Transcription factor binding to the promoter regions of target genes and in the case of HSD11B2, CpG methylation at Sp1 and NF1 recognition sequences prevents binding of these transcription factors and diminishes the transcriptional activity of HSD11B2. Increased hepatic HSD11B2 promoter methylation and decreased HSD11B2 mRNA has also been observed in neonatal offspring exposed to in utero magnesium deficiency. In rats, intrauterine growth restriction is associated with both reduced HSD11B2 expression and increased HSD11B2 promoter methylation in kidneys at birth and these epigenetic effects lead to altered transcription factor binding of Sp1 and NF-kB. These epigenetic effects were found to be sex-specific and present both at birth and postnatal day 21, indicating long-term consequences of prenatal HSD11B2 dysregulation. The sex-specificity of environmentally induced changes in DNA methylation is increasingly evident and indeed epigenetic modifications may be involved in the normal process of sexual differentiation. Though we do not find sex-specific effects of maternal Vismodegib stress on HSD11B2 expression or DNA methylation in the current study, it may be that large samples are needed to detect sex-differences in the epigenetic regulation of this gene or that sex-differences are more likely to emerge in later development. A candidate mechanism for the increased placental DNA methylation and increased HSD11B2 levels we have found in response to maternal stress during pregnancy may involve the upregulation of DNA methyltransferase levels in the placenta of stressed offspring. Our data indicate a placenta-specific increase in DNMT3a mRNA in response to maternal stress. This stressinduced effect has implications for genome-wide epigenetic changes, and may account for the diverse phenotypic outcomes associated with maternal adversity during pregnancy. DNMT1 and DNMT3a are enzymes active throughout the lifespan and thus could potentially serve as a mechanism for long-term epigenetic regulation, though it is possible that DNMT3b is similarly altered by prenatal stress to mediate HSD11B2 promoter methylation. Our data are consistent with previous findings indicating an up-regulation of DNMTs in the placenta of mice exposed to 1st trimester maternal stress. Targeted deletion of DNMT1 or DNMT3a in mice has been found to produce embryonic and postnatal lethality and widespread epigenetic changes – particularly amongst imprinted genes – in embryonic tissues. Amongst offspring that are heterozygous for a mutation in DNA methyltransferase 3-like protein, there are specific disruptions to placental development. DNMT3L interacts directly with DNMT3a to facilitate DNA methylation, and within the placenta, epigenetic regulation of DNMTs and DNMT3L may account for the changing epigenetic and transcriptional profiles in this tissue during the course of pregnancy. Within the fetal hypothalamus and cortex we observe discordance in the relationship between HSD11B2 mRNA, DNMT expression, and CpG methylation within the HSD11B2 gene promoter. Despite stress induced decreases in HSD11B2 CpG methylation in the fetal hypothalamus.