Chronodisruption

• Chronodisruption, in the form of shift work, increases the risk of breast cancer in women by about 50%.[9] 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.[10] Chronodisruption is associated with impeded homeostasis of the cell cycle; this is correlated with malignant growth acceleration and cancer, potentially due to obstruction of normal DNA damage repair.[11]

• 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.[8] Upon injection with Glasgow osteosarcoma cells, a rapid acceleration in cancer cell proliferation rate was observed in the mice experiencing an 8-hour phase advance every two days compared to the mice not experiencing phase advance.[12] 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.[8] The down-regulation of the p53 gene and over-expression of the c-Myc gene associated with the clock disturbance may also have contributed to tumor progression.[8]
  • Melatonin is known to be an endogenously produced oncostatic agent that inhibits tumor cell growth via various potential mechanisms.[8] Studies showed that perfusing the human breast cancer xenografts growing in animals in melatonin-rich blood collected from premenopausal women significantly inhibited all signs of rapid cancer cell proliferation. On the other hand, melatonin-deficient blood collected from the same set of women failed to restrict tumor growth. [8] In the originals studies done by Filipski et al., a mouse strain named B6D2F₁, which had a low level of circulating melatonin, was used.[13] The studies did not examine the melatonin rhythms of the mice, however, the design of the experiments surely would disturb the melatonin rhythms of the mice. 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.[8]
• Extreme cases of chronic jet lag (6-hour advance every 7 days) were observed to cause premature death in aged male mice compared to their counterparts kept in stable external LD cycles. 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.[8] The findings may have great implications for shift workers and people that frequently experience transmeridian travels that advance their internal clock.[8]

• Chronodisruption is associated with a significantly increased risk of cardiovascular disease in humans.[16] Shift work has been implicated as a major risk factor for coronary heart disease, hypertension, ischemic stroke, and sudden cardiac death.[15] Social jet lag may also be associated with increases in cardiovascular disease risk, as evidenced by increased triglyceride levels, decreased high-density lipoprotein-cholesterol levels, and decreased insulin sensitivity.[15]

• Mice exposed to a shortened 10:10 LD cycle (20-hour cycle) were observed to exhibit symptoms of abnormal cardiac pathophysiology, including decreased levels of cardiomyocytes and vascular smooth muscle cell hypertrophy, compared to mice in a typical 12:12 LD cycle (24-hour). [15]These symptoms were rescued when the mice were subsequently exposed to the typical 24-hour LD cycle.[15] Mutant mice with a 22-hour intrinsic period were affected with symptoms of cardiomyopathy and early death as a result when put under a 24-hour LD cycle; however, their cardiac functions were normalized under a shortened LD cycle (22-hour cycle) that matched their intrinsic period.[15]
• Experiment simulating “shift-work” in mice showed that mice misaligned with the external LD cycle had decreased metabolic efficiency and disrupted cardiac function.[15]
• 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.[15]

• There is an increased risk of Type 2 Diabetes associated with shift work, with even higher risks among rotating shift or night shift workers and health care workers.[4] Chronodisruption has been shown to disturb the regulation of glucose and insulin in the body, providing a potential pathway for this increased risk.[18]
• 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.[19] 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.[20]

• 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.[21]
  • 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.[21] However, melatonin level was not measured in the original experiments.[21] More recent articles also suggested that the majority of laboratory mouse strains, including the Swiss Webster mice, do not produce melatonin on their own.[22] [5] Thus, the role of melatonin in the metabolic consequences of circadian misalignment caused by altered timings of food intake remains unclear.
• Mice fed with a high-fat, obesogenic diet showed dampened rhythms in feeding and dampened hepatic circadian rhythms, promoting hyperphagia and obesity. [14][17] Studies investigating the effect of isocaloric time-restricted feeding (TRF) discovered that mice fed with a high-fat diet (HFD) in an 8-to-12-hour window during the normal feeding time (subjective night) had significantly less weight gain than the mice fed with HFD during the time when feeding is normally reduced (subjective day).[14][23] This observation in mice suggested that the timing of food intake is associated with obesity.[23]
  • Further human studies showed similar results. For example, 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.[23][24] Hence, timing of food intake is also correlated with obesity in human.
• Chronodisruption is often associated with shortened sleep. Studies using rodents demonstrate that sleep deprivation, which leads to a reduced leptin level (the “satiety hormone") and an increased ghrelin level (the “hunger hormone"), encourages increased food intake.[21]
• Experiments investigating clock gene mutants and knockouts show the strong linkage between obesity, metabolic disorders, and the circadian clock. ClockΔ19 mice with disrupted circadian rhythm (Clock gene mutant mice) have dampened diurnal feeding rhythm and are obese.[25] 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.[25] Similarly, mPer2-knockout mice fed a high-fat diet were significantly more obese than their wild-type counterpart.[25]

• Chronodisruption, in the form of shift work, has been associated with disturbances in menstrual period (increased irregularity and length of cycles) and mood.[26] This deterioration of the menstrual cycle has also been shown to increase with increasing duration of chronodisruption.[26]
• Chronodisruption during pregnancy is also associated with various negative outcomes, including low relative birth weight, preterm birth, and miscarriage.[27]

• Chronodisruption 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.[2] Deletion of the key clock gene, Bmal1, in mouse ovaries significantly reduces oocyte fertilization, early embryo development, and implantation.[2]
• Gestational chronodisruption (clock misalignment during pregnancy) induced by chronic phase shift is linked with detrimental effects on the health of mouse progeny, including persistent metabolic, cardiovascular, and cognitive dysfunctions.[28] 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.[28]

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.[29]

• Circadian regulation of metabolism and dopamine levels are hypothesized to contribute to the link between chronodisruption and PD.[30]
• Increased risk for AD may be influenced by increased levels of t-tau protein in the blood due to sleep loss, as well as certain AD-risk genes which are suggested to be controlled by the circadian clock, though these factors are still under investigation.[29]

• 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 increased amount of inflammatory markers in blood, diminished hippocampus neurogenesis, and impaired learning and memory.[31]
• 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.[31][32]