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

Maya Sudman; Reinhard Stöger; Gillian R Bentley; Philippa Melamed

doi:10.1093/ejendo/lvae156

. 2024 Dec 13;191(6):623–635. doi: 10.1093/ejendo/lvae156

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

Maya Sudman ¹, Reinhard Stöger ², Gillian R Bentley ³, Philippa Melamed ^4,^b,^✉

PMCID: PMC11656572 PMID: 39670713

Abstract

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.

Keywords: ALSPAC, adrenarche, DHEAS, puberty, DNA methylation

Significance.

Premature adrenarche is often associated with early puberty and increased likelihood of girls developing polycystic ovary syndrome (PCOS). While interaction with the reproductive axis is strongly indicated, adrenarche is not essential for sexual maturation, and these connections are poorly understood. Our analysis of Avon Longitudinal Study of Parents and Children cohort data confirmed association between dehydroepiandrosterone sulfate (DHEAS) concentration at 8.5 years and subsequent pubertal development in girls. Taking a novel approach to focus on DNA methylation at genomic regions most likely to impart function, we found negative linear correlation between DHEAS and methylation levels at key puberty-related genes. Beyond indicating that adrenarcheal DHEAS concentrations might predict rates of pubertal development in girls and possibly comprise an early indicator for PCOS, our study provides an underlying mechanism connecting these developmental milestones.

Introduction

Prior to puberty, through apparently distinct regulatory mechanisms, adrenarche signals development of the adrenal gland zona reticularis and its production of androgens, primarily dehydroepiandrosterone (DHEA) and the sulfated (DHEAS). DHEAS and DHEA concentrations are correlated, and both reflect adrenal development and adrenarche progression.¹ Adrenal androgen synthesis starts as early as 3 years, can be measured in the circulation by ∼6 years, and peaks during early adulthood.^2–6 The manifestations of adrenarche result from this increase in androgens, and include growth of pubic (“pubarche”) and axillary hair, body odor, oily skin and acne. If these clinical signs are evident before 8 years in girls and 9 years in boys, or DHEAS levels are >40 µg/dL at these ages, adrenarche is considered premature.⁷

Patients with various pathologies have demonstrated that adrenarche is not essential for sexual maturation,^8–12 although advanced puberty often occurs in congenital adrenal hyperplasia.^13,14 Furthermore, healthy girls with premature adrenarche characteristically experience earlier puberty.^15–24 This coordinated timing might be due to common activators, such as obesity, birth size, and accelerated early-life growth,^17,22,25,26 or because these androgens facilitate maturation of the HPG axis. In support of the latter, the very high concentrations of DHEA and DHEAS allow their binding to steroid receptors, even though their affinity is much lower than that of the cognate ligands²⁷; they can also be converted to more potent sex steroids.²⁷ Girls with premature adrenarche are at higher risk of developing polycystic ovarian syndrome (PCOS),^21,28–30 and postnatal administration of DHEA is a well-established animal model for PCOS.³¹ The adrenal androgens thus appear to facilitate activity of the HPG axis, though the underlying mechanisms are unclear.

One possible consequence of high adrenal androgens in early life might be through altering DNA methylation. DNA methylation patterns change throughout childhood and adolescence,^32–35 and following DHEA treatment in mice^36,37 and cultured cells.³⁸ Further, a cohort-based study revealed differential methylation at individual CpGs in girls whose DHEAS concentrations were defined as “high” or “low”,³⁹ without examining differences across the spectrum of concentrations normally present in the population. Still, any function for altered methylation at individual CpGs is ambiguous, given that genomic regions regulating gene activity are likely subject to similar modification.^40,41

We hypothesized that DHEAS concentrations in early childhood are associated with: (1) pubertal timing and/or progression and (2) altered DNA methylation at specific genes involved in this developmental transition. We looked for correlations across the entire range of DHEAS concentrations in children of adrenarcheal age, and considered the association between DHEAS and methylation both at specific CpGs and in regulatory regions of puberty-related genes. Our approach uncovered variation in DNA methylation of likely biological significance comprising a possible molecular mechanism underlying the connection between adrenarche and pubertal development.

