Effects Of Circadian Disruption Research Articles

An Update on the Role of Circadian Rhythms in Sleep Disorders

Background: The comprehension of the molecular, cellular, and biological mechanisms that underlie the management of the sleep-wake cycle, as well as the effects of circadian disruption on health and illness, has made significant strides. Methods: An extensive literature review was done from the standard databases such as Scopus, Elsevier, and PubMed using standard keywords “Circadian rhythm”, and “sleep disorders”. In this section, we examined circadian biology and provided adetailed description of the pathogenesis, clinical characteristics, diagnosis, and management of the most typical Circadian rhythm sleep disorders (CRSDs) seen in clinical practice. Conclusion: It can be concluded that the central circadian rhythm mechanism may be altered, or the intrinsic circadian clock and the environment may not be in sync, to produce circadian rhythm sleep disorders. As a consequence, we must focus on modifying our way of life in a constructive and healthy way. Even while the lifestyle is based on personal preferences and identities, it is important to examine it in isolation from its sociocultural environment.

Circadian Rhythm Disruption Increases Tumor Growth Rate and Accumulation of Myeloid-Derived Suppressor Cells.

Circadian rhythm disruption is implicated in the initiation and progression of many diseases, including cancer. External stimuli, such as sunlight, serve to synchronize physiological processes and cellular functions to a 24-h cycle. The immune system is controlled by circadian rhythms, and perturbation of these rhythms can potentially alter the immune response to infections and tumors. The effect of circadian rhythm disruption on the immune response to tumors remains unclear. Specifically, the effects of circadian disruption (CD) on immunosuppressive cell types within the tumor, such as myeloid-derived suppressor cells (MDSCs), are unknown. In this study, a shifting lighting schedule is used to disrupt the circadian rhythm of mice. After acclimation to lighting schedules, mice are inoculated with 4T1 or B16-F10 tumors. Tumor growth is increased in mice housed under circadian disrupting lighting conditions compared to standard lighting conditions. Analysis of immune populations within the spleen and tumor shows an increased accumulation of MDSCs within these tissues, suggesting that MDSC mediated immunosuppression plays a role in the enhanced tumor growth caused by circadian disruption. This paves the way for future studies of the effects of CD on immunosuppression in cancer.

The Role of Race, Sex, and Age in Circadian Disruption and Metabolic Disorders

The Role of Race, Sex, and Age in Circadian Disruption and Metabolic Disorders

Circadian Rhythm, Energy Metabolism, and the Gut Microbiome: a Review

This review discussed the interrelationship between the circadian rhythm of the host and of the intestinal microbiome and the implications of this new field on energy metabolism, specifically implications relating to obesity. Circadian rhythm, or the 24-hour system that bodies use to expect and to increase receptivity to certain factors in the environment, is present in almost every organ and system. However, the data that this review utilized relates mainly to the intestinal microbiome: a group of bacteria, yeasts, and viruses that inhabit the colon, with this review’s focus placed on bacteria. This interrelationship is mainly discussed through possible effects of circadian disruption and through an analysis of different methods by which the circadian rhythm of the host and the rhythm of the microbiome interact. TRF, or time-restricted feeding, has been identified as one of the potential methods to reduce the negative consequences of circadian dysregulation on metabolic processes, and various related studies were discussed in-depth. Data from four databases were analyzed to produce a variety of both experimental and review papers. All papers that related to the topic under review were thoroughly analyzed and incorporated into the review.

Implications of Lifestyle and Occupational Factors on the Risk of Breast Cancer in Shiftwork Nurses.

Shift work that involves circadian disruption has been highlighted as a likely carcinogenic factor for breast cancer in humans. Also, unhealthy lifestyle habits observed in night work nurses could be causally related to an increase in the incidence of estrogen-positive breast tumours in this population. Assessing baseline risk of breast cancer in nurses is essential. The objective of this study was to analyze the risk of breast cancer that nurses had in relation to their lifestyle and labour factors related to shift work. A cross-sectional descriptive study through a questionnaire about sociodemographic variables, self-perception of health, and working life was designed. The sample consisted of 966 nurses. The relationship between variables was tested. A binary logistic regression and a classification and regression tree were performed. The most significant labour variables in relation to the risk of breast cancer were the number of years worked (more than 16 years; p < 0.01; OR = 8.733, 95% CI = 2.811, 27.134) and the total years performing more than 3 nights per month (10 or more years; p < 0.05; OR = 2.294, 95% CI = 1.008, 5.220). Also, the nights worked throughout life (over 500; OR = 4.190, 95% CI = 2.118, 8.287) were significant in the analysis. Nurses who had or ever had breast cancer valued their self-perceived health more negatively (p < 0.001) and referred a lower quality of sleep (p < 0.001) than the non-cases nurses. The occupational factors derived from night work could have several impacts on nurses’ health and their family-work balance. Promoting healthy lifestyles, informing about shift work risks, and adjusting shift work schedules are critical methods to decrease the possible effects of circadian disruption in nurses.

Disruption of Circadian Clocks Promotes Progression of Alzheimer's Disease in Diabetic Mice.

The circadian clock is an endogenous system designed to anticipate and adapt to daily changes in the environment. Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is more prevalent in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disruption on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (a 6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability, and AD-related pathophysiology. Our results indicated that housing in these conditions led to disrupted diurnal circadian rhythms in the hippocampus of db/db mice and contributed to their weight gain. In the brain, the circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in amyloid protein (Aβ) plaque deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under the 6:18 light/dark cycle. Circadian alterations could promote the development of AD in T2DM.

