Association of childhood dehydroepiandrosterone sulfate concentration, pubertal development, and DNA methylation at puberty-related genes.

Objective: High concentrations of dehydroepiandrosterone sulfate (DHEAS) often precede premature puberty and sometimes polycystic ovary syndrome (PCOS). We hypothesized that the underlying mechanisms might involve DNA methylation. As an indicator of the downstream effects of DHEAS, we looked for associations between prepubertal DHEAS concentration, pubertal progression, and DNA methylation at puberty-related genes in blood cells.

Design: Blood methylome and DHEAS concentration at 7.5 and 8.5 years, respectively, were analyzed in 91 boys and 82 girls. Pubertal development data were collected between 8.1 and 17 years (all from UK birth cohort, Avon Longitudinal Study of Parents and Children [ALSPAC]).

Methods: Correlation between DHEAS and pubertal measurements was assessed by Spearman's correlation. DHEAS association with methylation at individual CpGs or regions was evaluated by linear regression, and nearby genes examined by enrichment analysis and intersection with known puberty-related genes.

Results: Boys and girls with higher childhood DHEAS concentrations had more advanced pubic hair growth throughout puberty; girls also had advanced breast development, earlier menarche, and longer menstrual cycles. DHEAS concentration was associated with methylation at individual CpGs near several puberty-related genes. In boys, 14 genes near CpG islands with DHEAS-associated methylation were detected, and in girls, there were 9 which included LHCGR and SRD5A2; FGFR1 and FTO were detected in both sexes.

Conclusions: The association between DHEAS and pubertal development, as reported previously, suggests a physiological connection. Our novel findings showing that DHEAS concentration correlates negatively and linearly with DNA methylation levels at regulatory regions of key puberty-related genes, provide a mechanism for such a functional relationship.