The cost of the circadian desynchrony on the Leydig cell function
Maja V. Pavlovic, Dijana Z. Marinkovic, Silvana A. Andrić, Tatjana S. Kostic
Abstract
The increased frequency of different lifestyles that disrupts circadian rhythms, together with a trend in the accretion of male idiopathic infertility, imposes the necessity to understand the contribution of circadian rhythms disruption to fertility regulation. In this study, the effects of circadian desynchrony (CD) on the steroidogenic capacity of adult Leydig cells were studied. Adult rats were housed under a disturbing light regime (2 days of constant light, 2 days of continual dark, and 3 days of 12:12 h light:dark schedule) designed to mimic shiftwork in humans. CD was characterized by changed and decreased rhythmic locomotor activity and reduced blood testosterone. In the Leydig cells changed transcription of the clock genes (Bmal1, Clock, Cry1 and Reverba/b increased while Per1/2 reversed phase) was detected. This was followed by reduced transcription of genes (Star, Cyp11a1, and Hsd3b1/2) primarily involved in mitosteroidogenesis. In parallel, mitochondrial membrane potential (Δψi) and ATP production declined losing their characteristic oscillatory pattern. Also, the main markers of mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Cytc), fusion (Mfn2), and mitophagy (Pink1 and Tfeb) were disturbed. Collectively, CD targets mitochondria in Leydig cells by reducing mitosteroidogenesis, mitoenergetics, and disturbing mitochondrial dynamics. These changes contribute to testosterone decline compromising androgen-dependent functions, including reproduction.