Abstract
BackgroundCircadian rhythm disruption impacts a wide range of physiological processes, including fertility. However, the effect of circadian disruption on male spermatogenesis and fertility, and treatments for these effects have been largely unexplored at the molecular level.MethodsIn this study, we examined the effects of genipin on improving the reproductive health problems caused by circadian disruption. Three groups of animals were fed under different conditions: control group (normal T cycle with saline), group of shortened T cycles (Light/Dark = 4 hours/4 hours) with saline, and a group of shortened T cycles with genipin by oral gavage. The male fertility was evaluated by fertility study and pups parameters analysis after successful sexual behavior and mating with female mice. We sacrificed the treated animals after 5 or 10 weeks and collected the testis, sperm and serum for histological analysis, sperm motility assay, and serum hormone detection, respectively. Furthermore, the effect of genipin was assessed by detection of progesterone secretion and steroidogenic key proteins expression, including StAR and CYP11A1, in mouse Leydig tumor MLTC-1 cells.ResultsMale mice exposed to shortened light-dark cycles, much shorter than 24 hours, had reduced fertility with decreased sperm concentrations and sperm motility. Male mice under circadian disruption have reduced testis size and abnormal morphology, leading to lower fertility rates, reduced litter size and pup body weight. Treatment with exogenous genipin, a natural plant-derived compound, alleviated circadian disruption-induced damage to fertility and spermatogenesis and normalized testosterone, dihydrotestosterone (DHT), and androstenedione (ASD) levels in the male mice. The levels of key proteins involved in steroidogenesis, StAR and CYP11A1, were reduced in mouse testes after the circadian disruption, but genipin treatment restored the reduction. The mRNA expression of SRD5A1, which encodes an androgen synthesis enzyme, was also upregulated by genipin treatment. Furthermore, genipin treatment showed a positive effect on steroidogenesis in MLTC-1 cells, resulting in an increase in hormone secretion and the upregulation of StAR and CYP11A1.ConclusionsOur results showed an association between circadian disruption and reproductive health problems in male mice and indicated that treatments with genipin have positive effects on the reproductive health of male mice with circadian rhythm disorders.
Highlights
Circadian rhythms are a fundamental feature in eukaryotes and coordinate numerous aspects of behavior, physiology, and metabolism [1]
Fertility parameters To analyze the fertility of male mice subjected to shortened T cycles and GNP treatment, we compared the fertility rates of Normal control (NC), SC, and SG male mice through natural mating
50% (n = 20) of female mice that mated with SC males produced offspring, whereas 75% (n = 20) of females that mated with SG males and 95% (n = 20) of females that mated with NC males produced offspring
Summary
Circadian rhythms are a fundamental feature in eukaryotes and coordinate numerous aspects of behavior, physiology, and metabolism [1]. The circadian clock system occurs at all levels of cellular organization, allows an organism to interact with external stimuli on the cell, organ, and organism levels, according to a transcriptional-translational feedback loop by light-dark cycles [2]. These 24-h circadian rhythms are orchestrated by a primary clock in the suprachiasmatic nucleus (SCN) of the hypothalamus in mammals. The circadian clock allows organisms to anticipate the predictable changes in the environment that occur at approximately the same time of day or adapt to daily variations in their environment. The effect of circadian disruption on male spermatogenesis and fertility, and treatments for these effects have been largely unexplored at the molecular level
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