Methods

ALSPAC cohort

The original Avon Longitudinal Study of Parents and Children (ALSPAC) cohort^42,43 consists of pregnant women resident in Avon, UK, with expected delivery dates between April, 1, 1991, and December, 31, 1992, who were invited to take part in the study. Of the initial pregnancies, 14 676 fetuses resulted in 14 062 live births and 13 988 children alive at 1 year of age. When the oldest children were ∼7 years old, the sample was bolstered with eligible cases who had failed to join the study originally. The total sample size using any data collected after the age of 7 is 15 447 pregnancies, resulting in 15 658 fetuses, of whom 14 901 were alive at 1 year of age.

This cohort comprises questionnaires, clinical measurements and biochemical measurements (“variables”) from mother–child pairs at several timepoints; the study website contains details of all available data through a searchable data dictionary and variable search tool (http://www.bristol.ac.uk/alspac/researchers/our-data/). We used puberty-related questionnaires (publicly available at ALSPAC data dictionary: https://www.bristol.ac.uk/alspac/researchers/our-data/questionnaires/puberty-questionnaires) filled by mother or child; fasting blood measurements at 8.5 years; behavioral questionnaires filled by teachers of the children at 6 years; and other variables derived from these and other data (exact variables used and form of collection in Table S1; more details are publicly available in ALSPAC data dictionary). Some data were missing.

The genome-wide DNA methylation data were from fasting blood samples of the same children at 7.5 years of age, measured using Illumina Infinium HumanMethylation450 BeadChip (450 K) arrays as part of the Accessible Resource for Integrated Epigenomic Studies project.⁴⁴ From this cohort, 91 boys and 82 girls had both DNA methylation data and DHEAS measurements and were analyzed in this study.

Ethical approval and informed consent

Ethical approval was obtained from the ALSPAC Ethics and Law Committee and Local Research Ethics Committees (NHS Haydock REC: 10/H1010/70). Consent for biological samples was collected in accordance with the Human Tissue Act (2004). Informed consent for use of data collected via questionnaires and clinics was obtained from participants following recommendations of the ALSPAC Ethics and Law Committee at the time. At age 18 years, study children were sent “fair processing” materials describing ALSPAC’s intended use of their health and administrative records and were given clear means to consent or object via a written form. Data were not extracted for participants who objected, or who were not sent fair processing materials. The study was performed in accordance with the principles of the Declaration of Helsinki.

Analysis of variables correlated with DHEAS concentrations

Variables provided by ALSPAC with only missing values or <3 unique values (nominal) are not suitable for correlation analysis and were removed. The remaining 227 variables in girls and 223 in boys were analyzed by Spearman’s correlation, which, together with rho, P-value, and n (number of samples), were calculated for each variable pair using the “rcorr” function in the “Hmisc” package in R. The full list of variables analyzed and their method of collection are given in Table S1. Spearman’s correlation was chosen since it is robust for variables not normally distributed and for ordinal parameters which are prevalent in the data.

CpG site and region methylation analysis

We adjusted beta values for cell-type composition using a regression-based approach.⁴⁵ We used annotations from the Illumina manifest “IlluminaHumanMethylation450kanno.ilmn12.hg19” to include only CpGs located in CpG island (CpGI) shores and shelves which are known to be most dynamic.⁴⁶ We performed linear regression between beta values of each CpG site methylation (dependent variable) and the log-transformed DHEAS concentration (independent variable), using “cpg.assoc” function from the R package “CpGassoc,” and adjusted P-values by the Benjamini and Hochberg method. Enrichment analysis for methylation of CpGs with P-value <.01 was performed using the “gometh” function in the “missMethyl” package in R, and the −log10(P-value) was calculated.

We also grouped CpGs located in shores and shelves of the same island, based on the “Island_Name” annotation from the Illumina manifest, and looked for linear associations between methylation in these groups and log-transformed DHEAS concentration. Groups with the number of CpGs higher than 20% of the number of samples (n-value) were excluded to avoid overfitting and spurious correlations. Linear regression between methylation at each CpG (dependent) within each group and the log-transformed DHEAS concentration (independent) was performed. Groups were chosen if methylation of >20% of their CpGs was significantly associated with DHEAS (P-value <.05), and for at least half of these significant sites, the correlation was in the same direction (positive or negative) (Figure S1). Enrichment analysis for genes annotated near the most significant regions was performed using “gometh,” and −log10(P-value) was calculated, as above.

