Chronodisruption

People with chronodisruption have increased risk for certain types of cancer. In 2020, the International Agency for Research on Cancer (IARC) found that chronodisruption due to chronic night-shift work is a probable carcinogen (cancer-causing agent) in humans. In humans • Chronodisruption, in the form of shift work, increases the risk of breast cancer in women by about 50%. The risk of developing other forms of cancers, such as prostate cancer in men and colorectal cancer in women, may also increase with chronodisruption; studies in this area have shown modest, but statistically significant, associations. In model organisms • In the studies investigating the relationship between experimental chronic jet lag and tumor progression done by Filipski et al., mice were kept under either 12:12 Light-Dark cycles (LD cycles) or under 12:12 LD cycles that would phase-advance by eight hours every two days. Moreover, clock gene expressions (e.g. mPer2) were suppressed in mice subjected to repeated phase advance, while the daily rhythm in clock gene expression was maintained in mice in a typical 12:12 LD cycle. Although no definite conclusion can be made on the possible effects of melatonin on cancer development in B6D2F1 mice based on the original studies, a general statement can be made: besides the direct effects of internal desynchronization with the external environment, the accelerated rate of cancer cell proliferation may also be a consequence of relative melatonin deficiency caused by chronodisruption. This consequence was not observed in mice experiencing chronic phase delays. This showed that persistent internal desynchronization as a result of repeated phase advances may be associated with reduced longevity. == Chronodisruption and cardiovascular disease ==

Chronodisruption is correlated with an increased risk for cardiovascular disease in humans. Experiments involving light-dark cycle manipulations, internal period mutations, and clock gene disruptions in rodents provide insights into the relationship between chronodisruption and the risk of cardiovascular diseases. In humans • Chronodisruption is associated with a significantly increased risk of cardiovascular disease in humans. Shift work has been implicated as a major risk factor for coronary heart disease, hypertension, ischemic stroke, and sudden cardiac death.) showed that mice misaligned with the external LD cycle had decreased metabolic efficiency and disrupted cardiac function. • Deletion or mutation of core clock genes (e.g. Bmal1, Clock, Npas2) was shown to have an adverse impact on cardiac function, including attenuating glucose utilization, accelerating cardiomyopathy, and reducing longevity. == Chronodisruption and metabolic disorders ==

Food is a strong Zeitgeber for peripheral clocks, and the timing of food intake can disrupt or amplify the coordination between the central pacemaker and peripheral systems. This misalignment can lead to detrimental effects on metabolic health, including symptoms like insulin resistance and increased body mass. • Additionally, shift workers exhibit a higher risk for obesity than day workers, which increases with the number of years exposed and the frequency of shifts. It is hypothesized that circadian regulation of hormonal secretion related to appetite, as well as the presence of circadian clocks in adipose tissue cells, may influence the increased obesity risk related to shift work, although further study will be necessary to confirm this pathway. • Timing of the food intake matching the proper circadian phase is also essential. Cross-sectional studies done by Wang et al. demonstrated that people who consumed ≥ 33% of their daily energy intake in the evening were two-fold more likely to become obese than those who received their energy intake in the morning. Hence, timing of food intake is also correlated with obesity. In model organisms • Swiss Webster mice (an all-purpose mouse strain used as a research model) that have altered timings of food intake due to exposure to artificial light at subjective night gained weight substantially beyond the control mice that were placed under a regular light-dark cycle. • The experimental design that included light exposure at night would have led to a reduction of nighttime melatonin level and disturbed the melatonin rhythm. Melatonin was suggested to have anti-obesity effects due to its ability to stimulate the growth and metabolic activity of Brown Adipose Tissue, inducing weight loss. The relative melatonin deficiency due to light exposure at night may lead to obesity. This observation in mice suggested that the timing of food intake is associated with obesity. ClockΔ19 mice with leptin knockout are significantly more obese than mice with leptin knockout only, implying the significant contribution of chronodisruption to obesity in mice. Similarly, mPer2-knockout mice fed a high-fat diet were significantly more obese than their wild-type counterpart. == Menstrual cycle ==

