reduction and binding, suggesting that these methylation changes are due to decreased CTCF occupancy and not directly caused by oxidative stress. The hypermethylation found suggests other higher order epigenetic changes, including histone modifications, may also be altered by oxidative stress and would be a target for future study. The activation of NF-kB occurs through distinct canonical and noncanonical pathways. The canonical pathway involves the activation of the NFkB subunits p50 and p65/RelA and is most consistent with our expression and binding data. Other research supports a noncanonical pathway promoting activation of the redox-sensitive NIK/IKK pathway. The current data did not observe the activation of p52 or RelB after exposing the cells to H2O2.