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Maternal chronodisruption

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Maternal chronodisruption refers to the misalignment of a mother’s circadian rhythms during pregnancy due to external or internal factors, such as shift work, irregular sleep patterns, exposure to artificial light at night, or metabolic disturbances. Circadian rhythms are ~24 hour oscillating endogenous cycles generated through the transcription translation feedback loop (TTFL).[1] In TTFL, proteins CLOCK and BMAL1 induce the transcription of period genes per1 and per2 and cryptochrome genes cry1 and cry2.[1] These genes are translated into proteins, which then dimerize and re-enter the nucleus to inhibit CLOCK and BMAL1, thereby suppressing their own transcription.[1] This feedback loop continually cycles as inhibitory proteins degrade and become transcribed again, maintaining a consistent period of ~24 hours.[1] Proper functioning of these circadian rhythms is critical for human physiological homeostasis. Disruption or alteration of these rhythms, termed chronodisruption, has numerous negative physiological consequences, including impaired reproductive health and fertility in both males and females, weakened immune responses, and metabolic dysregulation. Maternal chronodisruption, specifically, poses additional risks due to its impact on fetal development; it has been linked to adverse pregnancy outcomes, such as pre-eclampsia and preterm birth, as well as long-term consequences including increased risk for metabolic disorders and neurodevelopmental impairments in offspring.[1]

Menstrual cycle

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Chronodisruption, including shift work and social jet lag, has been linked to significant disturbances in menstrual regularity, manifesting as increased cycle irregularity and extended cycle lengths, as well as mood disruptions.[2][3] The severity of menstrual cycle disruptions appears to correlate positively with the duration of exposure to chronodisruptive conditions, suggesting a cumulative negative impact.[2][3] While some researchers have proposed that menstrual irregularities might serve as indicators of intolerance or vulnerability to shift work, current evidence is insufficient to justify restricting women from night-shift employment solely on these grounds.[2]

Female reproduction is regulated by the suprachiasmatic nucleus (SCN), the master circadian pacemaker in the brain. In particularly, SCN-derived nueropeptides like vasoactive intestinal polypeptide (VIP) and vasopressin (AVP) are critical for stimulating the secretion of gonadotropin-releasing hormone (GnRH). GnRH subsequently triggers the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), hormones essential for ovulation and follicular recruitment.[2][4][5] Studies in mice have demonstrated that abnormal or disrupted light-dark (LD) cycles and generic altercations to circadian clock components, including CLOCK, cry1, and AVP, significantly reduce the amplitude of GnRH and LH surges. Such disruptions impair ovulation and disturb the regularity of estrous cycles.[2][4][5] Furthermore, research has indicated that the administration of AVP specifically during the afternoon can induce LH release in mice during the proestrus stage, the critical period preceding ovulation, highlighting the circadian-dependent nature of reproductive hormone regulation.[5]

Researchers also found rhythmic expression patterns of circadian genes within the ovary, which play crucial roles in steroidogenesis, and follicular maturation.[2] Experimental evidence from mice with global deletion of Bmal1 revealed premature aging phenotypes characterized by ovarian shrinkage, weight loss, delayed onset of puberty, and decreased rates of ovulation, highlighting the essential function of circadian genes in reproductive health and timing.[6] In humans, studies have observed that decreased expression of circadian genes such as per1 and CLOCK in older women partially explains the age-related decline in fertility and reduced steroidogenesis.[2][7] Additionally, previous animal experiments demonstrated that continuous exposure to light induces symptoms resembling polycystic ovary syndrome (PCOS), including hormonal imbalance and metabolic disruptions, further underscoring the sensitivity of reproductive physiology to circadian disruption.[8] Moreover, targeted silencing of the CLOCK gene using short hairpin RNA (shRNA) in rodent models resulted in significantly decreased oocyte counts, elevated rates of cellular apoptosis, and increased risk of miscarriage, illustrating the direct impact of clock genes on ovarian viability and fertility outcomes.[9]

Pregnancy

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Evidence suggests that the circadian rhythm influences early embryo development, uterine implantation, placentation, and delivery. Studies in mice and humans display the different types of chronodisruption that can affect those various aspects of pregnancy and gestation.

In Mice

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Phase shift, or alterations to the circadian rhythm, induced by adjusting the LD cycle in mice's environment after mice copulation was shown to reduce proportion of pregnancies carried to term.[10] Similarly, genetic disruption in CLOCK genes in mice impaired the ability to be pregnant and to maintain pregnancy.[6][11][12] An experiment in mice showed that deletion of Bmal1 resulted in early pregnancy loss and reentry into estrus while 95% of the control mice were able to give birth to pups. Bmal1-deleted mice has either completely missing or underdeveloped implantation sites from down-regulation of Star gene product, which is essential for steroidogenesis, suggesting infertility from implantation failure.[6] Transplant of WT ovary in Bmal1-deleted mice rescued implantation and live birth, while that of Bmal1-deleted mice into WT mice led to decreases live birth.[6]

It was also found that long photoperiodic exposure, 18 hours of light instead of 12 hours per 24-hour cycle, led to a significantly reduced number of implantation sites in mice.[13] However, repetitive phase advances created no difference in pup and placental weights or uterine receptivity and maintenance of early gestation, suggesting that the detrimental effects of chronodisruption act upstream of implantation, possibly by influencing embryo quality or early developmental processes.[12] Yet, it is reported that chronic phase shift throughout gestation in mice alters rhythms of multiple hormones, timing in food intake, the circadian clock of the liver, and metabolic gene expression.[14] Maternal exposure to chronic photoperiod shifting was shown to increase pregnancy duration and result in heavier offspring.[13] It also led to abnormal hormone rhythms and increased inflammation markers in female offspring.[13] These effects were shown to be rescued by maternal supplementation of melatonin, the key hormone in regulating sleep-wake cycle and circadian rhythms.[2][13]