Functional analysis of annotated genes with known puberty-related function

The nearest gene to each CpGI was assigned based on the Illumina manifest. For islands with more than 1 annotated gene, all genes were taken for analysis. These genes were intersected with a list of puberty-related genes, generated using “Geneshot,” and a PubMed search for the term “puberty,” to create a literature-based list of relevant genes, where “AutoRIF” was chosen as the resource.⁴⁷

Results

DHEAS concentration and BMI at age 8.5 years were similar in girls and boys

In 8.5-year-olds, mean DHEAS concentrations were similar (P > .05) in boys (27.12 ± 2.45 mcg/dL; n = 91) and girls (27.59 ± 2.99 mcg/dL; n = 82: Figure S2A). The mean BMI at 8.1 years was also similar (P > .05) between sexes (16.84 ± 0.44 in boys and 16.64 ± 0.46 in girls: Figure S2B). There were 15 boys who, according to World Health Organization guidelines,⁴⁸ were overweight (BMI >17.5), 6 of whom were obese (BMI >19.7), while 2 were underweight (BMI <13.3). In girls, 8 were overweight (BMI >17.8), 2 of whom were obese (BMI >20.6) and 2 underweight (BMI <12.9). BMI data are partial (57/91 boys and 42/82 girls), and therefore, BMI was not accounted for in our linear regression models.

Known and novel variables were found to correlate with DHEAS concentration

We examined all variables to identify traits associated with DHEAS concentration at 8.5 years. In females, there were 36, and in males 32 variables that correlated significantly with DHEAS (P-value <.05); 12 were common to both sexes (Table S2). Androstenedione was the most significantly correlated in both sexes, and as previously reported,^49,50 SHBG was negatively correlated (Table S2).

In both sexes, DHEAS concentration was negatively correlated with age at peak height velocity and positively correlated with height at 11.6 years (in girls also at 8.1, 9.6, 10.6, and 13.1 years). It was positively correlated with weight at 9.6, 10.6, 11.6, and 13.1 years (in boys also at 8.1 years); and BMI in girls at 9.6 and 11.6 years, and in boys at 10.6 and 17 years. This accords with previous reports that children with higher DHEAS are more frequently overweight¹⁸ and the finding that level of boys’ participation in vigorous activities was negatively correlated. DHEAS also correlated positively with early-life caloric intake at 3, 7, and 13 years in both sexes, and with triglyceride levels. In boys, it correlated negatively with birthweight and IGFBP1 and positively with IGF1 and proinsulin, and in girls, with leptin (Table S2).

The number of traumas experienced between ages 0 and 17 years was correlated with DHEAS concentration at 8.5 years, though this was positive in boys and negative in girls. For girls, this included number of traumas between 0 and 5 years, degree to which the child had many fears at Year 6 in school, and the adverse childhood experience⁵¹ extended score (0-13) and categories (low, low-mid, mid-high, and high). These findings suggest that traumatic experiences might affect adrenarche timing, and/or that DHEAS might impact fearfulness and anxiety.

Verbal ability at age 6 years was positively correlated with DHEAS only in boys. Boys also had more social difficulties associated with higher DHEAS concentrations, being negatively correlated with “degree to which the child was generally liked by his peers” and “degree to which he shared readily with others,” and a positive correlation with “degree to which the child was bullied” (from the Strengths and Difficulties Questionnaire peer problems score: Table S2). These parameters are consistent with reported DHEAS effects on childhood social interactions and aggression,^52,53 and brain development^54–57

Girls with higher DHEAS concentration at 8.5 years proceeded to have more advanced pubertal development

At 8.1 years, 92.6% of girls were Tanner Stage 1 for pubic hair growth; the rest were Stage 2. Pubic hair growth at 8.1 years was correlated with DHEAS at 8.5 years (Figure 1A and B). Breast development was Tanner Stage 1 for 83.6% of girls at 8.1 years, and the rest were Tanner Stage 2 (Figure 1A); this was not correlated with DHEAS (Figure 1F). None of the girls reported menarche at this age.

