Abstract
BackgroundThe circadian clock has been linked to reproduction at many levels in mammals. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, although whether the cause is circadian disruption or another factor associated with shift work is unknown. Here we test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice.Methodology/Principal FindingsYoung adult female C57BL/6J (B6) mice were paired with B6 males until copulation was verified by visual identification of vaginal plug formation. Females were then randomly assigned to one of three groups: control, phase-delay or phase-advance. Controls remained on a constant 12-hr light:12-hr dark cycle, whereas phase-delayed and phase-advanced mice were subjected to 6-hr delays or advances in the LD cycle every 5–6 days, respectively. The number of copulations resulting in term pregnancies was determined. Control females had a full-term pregnancy success rate of 90% (11/12), which fell to 50% (9/18; p<0.1) in the phase-delay group and 22% (4/18; p<0.01) in the phase-advance group.Conclusions/SignificanceRepeated shifting of the LD cycle, which disrupts endogenous circadian timekeeping, dramatically reduces pregnancy success in mice. Advances of the LD cycle have a greater negative impact on pregnancy outcomes and, in non-pregnant female mice, require longer for circadian re-entrainment, suggesting that the magnitude or duration of circadian misalignment may be related to the severity of the adverse impact on pregnancy. These results explicitly link disruptions of circadian entrainment to adverse pregnancy outcomes in mammals, which may have important implications for the reproductive health of female shift workers, women with circadian rhythm sleep disorders and/or women with disturbed circadian rhythms for other reasons.
Highlights
Diverse and compelling evidence indicates that a profound connection exists between the circadian and reproductive systems at multiple levels of organization and at multiple stages of the reproductive cycle in mammals
A previous study in pregnant rats subjected to 12-hour phase reversals every 3–4 days failed to observe any adverse pregnancy outcomes [21], this may be due to the possibility that such frequent and dramatic changes in the light cycle are beyond the limits of entrainment, causing the circadian clock to run independently of the light cycle, as has been observed in rodents under non-circadian entrainment conditions [22]
Activity records of the mice in the study described here indicate that the 6-hour phase shift protocol does result in repeated attempts at entrainment, indicating that the circadian system is continuously adapting to the changing light cycle (Fig. 2a)
Summary
Diverse and compelling evidence indicates that a profound connection exists between the circadian and reproductive systems at multiple levels of organization and at multiple stages of the reproductive cycle in mammals. Several epidemiological studies have observed associations between shift work or repeated travel across time zones and reduced fertility [4] as well as negative pregnancy outcomes, including increased incidence of low birth weight, preterm birth and miscarriage [5,6,7], whether these adverse outcomes are due to circadian dysregulation or some other lifestyle factor associated with shift work is not known. Epidemiological studies of female shift workers have reported increased rates of reproductive abnormalities and adverse pregnancy outcomes, whether the cause is circadian disruption or another factor associated with shift work is unknown. We test whether environmental disruption of circadian rhythms, using repeated shifts of the light:dark (LD) cycle, adversely affects reproductive success in mice
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