In Humans

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There's limited study on the rhythmic secretion of melatonin during pregnancy but evidence suggests a increased nighttime melatonin secretion as the pregnancy progresses, that quickly diminishes postpartum, with no significant change in daytime secretion.[15]

Though evidence is lacking regarding the role of insemination timing on embryo viability, it is hypothesized that inappropriate uterine CLOCK gene expression could contribute to the relatively low fertility rates observed in humans.[2]

Shift work during pregnancy has been associated with several adverse reproductive outcomes, including increased gestation length in twin pregnancies, higher risk of endometriosis, elevated miscarriage rates, greater incidence of low birth weight, and a heightened likelihood of early—but not late—preterm births.[2][16] Additionally, abnormal expression of the CLOCK gene has been observed in human fetal tissues obtained from spontaneous miscarriages, suggesting a potential mechanistic link between circadian disruption and pregnancy loss.[2][17] The CLOCK gene is also implicated in pregnancy-related complications such as preeclampsia, pregnancy induced hypertension, and elevated urine protein levels, further underscoring the importance of maintaining circadian integrity during pregnancy for maternal-fetal health outcomes.[2][18][17]

Lactation

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In a rodent model, exposure to constant light during lactation was found to increase weight gain in offspring and disrupt daily rhythms of glucose and fat levels. Notably, even when these offspring were later exposed to a standard light-dark cycle, their metabolic rhythms and the expression of circadian markers in the SCN remained impaired, suggesting permanent damage to the SCN.[2]

In cows, exposure to chronic phase shifts during the prepartum period was associated with increased milk fat and milk yield postpartum and decreased blood glucose pre- and postpartum, suggesting that a more stable circadian environment facilitates the initiation of lactogenesis.[2][19] Melatonin is also shown to support the development of the mammary glands for breastfeeding.[20]

Fetal and postnatal development

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Studies in several species reported the necessity of a functional molecular circadian clock for developmental processes and the release of reproductive hormones into the fetal bloodstream, whose disruptions could influence fetal organ development in utero and long-term health.[2]

Fetal Development

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The fetal pineal gland does not secrete melatonin in human, sheep, or rats, and the fetus circadian rhythm is primarily controlled by the maternal melatonin that pass freely through the placenta and provides light-to-dark information to the fetus. The exact transformation mechanism is still being investigated.[2][20]

Mice deficient in melatonin had negative alterations on pregnancy, including fetal organ development, neurodevelopmental, and cognitive functions in their offspring.[21] However, mice with mutations in CLOCK that still produced melatonin had normal pregnancy outcomes.[22] Melatonin appears to play a protective role by reducing cell apoptosis and may improve placental perfusion and protect against oxidative stress and hypoxic injury.[23] In animal models, maternal melatonin pretreatment reduced placental inflammation following bacterial exposure, though more robust, dose-dependent studies are needed. Additional findings suggest melatonin improves placental perfusion and protects against oxidative stress and hypoxic injury.[2] Circadian disruption may also influence placental metabolism. Elevated BMAL1 expression in placentas is shown to be associated with increased fat levels.[2]

Postnatal Development into Adulthood

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Animal studies suggest that maternal chronodisruption during pregnancy can impair fetal and postnatal metabolic and circadian regulation. In rats, chronic phase shifts throughout gestation led to adult offspring with insulin resistance, obesity, and metabolic syndrome.[24] Disruptions also affect adrenal function and fetal gene expression, potentially leading to long-term adverse physiological effects.[25] Offspring of mothers exposed to chronic phase shift (CPS), or prolonged interruption to the circadian rhythm, had constant low level of melatonin, reversed corticosterone rhythms, and disrupted rhythm in heart rate and adrenal stress hormone corticosterone important for adaptation.[21] Maternal circadian preferences were also found to be associated with infants' sleep rhythm in early childhood.[2][26] Increased maternal eveningness, or having a later chronotype, was associated with slower circadian rhythm development in infants at 3, 8, 18 and 24 months. It created different effects at different ages of the infant: it was associated with shorter sleep duration during daytime at 8 months and during nighttime at 3 and 8 months, to long sleep-onset latency at 3,18 and 24 months, to late bedtime at 3, 8 and 18 months, and to the prevalence of parent-reported sleep difficulties at 8 and 24 months.[26]

In rodent models, when mothers experienced chronodisruption and photoperiod reversal during pregnancy, it was observed that male offspring experienced body weight gain, glucose homeostasis, adipose tissue content, adipose tissue response to norepinephrine, and adipose tissue proteomic in the basal condition in both standard diet and high fat diet lifestyles.[27]

In female offspring, maternal CPS resulted in disrupted hormone rhythms, higher levels of inflammatory markers, Interleukin 1-alpha(IL-1a) and Interleukin 6 (IL-6), as well as lower levels of anti-inflammatory Interleukin 10 (IL-10) markers, and altered gene activity in vital organs such as the heart, kidney, and adrenal gland.[13]

Chronodisruption during gestation affects adult offspring negatively. Research has found that gestational chronodisruption can lead to abnormal stress behavior, disrupted daily hormone patterns, poor response to stress hormones, lower global DNA methylation, and steroid hormone CLOCK related genes becoming out of sync in adult offspring.[28]

References

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