DHEAS concentration at 8.5 years also correlated with pubic hair growth at later timepoints (11.7, 13.1, and 14.6 years; Figure 1C-E), and with subsequent breast development (at 9.6, 10.7, and 11.7 years; Figure 1G-I). It was negatively correlated with age of menarche (Figure 1J), as reported previously,^{16,17,19,20,22,58} and positively correlated with length of menstrual cycle at 15.5 years (Figure 1K).

Boys with higher DHEAS concentration at 8.5 years had more advanced pubic hair growth at later ages

At 8.1 years, 62/63 boys were Tanner Stage 1 for pubic hair development (Figure 2A). DHEAS at 8.5 years correlated with pubic hair measured at later timepoints (10.7, 11.7, 15.5, and 16 years; Figure 2B-F). Tanner stages of testis and penis development reported at 8.1 years were surprisingly advanced (Figure 2A), perhaps due to inconsistency in reporting this measurement,^59,60 and no correlation with DHEAS was evident at any age examined (Figure 2G-I).

Methylation levels of many individual CpGs showed some correlation with DHEAS concentration

Linear regression analysis identified 10 752 individual CpGs in boys and 5505 in girls where methylation levels appeared to correlate with DHEAS concentration (P-value <.05; Table S3). The most significant CpGs with nearby annotated genes (Table 1) included LGR4 whose sequence variants are linked to delayed puberty.⁶¹ Other genes have connections to puberty (eg, PTPRN2, DIO1) and spermatogenesis (CLU, LMTK2, SPAG8) or are involved in neuronal activity (PRRT1, C11ORF9, IQSEC, LMTK2), growth and metabolism (RPH3AL, SHOX2).

Table 1.

The top 15 individual CpG sites associated with annotated genes for which the methylation levels are linearly associated with DHEAS concentration.

CpG site	P value	Nearest gene	Relation to gene	Enhancer
Females
cg02593958	6.50E−05	MEGF11	5′UTR
cg26849331	7.26E−05	PRRT1	3′UTR
cg16970748	1.75E−04	FAM155B	TSS1500
cg23634928	1.95E−04	PTPRN2	Body	TRUE
cg17315281	2.09E−04	SORCS2	TSS1500
cg04764584	2.48E−04	SLC9A3	Body	TRUE
cg02238136	2.85E−04	ZNF620	Body; 5′UTR
cg16290399	3.26E−04	RAD17;TAF9	5′UTR; TSS200
cg20996314	3.33E−04	HR	TSS1500	TRUE
cg07195126	3.40E−04	VANGL2	5′UTR
cg09374648	3.41E−04	PNRC1	TSS1500
cg14346046	3.44E−04	LGR4	TSS1500
cg17091610	3.48E−04	L3MBTL	TSS1500
cg03585598	3.56E−04	LYRM4;FARS2	Body; TSS1500
cg04426862	3.68E−04	PAX9	5′UTR
Males
cg10503298	1.55E−05	CTBP1	Body
cg11783834	1.77E−05	CLU	Body; TSS200; TSS1500	TRUE
cg09584521	1.92E−05	CD58	Body
cg18171955	2.97E−05	C11orf9	Body
cg25051248	2.98E−05	CASKIN2	Body
cg21193975	3.02E−05	WDR5	3′UTR
cg18276808	3.23E−05	MUC2	Body
cg03886898	3.29E−05	DIO1	TSS1500
cg05897163	4.50E−05	PPP1R1B	TSS1500	TRUE
cg14666369	5.25E−05	ACADS	Body
cg24871089	5.42E−05	RPH3AL	5′UTR
cg09437283	5.93E−05	IQSEC1	Body
cg20501518	6.33E−05	SHOX2	Body	TRUE
cg17279887	6.74E−05	LMTK2	TSS1500
cg14353508	7.79E−05	SPAG4	Body

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For functional understanding of the methylation sites that were most significantly correlated (P-value <.01), we performed enrichment analysis of their associated genes. In girls, “hormone-protein receptor activity” was among the most enriched molecular functions (Figure S3A), while in boys, the most enriched biological processes included “positive regulation of steroid metabolic process” (Figure S3B). However, none of these individual CpGs remained significant following multiple comparison adjustment (FDR <0.05).

