Contribution of testosterone to the clock system in rat prostate mesenchyme cells

Abstract

SUMMARYCircadian rhythms are modulated in a variety of peripheral tissues including the prostate, in which the mesenchyme and epithelium cells are controlled under androgens. Here, we investigated the testosterone regulation of core clock genes such as Bmal1, Clock, Per2 and Nr1d1 under a deficient state of testosterone. In vivo studies showed that the Bmal1 mRNA expression in the prostates displayed a peak at ZT 20 and a trough at ZT 12. Both Bmal1 and Clock transcripts decreased after castration. Conversely, the expression of Per2 that is promoted by binding of Bmal1 and Clock heterodimers to the E-box, enhanced or did not decease at least within 1 week after castration. The clock gene transcripts were recovered to the intact levels, when 1 mg testosterone was administered daily for 5 days. Fluorescent immunohistochemical studies revealed the increased staining of caspase 3 in the epithelium and Per2 in both the mesenchyme and epithelium after 1-week castration. In the mesenchyme cells prepared from castrated rats, the Per2 oscillation was generated in response to dexamethasone. The circadian rhythms of Bmal1 and Nr1d1 transcripts were obviously antiphase in the cells. However, the mesenchyme cells displayed the different profiles in the presence or absence of testosterone; the amplitude of the first phase was significantly decreased by testosterone. Addition of testosterone significantly increased the transcripts of Bmal1, Clock and Casp3 in cultured cells, whereas the Per2 and Nr1d1 transcripts were significantly inhibited. Collectively, the present results demonstrated that Bmal1 and Clock, but not Per2 and Nr1d1, are down-regulated in mesenchyme cells by testosterone deficiency. In addition to the conservative interlocked transcriptional-translational feedback loop, it is strongly suggested that the prostate clock system is controlled under androgen.

WOMEN IN CANCER THEMATIC REVIEW: Circadian rhythmicity and the influence of ‘clock’ genes on prostate cancer

“…This shift in Per2 levels was coincident with testosterone synthesis, suggesting strong association between androgen production and the expression of Per2. Additional reports showed that Bmal1 and Clock, but not Per2 and Nr1d1/Rev–ErbAα, are down-regulated by testosterone deficiency (Kawamura, et al 2014). Thus, it is likely that Per2 that drives testosterone levels.…”

“…Both male and female Bmal1 knockout (K/O) mice are infertile (Alvarez, et al 2008). Male Bmal1 K/O mice had low testosterone and high luteinizing hormone serum concentrations, suggesting a role for Bmal1 in androgen production, while in turn, Bmal1 and Clock are down-regulated by testosterone deficiency (Kawamura et al 2014). Importantly, Leydig cells, which produce testosterone, rhythmically express Bmal1 protein (Alvarez et al 2008).…”

TRH and TRH-Like Peptide Levels Co-Vary with Reproductive and Metabolic Rhythms

“…Transcription factors mediating circadian rhythms are found in all cells and can function autonomously [25]. There is evidence for a number of different mechanisms coordinating the master clocks [26] within the suprachiasmatic nucleus (SCN) with peripheral cycling [8][9][10][25][26][27][28][29][30]. During neonatal development, the phase relationship of the circadian clock gene Per2 expression within the SCN and peripheral tissues can shift suggesting entrainment to organ-specific time cues at different developmental stages [27].…”

Developmental Programming by Androgen Affects the Circadian Timing System in Female Mice1

“…liver, oviduct) are unknown. Further, the threshold for the effects of androgens on clock gene expression have not been established, though some evidence suggests a potent effect in the nanomolar range [47,48]. We have attempted to determine if androgen can affect the timing of PER2::LUC expression at a level several fold higher than that found in serum from women with PCOS.…”

“…The mechanism whereby excess androgen can alter the timing of the clock remains to be determined, though it is likely due to a direct influence of ligand bound androgen receptor on clock gene expression [47,48]. To address this hypothesis we treated tissue explant cultures of liver, lung, pituitary, ovarian follicles, oviduct, WAT and SCN from adult female PER2::LUC mice (congenic on C57BL6/j) with several concentrations of DHT (100nM-1μM).…”