Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

The relationship between circadian rhythmicity and rodent reproductive cyclicity is well established, but the impact of disrupted clock gene function on reproduction has not been investigated. This study evaluated the reproductive performance of melatonin deficient and proficient mice carrying a mutation in the core circadian gene, Clock. In natural matings, melatonin deficient Clock mutant mice took 2 to 3 days longer to mate and to subsequently deliver pups than their control line. The melatonin proficient mutants (Clock-MEL) had a smaller, but still significant delay (P < 0.05). The Clock mutation resulted in smaller median litter sizes compared to the control lines (7 v. 8 pups, P < 0.05) while melatonin proficiency reversed this difference. Survival to weaning was 84% and 80% for the melatonin deficient and proficient Clock mutant lines respectively, compared to 94 to 96% for their control lines. When immature mice were subjected to a standard PMSG/HCG superovulation protocol, Clock-MEL mice had lowered fertility and significantly fewer ovulations than their control line although embryo development appeared to be only slightly affected (Table 1). 19 ± 5 17% 48% 32% 3% When kept in constant darkness, 7 of 15 Clock-MEL mice, became arrhythmic, but still became pregnant. The 7 mice that free ran for at least 14 days in constant darkness with a period of 27.1 h also became pregnant.This study has shown that a mutation in the Clock gene that results in a protein incapable of initiating the transcription of target genes has significant, but subtle effects on reproductive performance. The capacity to produce melatonin or additional genes introduced along with the genes for the melatonin synthesising enzymes reduced the impact of the mutation further. It would appear that redundancy within the circadian timing system allows the reproductive cyclicity to persist in Clock mutant mice, albeit at a suboptimal level.

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There is strong epidemiological evidence indicating that disruption of the endogenous circadian rhythms can cause a range of health problems ranging from metabolic and cardiovascular disorders to reproductive failure. Circadian rhythmicity is generated by a suite of genes called ‘clock genes’ that are cyclically expressed in the brain and peripheral tissues. The CLOCK and BMAL1 transcription factors regulate the expression of many genes involved in cell growth, angiogenesis and development. The Bmal1 knockout mouse provides an interesting model to analyse the impact of arrhythmicity on reproductive physiology. Female Bmal1–/– mice show a delay in the onset of puberty (WT = 32.7 d, KO = 38.6 d, n = 8–16). Female Bmal1–/– mice reproductive tissues are significantly smaller than in WT mice (Ovaries –40%, Oviduct –25%, Uterus –60%, n = 10). Female Bmal1–/– mice have essentially normal estrus cycles (cycle length WT = 4.2 d, KO = 4.8 d, n = 8) and are able to ovulate and mate but are unable to establish viable pregnancies. They are as responsive to a standard superovulation protocol as their wild type littermates (ovulated oocytes WT = 23.8, KO=22.8, n = 7–10), suggesting the ovaries are developmentally competent. These results suggest disruption of circadian rhythmicity in the mouse affects fertility at multiple sites. Further investigation into the importance of rhythmicity, particularly post ovulation and post fertilisation is required.

Circadian rhythms are generated by a suite of genes called clock genes that are expressed in the brain and also in many peripheral tissues. In the peripheral tissues, these genes assist in regulating the expression of many genes involved in cell growth, angiogenesis and development. Bmal1 is a critical gene involved in circadian rhythm generation. Here we report on the fertility and fecundity of Bmal1 knockout mice (Bmal1–/–). Male Bmal1–/– mice have impaired fertility compared to controls [(litters produced/number of animals) wild type (5/5), CBA controls (5/5), Bmal1–/– (1/15)]. Fifty percent of male Bmal1–/– mice had defective caudal sperm, showing sperm that was both non-motile and malformed. Seminal vesicle weight was significantly reduced in the Bmal1–/– mice (50% reduction) in males at both 4 and 5.5 months old. Female Bmal1–/– mice had irregular oestrus cycles and failed to maintain a pregnancy to term following natural mating [(litters produced/number of animals) wild type (5/5) CBA controls (5/5) Bmal1–/– (0/5)]. When embryos were flushed from the uterus 4 days after natural mating, there was a reduced number of released oocytes and a reduced development to blastocysts in the Bmal1–/– female mice. Following a standard PMSG/HCG super ovulation protocol, Bmal1–/– mice showed both a reduction in ovulation rate as well as a slowed progression of embryos to blastocyst stage (Table 1, see PDF file). These results suggest that disruption of a key clock gene has detrimental consequences on fertility in the mouse. Further, this reduction in fertility appears to be acting at multiple levels. Continued investigation into the importance of rhythm genes in reproductive function is required.