Regional analysis reveals CpGIs with DHEAS-associated changes in methylation

The above analysis examined individual CpGs, but functional changes in methylation comprising part of a regulatory mechanism are expected to be coordinated and occur primarily at CpGI shores and shelves.⁴⁶ We thus performed region-based analysis using linear regression to model the relationship in the context of CpGI shores and shelves.

There were 1824 and 3627 islands that met our criteria in girls and boys, respectively, with 8529 shore or shelf CpGs in girls and 17 722 in boys (Table S4). Of these CpGs, methylation of 2766 in girls and 8588 in boys was positively correlated with DHEAS, the remaining being negatively correlated. Among the islands where methylation correlated with DHEAS, 1286 in girls and 2726 in boys had at least 1 annotated gene in their proximity (Table 2). We intersected these genes between boys and girls, and 449 genes had methylation associated with DHEAS in both sexes (Table S5).

Table 2.

Number of islands whose methylation correlated with DHEAS concentration and the number of CpGs in their shores and shelves.

	Total		Near at least 1 annotated gene
	M	F	M	F
Islands associated with DHEAS concentration	3627	1824	2726	1286
CpGs included in associated islands	17 722	8529	13 846	6146
Positively associated CpGs	8588	2766	6929	1978
Negatively associated CpGs	9134	5763	6917	4168

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Analysis of these genes in girls revealed enriched molecular function terms related to activity of ion channels, and biological processes relating to cell adhesion and morphogenesis (Figure 3A). In boys, the most enriched molecular function term was transcriptional activity, and biological processes included regulation of I/NF-kappaB signaling, axon myelination, RNA metabolic process, Wnt signaling, and growth (Figure 3B).

Figure 3. — Top 10 most enriched GO terms of genes near CpGIs whose changes in methylation levels were linearly correlated with DHEAS concentration. The top 10 highest −log10(P-value) molecular functions and biological processes of genes near islands with DHEAS-associated methylation levels, for (A) girls and (B) boys. The shade indicates the number of genes intersecting with the GO term genes.

CpGIs with DHEAS-associated differential methylation are located near puberty-related genes

We next intersected the full list of genes (ie, with DHEAS-associated CpGI shore/shelf methylation) and a set of 248 puberty-related genes (Table S6). This revealed 12 puberty-related genes with DHEAS-associated levels of methylation evident only in boys, 7 only in girls, and 2 common to both sexes (Figure 4; Table S7 lists these CpGs, their location relative to the gene, and correlation with DHEAS).

Figure 4. — Puberty-related genes intersecting with genes located near CpGIs with DHEAS-associated methylation levels. Intersection of genes associated with the differential methylation in females, males, and a set of puberty-related genes. The 9 intersecting genes between the female set and the puberty-related gene set are listed on the left and the 12 in the males are on the right. *FGFR1* and *FTO* are found in all groups.

Methylation of the promoter/5′end of FGFR1 was strikingly negatively correlated with DHEAS in both sexes, at 3 CpGs in boys and 2 in girls (Figure 5A-C; Table S6). These sites are located in putative regulatory regions: in boys, they are 400-800 bp upstream of the first transcriptional start site (from FANTOM5 CAGE data), 2 are in a predicted promoter region (Genehancer⁶²), and 400-800 bp upstream of an androgen receptor (AR)-binding site (Remap ChIP-seq⁶³). In girls, the affected CpGs are in FGFR1 first intron, 200-400 bp from a distinct AR-binding site and a peak in CAGE reads, suggesting another regulatory element, and mechanism mediating the DHEAS effect (Figure 5C).

The methylation level at the promoter/5′ end of RPGRIP1L;FTO was also associated with DHEAS concentrations in both sexes: though positively correlated in males, in females one of these same sites was negatively correlated (Figure 5D and E), leaving any functional connection unclear.

In girls, the negative correlation between DHEAS and methylation of a CpG at the promoter of LHCGR (Figure 5F) was particularly notable, given its location and the role of LH receptor in reproductive function. There was also a negative correlation between DHEAS and methylation at a site 891 bp upstream of SRD5A2 which encodes 5α-reductase-2, the enzyme catalyzing synthesis of dihydrotestosterone. This genomic region binds many proteins (ReMAP: ChIP-seq data; Figure 5G), indicating a regulatory region and functional consequences of methylation.

We further detected a site near INHBB where changes in methylation met the criteria for association with DHEAS, though it was not listed among the puberty-related genes. It has, however, a recognized role in reproductive function and is associated with pubertal timing.^64,65 The CpG methylation, which was negatively correlated with DHEAS (Figure 5H), occurs 2240 bp upstream of INHBB near (∼350 bp) an estrogen receptor α (ERα)-binding site (ChIP-seq)^66–68 This region is transcribed (CAGE peak) and enriched with H3K4me1 (ENCODE), suggesting function as a distal enhancer (Figure 5I).

Discussion

Our findings confirm previous reports connecting childhood DHEAS with various aspects of physical and psychosocial development, metabolic risk factors in both sexes, and pubertal development in girls.^{16–20,26,69–76} Although DHEAS might affect pubertal development indirectly by altering metabolic status,¹⁵ our novel findings that its concentrations correlate negatively and linearly with DNA methylation at regulatory regions of key puberty-related genes, provide a mechanism for a direct functional relationship.

Our initial approach revealed several genes with known roles in sexual maturation or reproduction near individual CpGs with DHEAS-correlated methylation. However, because none of these remained significant following multiple comparison adjustment, we analyzed regions where functional changes in methylation most likely occur. This selective approach identified FTO and FGFR1 in both sexes. FTO encodes an α-ketoglutarate-dependent dioxygenase associated with obesity,^77,78 PCOS,⁷⁹ and pubertal timing.⁸⁰ However, the methylation patterns at this locus differed between sexes, perhaps reflecting the association between increased childhood weight and precocious puberty which is more prominent in girls,⁸¹ though the correlations are not strong enough to reach clear conclusions. In contrast, the affected CpGs near FGFR1, in both sexes, are located in putative regulatory regions near AR-binding sites. Sequence variation in FGFR1 is associated with delayed puberty and congenital hypogonadotropic hypogonadism.^82–86 Methylation at the FGFR1 promoter, including at one of the CpGs that we identified, was found negatively associated with FGFR1 expression,⁸⁷ pointing to a role for DHEAS-regulated demethylation on its expression, and likely effects on pubertal onset.

The association between DHEAS and methylation at LHCGR and SRD5A2, both of which play roles in androgen synthesis, is also in line with likely effects on pubertal timing and possibly PCOS. Variants of LHCGR are associated with PCOS,^88,89 and its expression in granulosa cells is higher in PCOS women.^90,91 Furthermore, the LHCGR promoter is hypomethylated in women with PCOS and in the DHEA-induced PCOS mouse model.^36,92,93 Activity of 5α reductases, one of which is encoded by SRD5A2, is elevated in PCOS women and their daughters, suggesting epigenetic regulation,^94,95 and we reported previously that the related SRD5A1 is epigenetically regulated in accordance with early-life environments.^96,97 Premature adrenarche has been suggested as a risk factor for PCOS,^30,98 and our findings suggest that DHEAS might facilitate the drop in LHCGR and SRD5A2 promoter methylation, leading to their increased expression. Elevated levels of LHCGR could promote more ovarian steroidogenesis to increase DHEAS further, while SRD5A2 would increase androgen potency, driving PCOS progression and severity, supporting this connection.

DHEAS-associated changes in DNA methylation were also apparent upstream of INHBB. INHBB encodes the βB subunit of inhibin B, activin B, and activin AB which play multiple roles in reproductive function, including driving growth of ovarian granulosa cells.⁹⁹ Levels of inhibin B increase throughout puberty¹⁰⁰ and were suggested to serve as a marker for precocious puberty.^64,65 The most affected CpG is found in a locus that carries several markers of a transcriptional enhancer. This CpG is located near an ERα-binding site, and INHBB expression is regulated by estrogen,^101–103 suggesting DHEAS-regulated demethylation possibly via, or impacting, ERα-mediated regulation of this gene.

In summary, our study supports a positive correlation between DHEAS concentration in 8.5-year-old girls and their subsequent pubertal development, and indicates that it might serve as an early indicator for PCOS which is characterized by irregular cycles, high androgen concentration, and metabolic dysfunction.^98,104–110 Correlation between pubertal development and DHEAS in boys was less clear, perhaps due to shortcomings associated with some of the self-assessed data.¹¹¹ Still, the accessibility of this approach to children and adolescents allows establishment of larger cohorts and more accurate statistical analysis.

