Dexamethasone is a regulator of clock genes in testicular peritubular cells

Nov 7, 2024Andrology

Dexamethasone controls daily rhythm genes in cells surrounding testicular tubes

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Abstract

Dexamethasone (1 µM) significantly increased mRNA levels of clock genes BMAL1 and PER1 in testicular peritubular cells within 6 hours.

Testicular peritubular cells exhibit an endogenous , particularly for the clock gene BMAL1.
Activation of the by dexamethasone leads to increased expression of multiple clock genes.
In organotypic testicular samples from nonhuman primates, mRNA levels of BMAL1 and PER1 increased in two out of three animals after Dex treatment.
No significant changes in the testicular proteome were observed, potentially due to the short duration of the experiment.
Glucocorticoids may play a critical role in regulating the internal clock system of testicular peritubular cells.

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BACKGROUND: We recently found that peritubular cells of the human testis are a dominant site of expression of the (GR; encoded by NR3C1). Activation of GR by dexamethasone (Dex) strongly influences the phenotype of cultured human testicular peritubular cells (HTPCs), causing massive changes of their proteome and secretome. As glucocorticoids (GC) are also known to set the internal clock of peripheral organs by regulating clock genes, we tested such an influence of Dex in HTPCs.

METHODS: We performed cellular studies with HTPCs and immortalized nonhuman primate (Callithrix jacchus; Cj)-derived peritubular cells, organotypic incubations of testicular fragments of Cj, qPCR and proteomic, as well as immunohistochemical studies.

RESULTS: Basal clock gene expression levels, when monitored by qPCR under standard culture conditions, showed alterations over 24 h, suggesting an endogenous , especially for BMAL1. Dex (1 µM) when added to cells, caused a strong and significant increase of PER1, followed by elevations of BMAL1, and other clock genes. This action was observed as early as 4 h after the addition of Dex. Immunohistochemistry and data mining revealed GR in testicular peritubular cells and other somatic cells of Cj, in situ. We therefore performed organotypic incubations of testicular fragments of Cj (n = 3) and found that upon addition of Dex (1 µM), mRNA levels of BMAL1 and PER1 also increased in samples of two out of three animals after 6 h. Mass spectrometry did, however, not reveal significant alterations of the testicular proteome, possibly due to the short time point and/or the fact that the somatic GR-expressing cells represent only a small portion of the testis. In support for this assumption, Dex (1 µM; 6 h) significantly increased mRNA levels of BMAL1 and PER1 in Cj-derived immortalized testicular peritubular cells.

CONCLUSION: The results indicate that an internal clock system likely exists in peritubular cells of the testis and that Dex, via testicular GR expressed by peritubular cells and other somatic cells, is a strong regulator of this system. In a physiological situation, GC thus may be important regulators of the testicular clock, while in a situation of prolonged stress or GC-medication, derangements in clock gene expression may result.

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Increase in PER1 Expression

Observed at 4 hours post Dex treatment in HTPCs.

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Increase in BMAL1 and PER1 mRNA Levels

Testicular fragments from nonhuman primates showed increased levels after 6 hours of Dex treatment.

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Dexamethasone is a regulator of clock genes in testicular peritubular cells

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