The aim was to provide theoretical support for male reproductive health in an increasingly aging society. The influence of microtubule movement and selenium metabolism in DKO male mice is discussed. The current study used 15-month-old male mice, considered equivalent to middle or old age, with a double knockout (DKO) of the Per1/Per2 gene to investigate the effect of abnormal circadian rhythms on the expression of testosterone synthesis genes and corresponding signaling pathways. However, the impact of long-term abnormal circadian rhythms on the reproductive ability of middle-aged and elderly men is poorly understood. Normally, spermatogenesis is well preserved into old age with decreases taking place over decades, so that only 50% of men over 80 years old are completely infertile. Fluctuations in testosterone synthesis are affected not only by rhythmic genes expressed in the testis but also by circadian rhythms throughout the body, including oscillations of plasma luteinizing hormone (LH). Indeed, sperm concentration and total sperm count were highest in semen collected before 7:30 a.m. Testosterone synthesis in testicular tissue shows a diurnal fluctuation, reaching a peak in adult males at 08:00 a.m. Clock mRNA is known to be expressed in spermatogonia cells and spermatocytes up to first meiosis, but expression patterns of other clock genes in the testis remain unclear. For example, Per1 mRNA was only expressed in stage VII–XII of spermatogenesis in secondary spermatocytes and Per2 mRNA expression did not show a circadian oscillation in testicular interstitial cells. The expression patterns of various clock genes in testicular tissues are not consistent and the relationship with reproductive ability is not clear. However, it is not clear how Per1/Per2 mutations affect the reproductive capacity in male mice. The Per2 gene modulates the circadian rhythms that influence biological processes and female Per1/Per2 mutants show premature ovarian failure and impaired ovarian function. Bmal1 gene-deficient mice have disrupted mating behavior accompanied by testosterone levels that are only 70% of that of WT mice. Male mice with the ClockΔ19 mutation had reduced fertility, in vitro fertilization rate, and sperm acrosin activity. Increasing evidence suggests that the deletion of core circadian genes will attenuate circadian rhythms and impair reproductive ability. An accumulation of nuclear Per and Cry inhibit Clock/Bmal1 activity which, in turn, represses Per and Cry, generating oscillations in their expression. The transcriptional activator, CLOCK/BMAL1, forms heterodimers to initiate the expression of Period (Per1/2/3) and Cryptochrome (Cry1/2) genes to allow feedback loops to operate. Īt the molecular level, circadian clocks operate through a core transcriptional negative feedback loop plus auxiliary feedback loops. The SCN controls circadian rhythms in synchrony with the earth’s rotation and the peripheral biological clock relays the signal to peripheral organs, allowing animals to adapt their feeding, activity, and metabolism to daily environmental changes. The circadian clock encompasses a “master clock” within the hypothalamic suprachiasmatic nucleus (SCN) and “peripheral clocks” within other tissues. Mammalian circadian rhythms regulate many physiological, biological, and behavioral processes. Therefore, Per1/Per2 disruption reduced testosterone synthesis and sperm motility by affecting the PKA-StAR pathway, leading to decreased fertility. Western-blotting showed that steroid acute regulatory protein (StAR) and p-CREB, PKA and AC1 were reduced in testicular tissue of DKO mice compared to WT. Seleno-compound metabolic loci, Scly and Sephs2, were up-regulated and Slc7a11 and Selenop were down-regulated. Spermatogenesis genes, Tubd1 and Pafah1b were down-regulated, influencing tubulin dynamics and leading to impaired motility. Transcriptomic analysis of testicular tissue showed the down-regulation of testosterone synthesis-related enzymes (Cyp11a1, Cyp17a1, Hsd17b3, Hsd3b1, and Star) in the steroid hormone synthesis pathway. Hormone-targeted metabolomics showed reduced plasma levels of free testosterone in DKO male mice compared with WT male mice. The sperm motility and spermatogenic capacity of male DKO mice were weak. The current study reports that the mechanism of Per1/Per2 Double knockout (DKO) reduced the reproductive capacity of elderly male mice. Circadian rhythm disorders caused by genetic or environmental factors lead to decreased male fertility but the mechanisms are poorly understood.
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