Background: Prenatal treatment with dexamethasone (DEX) has been used since the mid 80s to minimize virilisation of girls with congenital adrenal hyperplasia. Long-term data on treatment safety and health outcome are still limited. It has been shown in animal models that prenatal dexamethasone treatment affects DNA methylation signatures as well as metabolism and behavior. We have previously shown that DEX affects working memory in children who were treated with DEX during fetal life. There is therefore an absolute necessity for further evaluation of patients with respect to treatment related risk.
Objective: To test the hypothesis that prenatal treatment with DEX is associated with a distinct DNA methylation profile that persists into adolescence and adulthood. We also hypothesize that the effects on the epigenetic state may be different in healthy, short-term treated individuals versus long-term treated girls with CAH.
Method: We isolated DNA from CD4+T-cells from 108 DEX treated individuals and controls (31 healthy, DEX-treated; 38 non-treated population controls; 11 CAH, DEX-treated; 28 CAH, non-treated). The Illumina Infinium Human Methylation 450 BeadChip Array was used to determine locus specific DNA methylation levels in T cells at 480.000 CGs across the genome in search for changes associated with prenatal DEX treatment. The GREAT annotation tool was used to investigate the functional relevance of the differentially methylated CpG sites.
Results: Global methylation changes could not be identified in DEX treated cases. However, locus-specific changes in methylation were observed in DEX treated cases. Functional investigation in GREAT showed that the changes occurred in several important biological systems with a clear difference between long- and short-term treated subjects. Investigation of short term treated healthy subjects also showed that effects on DNA methylation associated with DEX were moderated by gender.
Conclusion: These data provide the first evidence in humans that prenatal dexamethasone treatment causes long-lasting and functionally organized DNA methylation signatures in T cells and that the epigenetic changes are modified by duration of DEX treatment and sex. The findings may have important implications for the future health of DEX treated individuals.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology