Adrenal androgen production in catarrhine primates and the evolution of adrenarche

Abstract

Adrenarche is a developmental event involving differentiation of the adrenal gland and production of adrenal androgens, and has been hypothesized to play a role in the extension of the preadolescent phase of human ontogeny. It remains unclear whether any nonhuman primate species shows a similar suite of endocrine, biochemical, and morphological changes as are encompassed by human adrenarche. Here, we report serum concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) measured in 698 cross-sectional and mixed longitudinal serum samples from catarrhine primates ranging from 0.6 to 47 years of age. DHEAS in Pan is most similar to that of humans in both age-related pattern and absolute levels, and a transient early increase appears to be present in Gorilla. DHEA levels are highest in Cercocebus, Cercopithecus, and Macaca. We also tested for evidence of adaptive evolution in six genes that code for proteins involved in DHEA/S synthesis. Our genetic analyses demonstrate the protein-coding regions of these genes are highly conserved among sampled primates. We describe a tandem gene duplication event probably mediated by a retrotransposon that resulted in two 3-β-hydroxysteroid dehydrogenase/Delta 5-Delta 4 genes (HSD3B1 and HSD3B2) with tissue specific functions in catarrhines. In humans, HSD3B2 is expressed primarily in the adrenals, ovary, and testis, while HSD3B1 is expressed in the placenta. Taken together, our findings suggest that while adrenarche has been suggested to be unique to hominoids, the evolutionary roots for this developmental stage are more ancient.

Fig. 1

Enzymes involved in the DHEA/DHEAS conversion pathway; asterisks indicate hormones and enzymes included in endocrine and evolutionary analysis in the current paper (modified from Nakamura et al., 2009). Abbreviations explained in text.

Fig 2

DHEAS with age in Pan (filled circles) and Papio (crosses).

Fig 3

DHEAS with age in Pan (filled circles) and Gorilla (crosses).

Fig 4

Gene duplication event in the HSD3B gene family in primates. Maximum likelihood HSD3B1 and HSD3B2 gene tree with percentage bootstrap support (1000 replicates) given for each node (full tree given in Supporting Information Fig. S2).

Fig 5

CYB5A, POR, HSD3B gene family and CYP17A1 M1 trees. The free ratio model (M1) is a significantly better fit to the data than the one ratio model (M0) for all four loci. ω Values are given for primate branches (full dataset shown in Supporting Information Figs. S3–S6). Arrows denote branches with evidence suggesting positive selection. The square denotes a gene duplication event.

Fig 6

Functionally active binding sites in the promoter region of CYP17A1 (A) and SULT2A1 (B). For each gene, (1) a schematic of binding site positions upstream of the transcription start site and (2) alignments of binding site regions showing matched sequences (denoted by ‘.’) to the human sequence are shown. Binding site regions are based on the human sequence as reported by Lin et al. (2001), Fluck and Miller (2004), Saner et al. (2005). Functionally active transcription factor binding site regions are aligned for all currently available primate sequences (downloaded from Ensembl). Flanking sequences are not shown. Symbol key: circle = Sp1/Sp3 binding site; diamond = GATA-6 binding site; and squares = SF1 binding sites.