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Menegaux, F., Truong, T., Anger, A., Cordina-Duverger, E., Lamkarkach, F., Arveux, P., et al. (2013). Night work and breast cancer: a population-based case-control study in France (the CECILE study). Int J Cancer, 132(4), 924–931.
Abstract: Night work involving disruption of circadian rhythm was suggested as a possible cause of breast cancer. We examined the role of night work in a large population-based case-control study carried out in France between 2005 and 2008. Lifetime occupational history including work schedules of each night work period was elicited in 1,232 cases of breast cancer and 1,317 population controls. Thirteen percent of the cases and 11% of the controls had ever worked on night shifts (OR = 1.27 [95% confidence interval = 0.99-1.64]). Odds ratios were 1.35 [1.01-1.80] in women who worked on overnight shifts, 1.40 [1.01-1.92] in women who had worked at night for 4.5 or more years, and 1.43 [1.01-2.03] in those who worked less than three nights per week on average. The odds ratio was 1.95 [1.13-3.35] in women employed in night work for >4 years before their first full-term pregnancy, a period where mammary gland cells are incompletely differentiated and possibly more susceptible to circadian disruption effects. Our results support the hypothesis that night work plays a role in breast cancer, particularly in women who started working at night before first full-term pregnancy.
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Nehme, P. A., Amaral, F., Lowden, A., Skene, D. J., Cipolla-Neto, J., & Moreno, C. R. C. (2019). Reduced melatonin synthesis in pregnant night workers: metabolic implications for offspring. Medical Hypotheses, 132, 109353.
Abstract: Several novel animal studies have shown that intrauterine metabolic programming can be modified in the event of reduced melatonin synthesis during pregnancy, leading to glucose intolerance and insulin resistance in the offspring. It is therefore postulated that female night workers when pregnant may expose the offspring to unwanted health threats. This may be explained by the fact that melatonin is essential for regulating energy metabolism and can influence reproductive activity. Moreover, the circadian misalignment caused by shift work affects fertility and the fetus, increasing the risk of miscarriage, premature birth and low birth weight, phenomena observed in night workers. Thus, we hypothesize that light-induced melatonin suppression as a result of night work may alter intrauterine metabolic programming in pregnant women, potentially leading to metabolic disorders in their offspring.
Keywords: Human Health; Pregnancy; Melatonin; Melatonin synthesis; Circadian disruption; shift work
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Rahman, S. A., Bibbo, C., Olcese, J., Czeisler, C. A., Robinson, J. N., & Klerman, E. B. (2019). Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy. J Pineal Res, 66(4), e12566.
Abstract: In humans, circulating levels of the hormone melatonin and the initiation of spontaneous labor are both higher at night than during the day. Since activation of uterine melatonin receptors can stimulate human in vitro uterine contractions and these receptors are only expressed on the uterine tissue of women in labor, we hypothesized that circulating melatonin concentrations would affect uterine contractions in vivo. We evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during late third-trimester (~36-39 weeks) of pregnancy in two inpatient protocols. We found a significant (p<0.05) positive linear association between circulating melatonin concentrations and the number of uterine contractions under both protocols. On average, uterine contractions increased between 1.4 to 2.1 contractions per 30 minutes for every 10 pg/ml*h increase in melatonin concentration. These findings have both basic science and clinical implications for pregnant women, since endogenous melatonin levels and melatonin receptor activity can be altered by light and/or pharmaceutical agents.
Keywords: Human Health; Melatonin; Pregnancy
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Reiter, R. J., Tan, D. X., Korkmaz, A., & Rosales-Corral, S. A. (2014). Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Hum Reprod Update, 20(2), 293–307.
Abstract: BACKGROUND: Research within the last decade has shown melatonin to have previously-unsuspected beneficial actions on the peripheral reproductive organs. Likewise, numerous investigations have documented that stable circadian rhythms are also helpful in maintaining reproductive health. The relationship of melatonin and circadian rhythmicity to maternal and fetal health is summarized in this review. METHODS: Databases were searched for the related published English literature up to 15 May 2013. The search terms used in various combinations included melatonin, circadian rhythms, biological clock, suprachiasmatic nucleus, ovary, pregnancy, uterus, placenta, fetus, pre-eclampsia, intrauterine growth restriction, ischemia-reperfusion, chronodisruption, antioxidants, oxidative stress and free radicals. The results of the studies uncovered are summarized herein. RESULTS: Both melatonin and circadian rhythms impact reproduction, especially during pregnancy. Melatonin is a multifaceted molecule with direct free radical scavenging and indirect antioxidant activities. Melatonin is produced in both the ovary and in the placenta where it protects against molecular mutilation and cellular dysfunction arising from oxidative/nitrosative stress. The placenta, in particular, is often a site of excessive free radical generation due to less than optimal adhesion to the uterine wall, which leads to either persistent hypoxia or intermittent hypoxia and reoxygenation, processes that cause massive free radical generation and organ dysfunction. This may contribute to pre-eclampsia and other disorders which often complicate pregnancy. Melatonin has ameliorated free radical damage to the placenta and to the fetus in experiments using non-human mammals. Likewise, the maintenance of a regular maternal light/dark and sleep/wake cycle is important to stabilize circadian rhythms generated by the maternal central circadian pacemaker, the suprachiasmatic nuclei. Optimal circadian rhythmicity in the mother is important since her circadian clock, either directly or indirectly via the melatonin rhythm, programs the developing master oscillator of the fetus. Experimental studies have shown that disturbed maternal circadian rhythms, referred to as chronodisruption, and perturbed melatonin cycles have negative consequences for the maturing fetal oscillators, which may lead to psychological and behavioral problems in the newborn. To optimize regular circadian rhythms and prevent disturbances of the melatonin cycle during pregnancy, shift work and bright light exposure at night should be avoided, especially during the last trimester of pregnancy. Finally, melatonin synergizes with oxytocin to promote delivery of the fetus. Since blood melatonin levels are normally highest during the dark period, the propensity of childbirth to occur at night may relate to the high levels of melatonin at this time which work in concert with oxytocin to enhance the strength of uterine contractions. CONCLUSIONS: A number of conclusions naturally evolve from the data summarized in this review: (i) melatonin, of both pineal and placental origin, has essential functions in fetal maturation and placenta/uterine homeostasis; (ii) circadian clock genes, which are components of all cells including those in the peripheral reproductive organs, have important roles in reproductive and organismal (fetal and maternal) physiology; (iii) due to the potent antioxidant actions of melatonin, coupled with its virtual absence of toxicity, this indoleamine may have utility in the treatment of pre-eclampsia, intrauterine growth restriction, placental and fetal ischemia/reperfusion, etc. (iv) the propensity for parturition to occur at night may relate to the synergism between the nocturnal increase in melatonin and oxytocin.
Keywords: Human Health; Animals; Antioxidants/physiology; Biological Clocks/physiology; Circadian Rhythm/*physiology; Female; Fetus/*physiology; Humans; Mammals; Melatonin/biosynthesis/*physiology; Mice; Oxidative Stress/physiology; Parturition/physiology; Placenta/metabolism/*physiology; Pre-Eclampsia/etiology/metabolism; Pregnancy; Uterus/metabolism; circadian rhythms; fetus; melatonin; placenta; pre-eclampsia
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Summa, K. C., Vitaterna, M. H., & Turek, F. W. (2012). Environmental perturbation of the circadian clock disrupts pregnancy in the mouse. PLoS One, 7(5), e37668.
Abstract: BACKGROUND: The 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 FINDINGS: Young 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/SIGNIFICANCE: Repeated 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.
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