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Per1/Per2 Disruption Reduces Testosterone Synthesis and Impairs Fertility in Elderly Male Mice
Qinrui Liu1, Hu Wang1, Hualin Wang1
1School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China.
Abstract:
Circadian rhythm disorders caused by genetic or environmental factors lead to decreased male fertility but the mechanisms are poorly understood. The current study reports that the mechanism of Per1/Per2 Double knockout (DKO) reduced the reproductive capacity of elderly male mice. The sperm motility and spermatogenic capacity of male DKO mice were weak. Hormone-targeted metabolomics showed reduced plasma levels of free testosterone in DKO male mice compared with WT male mice. 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. Spermatogenesis genes, Tubd1 and Pafah1b were down-regulated, influencing tubulin dynamics and leading to impaired motility. Seleno-compound metabolic loci, Scly and Sephs2, were up-regulated and Slc7a11 and Selenop were down-regulated. 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. Therefore, Per1/Per2 disruption reduced testosterone synthesis and sperm motility by affecting the PKA-StAR pathway, leading to decreased fertility.
Insights
Disrupting the Per1/Per2 genes in elderly male mice impaired sperm motility and testosterone production. This circadian rhythm disruption affects the PKA-StAR pathway, ultimately reducing male fertility.
Area of Science:
- Chronobiology
- Reproductive Biology
- Molecular Endocrinology
Background:
- Circadian rhythm disruption is linked to decreased male fertility, but underlying mechanisms remain unclear.
- The roles of core circadian clock genes, Period 1 (Per1) and Period 2 (Per2), in male reproductive function are not fully elucidated.
Purpose of the Study:
- To investigate the impact of Per1/Per2 gene disruption on male reproductive capacity in elderly mice.
- To elucidate the molecular mechanisms by which Per1/Per2 deficiency affects testosterone synthesis and sperm function.
Main Methods:
- Utilized Per1/Per2 Double knockout (DKO) and wild-type (WT) elderly male mice.
- Performed hormone-targeted metabolomics, testicular transcriptomic analysis, and Western-blotting.
Main Results:
- DKO mice exhibited reduced sperm motility, spermatogenic capacity, and plasma free testosterone levels compared to WT mice.
- Testicular transcriptomics revealed down-regulation of key testosterone synthesis enzymes (e.g., Star) and spermatogenesis genes (e.g., Tubd1).
- Western-blotting confirmed reduced steroid acute regulatory protein (StAR), p-CREB, protein kinase A (PKA), and adenylyl cyclase 1 (AC1) in DKO testes.
Conclusions:
- Per1/Per2 gene disruption impairs male fertility by reducing testosterone synthesis and sperm motility.
- The PKA-StAR signaling pathway is a critical mediator of these effects in Per1/Per2 deficient mice.