Our findings also provide a mechanistic basis for these observations through DHEAS linearly-associated changes in DNA methylation at regulatory regions of key puberty-related genes. This might contribute to development of methylome-based diagnostic tools for predicting early puberty. The relevance of such modifications in peripheral blood cells is not always clear and serves only as a proxy to indicate similar methylation in the inaccessible hypothalamic and pituitary tissues that regulate the reproductive axis. However, a greater response might be expected in functional tissues which contain the complete machinery involved in regulating their expression. Still, the correlations observed may well not signify simple cause–effect relationships, and these findings will need to be examined further in suitable animal or cell models to clarify the complex and multifactorial connection between adrenarche and pubertal development.

Supplementary Material

lvae156_Supplementary_Data

lvae156_supplementary_data.zip^{(41.9MB, zip)}

Acknowledgments

The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.

Contributor Information

Maya Sudman, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

Reinhard Stöger, School of Biosciences, University of Nottingham, Nottingham LE12 5RD, United Kingdom.

Gillian R Bentley, Department of Anthropology, Durham University, Durham DH1 3LE, United Kingdom.

Philippa Melamed, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

Supplementary material

Supplementary material is available at European Journal of Endocrinology online.

Funding

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors who will serve as guarantors for the contents of this paper. This research was specifically funded by Wellcome Trust and MRC (core) (076467/Z/05/Z), BBSRC (BBI025751/1 and BB/I025263/1), IEU grant codes (MC_UU_12013/1, MC_UU_12013/2, and MC_UU_12013/8), National Institute of Child and Human Development grant (R01HD068437), NIH (5RO1AI121226-02), CONTAMED EU Collaborative Project (212502), Center for Disease Control (AY5350), Wellcome Trust and MRC (092731), and Department for Education and Skills (EOR/SBU/2002/121). In addition, this research was funded by the University of Nottingham, Faculty of Science Pump-Prime Research Accelerator Fund.

Authors’ contributions

Maya Sudman (Conceptualization [supporting], Formal analysis [lead], Investigation [lead], Methodology [lead], Writing—original draft [lead], Writing—review and editing [supporting]), Reinhard Stöger (Conceptualization [equal], Funding acquisition [equal], Writing—review and editing [supporting]), Gillian Bentley (Conceptualization [equal], Funding acquisition [supporting], Writing—review and editing [supporting]), and Philippa Melamed (Conceptualization [equal], Funding acquisition [equal], Project administration [lead], Supervision [lead], Writing—review and editing [lead]).

Data availability

All data used in this study were taken from and are available through ALSPAC.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

lvae156_Supplementary_Data

lvae156_supplementary_data.zip^{(41.9MB, zip)}

Data Availability Statement

All data used in this study were taken from and are available through ALSPAC.

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PERMALINK

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

Maya Sudman

Reinhard Stöger

Gillian R Bentley

Philippa Melamed

Roles

Abstract

Objective

Design

Methods

Results

Conclusions

Significance.

Introduction

Methods

ALSPAC cohort

Ethical approval and informed consent

Analysis of variables correlated with DHEAS concentrations

CpG site and region methylation analysis

Functional analysis of annotated genes with known puberty-related function

Results

DHEAS concentration and BMI at age 8.5 years were similar in girls and boys

Known and novel variables were found to correlate with DHEAS concentration

Girls with higher DHEAS concentration at 8.5 years proceeded to have more advanced pubertal development

Figure 1.

Boys with higher DHEAS concentration at 8.5 years had more advanced pubic hair growth at later ages

Figure 2.

Methylation levels of many individual CpGs showed some correlation with DHEAS concentration

Table 1.

Regional analysis reveals CpGIs with DHEAS-associated changes in methylation

Table 2.

Figure 3.

CpGIs with DHEAS-associated differential methylation are located near puberty-related genes

Figure 4.

Figure 5.

Discussion

Supplementary Material

Acknowledgments

Contributor Information

Supplementary material

Funding

Authors’ contributions

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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