Chronodisruption, in the form of shift work, 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. The severity of menstrual cycle disruptions appears to correlate positively with the duration of exposure to chronodisruptive conditions, suggesting a cumulative negative impact. 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. 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. 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. 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. ==Maternal chronodisruption==

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). In TTFL, proteins CLOCK and BMAL1 induce the transcription of period genes per1 and per2 and cryptochrome genes cry1 and cry2. Chronodisruption in model organisms has a detrimental effect on the reproduction and development of offspring in rodents. Both clock gene mutations and experiencing phase advances or delays after copulation were observed to interfere with the ability to complete pregnancies. However, these conditions were reversed when the chronodisrupted mother received melatonin in the subjective night, suggesting that maternal plasma melatonin rhythm may drive the fetal rhythm. Similarly, genetic disruption in CLOCK genes in mice impaired the ability to be pregnant and to maintain pregnancy. 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. Maternal exposure to chronic photoperiod shifting was shown to increase pregnancy duration and result in heavier offspring. In humans There's limited study on the rhythmic secretion of melatonin during pregnancy but evidence suggests an increased nighttime melatonin secretion as the pregnancy progresses, that quickly diminishes postpartum, with no significant change in daytime secretion. 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. 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. 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 SCN remained impaired, suggesting permanent damage to the SCN. Melatonin is also shown to support the development of the mammary glands for breastfeeding. Fetal and postnatal development 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. 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. Disruptions also affect adrenal function and fetal gene expression, potentially leading to long-term adverse physiological effects. 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. Maternal circadian preferences were also found to be associated with infants' sleep rhythm in early childhood. 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. 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. == Chronodisruption and neurodegenerative diseases ==

In humans Chronodisruption has also been implicated as a risk factor for neurodegenerative diseases such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) in humans. • Circadian regulation of metabolism and dopamine levels are hypothesized to contribute to the link between chronodisruption and PD. In model organisms • The misalignment between the sleep/wake cycle and feeding rhythms in mice causes circadian desynchrony between the SCN and hippocampus. Mice exposed to "jet lag" experimental conditions experience circadian misalignment, exhibiting an increased amount of inflammatory markers in blood, diminished hippocampus neurogenesis, and impaired learning and memory. • Being exposed to altered LD cycles (e.g. 10:10 LD cycle) also disrupts SCN-mediated rhythms and causes peripheral metabolic alterations in mice, leading to decreased dendritic branching of cortical neurons, decreased cognitive flexibility, and behavioral impairments. == Notable researchers ==

Chronodisruption first became a notable concept in 2003 when three researchers from the University of Cologne in Germany, Thomas C. Erren, Russel J. Reiter, and Claus Piekarski, published the journal, Light, timing of biological rhythms, and chronodisruption in man. At the time, Erren, Reiter, and Piekarski were studying how biological clocks can be used to understand cycles and causes of cancer, suggesting that cancer follows a rhythmic light cycle. These three men are considered to have conceived the term "chronodisruption", making large conceptual strides from "chronodisturbance", and even further, "circadian disruption". Circadian disruption is a brief or long period of interference within a circadian rhythm. Chronodisturbance is the disruption of a circadian rhythm which leads to adaptive changes, leading to a less substantial negative impact in comparison to chronodisruption, which leads to disease. Russel Reiter is employed by UT Health, San Antonio and involved in processes of aging and disease, specifically how oxygen interacts with neurodegenerative diseases. His research group is also studying properties of melatonin, its relations with circadian disruptions, and the resulting physiology. Mary E. Harrington is employed by Smith College, where she is the head of their neuroscience program. Her research is focused on the impact of disruptions to the central and peripheral clocks, as well as the impact of disruptions on Alzheimer's and aging. == References ==