User:ClockWatcher2025/Chronodisruption

Chronodisruption and Reproduction

In Menstrual Cycle

The suprachiasmatic nucleus (SCN), a major circadian pacemaker in the brain, is shown to play a central role in female reproduction, particularly ovulation. In rodent studies, it was shown that SCN-derived peptides such as vasoactive intestinal polypeptide (VIP) and vasopressin help coordinate the luteinizing hormone (LH) surge necessary for ovulation and BMAL1 expression.

Researchers also found rhythmicity in circadian gene expression in the ovary important for ovulation timing, steroidogenesis, and follicular maturation. In mice, lack of Bmal1 was shown to result in severe infertility from ovarian luteinization implications. In humans, decreased PER1 and CLOCK expression in older women was considered a partial explanation for decreased fertility and steroidogenesis in aging. Previous experiments also showed that continuous light treatment induces polycystic ovary syndrome (PCOS)-like symptoms in rodents. Silencing of the CLOCK gene with its shRNA in rodents was shown to decrease the number of oocytes and increase cell apoptosis and miscarriage risk. Abnormal LD cycle and mutations in clock genes were shown to cause irregular estrous cycles and impaired ovulation.

Chronodisruption, in the form of shift work and social jet lag, has been associated with disturbances in menstrual period (increased irregularity and length of cycles) and mood. This deterioration of the menstrual cycle has also been shown to increase with increasing duration of chronodisruption. Although some investigators proposed menstrual irregularity as a possible indicator of intolerance to shift work, current evidence does not warrant restricting women from night shift employment.

In Pregnancy

Evidence suggests that the circadian rhythm influences early embryo development, uterine implantation, placentation, and delivery. In mice, exposure to phase shifts following copulation showed a reduced proportion of pregnancies carried to term. Similarly, genetic disruption in clock genes in mice impaired the ability to be pregnant and to maintain pregnancy. Rhythmic expression of PER1 and PER2 in the uterus in both pregnant and non-pregnant mice suggests a regulatory role in reproduction. Mutation in Clock was shown to disrupt the ability to complete pregnancy and the conditional deletion of Bmal1 in mice ovary resulted in failure of implantation.

It was also found that long photoperiodic exposure led to a significantly reduced number of implantation sites in mice. 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. 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. The light's interference to melatonin was also shown to increase longer pregnancies, but also result in heavier babies and abnormal hormone hormone rhythms and inflammation markers in the female offspring, all of which can be largely rescued with maternal melatonin injection. 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.

Shift work during pregnancy was also demonstrated to increase gestation length in twin pregnancies, risk of endometriosis, miscarriage, the incidence of low birth weight, and early, but not late, preterm birth. There’s also evidence of abnormal expression of CLOCK in human fetuses from spontaneous miscarriage and Clock is involved in preeclampsia, hypertension and urine protein levels during pregnancy.

In Lactation

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 suprachiasmatic nucleus(SCN) remained impaired, suggesting permanent damage to the suprachiasmatic nucleus(SCN).

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, indicating that a more stable circadian environment may facilitate the initiation of lactogenesis. melatonin is also shown to support the development of the mammary glands for breastfeeding.

In Fetal and Postnatal Development

Circadian rhythms in humans develop gradually and the fetal clock is primarily regulated by maternal signals (the fetus does not produce its own supply of melatonin).

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. Disruptions also affect adrenal function and fetal gene expression, potentially leading to long-term adverse physiological effects. Maternal circadian preferences were also found to be associated with infants' circadian rhythm development in early childhood.

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.

While a melatonin-producing mutant in mice Clock gene did not show any significant negative alterations on pregnancy or the offspring, the absence of maternal melatonin delayed physical characteristics and neurodevelopmental and cognitive functions in rodent male offspring. Melatonin appears to play a protective role by reducing cell apoptosis and may improve placental perfusion and protect against oxidative stress and hypoxic injury. 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.

Circadian disruption may also influence placental metabolism. Elevated BMAL1 expression in placentas is shown to be associated with increased fat levels.

In rodent models, when mothers experienced chronodisruption and photoperiod reversal during pregnancy it is observed that male offspring experience 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.

In female offspring, maternal chronic photoperiod shifting (also known as CPS, another term for disrupted sleep patterns), 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.

Gestational chronodisruption, or light exposure at night during pregnancy, 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.