The effects of ovariectomy on the behavioral and physiological responses to constant light in C57BL6/J Mice

ABSTRACT Circadian disruptions, including exposure to constant light, are known to produce behavioral and physiological issues. However, sex differences exist in how those problems manifest, as males tend to have increased susceptibility to the negative consequences of circadian disruption. As gonadal hormones play a role in circadian timekeeping, we decided to investigate whether ovariectomized C57BL6/J mice would exhibit increased behavioral and physiological sensitivity to constant light compared to female mice with intact estrogen circulation. Mice, half of which underwent an ovariectomy and the other half received sham surgery, were then placed in either constant light or a 12:12 light-dark cycle. After six weeks of photoperiod exposure, we measured their circadian locomotor activity, anxiety-like behaviors and physiological responses. Mice which underwent ovariectomy and placed into constant light experienced altered glucose levels and reduced robustness of the circadian rhythm, with some becoming arrhythmic, compared to sham surgery animals in constant light. Additionally, ovariectomy led to delayed circadian activity onsets and reduced both home-cage and novelty-induced activity. Meanwhile, constant light produced increases to ambulatory activity in the behavioral assays and reduced circadian home-cage activity. These results indicate that removal of the ovaries can mediate the circadian, behavioral, and physiological responses to continuous light.

The Effects of Circadian Rhythm Disruption on Mental Health and Physiological Responses among Shift Workers and General Population.

Background: The effect of circadian disruption on the bio-psychological clock system has been widely studied. However, the mechanism and the association of circadian rhythm disruption with mental health and physiological responses are still unclear. Therefore, this study was conducted to investigate the effects of circadian rhythm disruption on mental health and physiological responses among shift workers and the general population. Methods: A total of 42 subjects participated in this quasi-experimental study. Participants were divided into a group of shift workers (n = 20) and a general population group (n = 22). Polysomnography tests, blood tests (cortisol, triglycerides and glucose), and psychological tests (Abbreviated Profile of Mood States, General Health Questionnaire-28, Working Memory and Processing Speed Indexes of the Wechsler Adult Intelligent Scale (WAIS-IV) were used to examine the effects of circadian rhythm disruption. Results: The results showed a significant relationship between circadian rhythm disruption and mood (r = 0.305, p < 0.05). The findings of this study also indicated that there was a significant effect of circadian rhythm disruption on mood (F(2,40) = 8.89, p < 0.001, η2 =0.182), processing speed (F(2,40) = 9.17, p < 0.001, η2 = 0.186) and working memory (F(2,40) = 4.963, p < 0.01, η2 = 0.11) in shift workers and the general population. Conclusions: Our findings showed that circadian rhythm disruption affects mood and cognitive performance, but it does not significantly affect psychological wellbeing and physiological responses. Future studies are warranted to examine moderator and mediator variables that could influence the circadian rhythm disruption.

Circadian Rhythms and the Gastrointestinal Tract: Relationship to Metabolism and Gut Hormones

Circadian rhythms are 24-hour biological rhythms within organisms that have developed over evolutionary time due to predefined environmental changes, mainly the light-dark cycle. Interestingly, metabolic tissues, which are largely responsible for establishing diurnal metabolic homeostasis, have been found to express cell-autonomous clocks that are entrained by food intake. Disruption of the circadian system, as seen in individuals who conduct shift work, confers significant risk for the development of metabolic diseases such as type 2 diabetes and obesity. The gastrointestinal (GI) tract is the first point of contact for ingested nutrients and is thus an essential organ system for metabolic control. This review will focus on the circadian function of the GI tract with a particular emphasis on its role in metabolism through regulation of gut hormone release. First, the circadian molecular clock as well as the organization of the mammalian circadian system is introduced. Next, a brief overview of the structure of the gut as well as the circadian regulation of key functions important in establishing metabolic homeostasis is discussed. Particularly, the focus of the review is centered around secretion of gut hormones; however, other functions of the gut such as barrier integrity and intestinal immunity, as well as digestion and absorption, all of which have relevance to metabolic control will be considered. Finally, we provide insight into the effects of circadian disruption on GI function and discuss chronotherapeutic intervention strategies for mitigating associated metabolic dysfunction.

Abstract 3811: Circadian disruption enhances development of pancreatic inflammation and pancreatic cancer precursors

Abstract Introduction: Emerging data suggest a role for circadian disruption in tumor formation and progression. Yet little is known regarding the effects of circadian disruption on the oncogenesis of pancreatic ductal adenocarcinoma (PDAC). We sought to determine if circadian disruption enhances PDAC development through a genetically engineered mouse model, and evaluate possible mechanisms with transcriptomic analysis. Methods: KrasG12D/+ mice (K) were crossed with Pdx-1 Cre (C) mice on a C57BL/6 background to generate KC mice. At 4 weeks, mice were subjected to standard lighting conditions (KC normal circadian [KCNC]) or a chronic jet-lag protocol known to induce circadian disruption (KCCD), with light/dark cycles shifted 8 hours every 2-3 days. Mice were sacrificed at 9 months for histologic analysis, examining for PDAC and its precursor lesions (PanINs). Comparisons were made with Fischer's Exact Test. For pancreatic transcriptomic profiling, 144 4-week-old wild-type (WT) C57BL/6 mice underwent disruption (WTCD, n = 72) or standard lighting conditions (WTNC, n = 72) for 4 weeks to identify cycling genes over a 48 hour period. Four weeks was chosen to understand the effects of disruption on gene expression impacting tumor initiation. Standard gene cycling analysis was performed with meta2d utilizing a false discovery rate of q = 0.1, and comparisons were made with the Audic-Claverie Distribution tool. Results: All KC mice (27 KCNC &amp; 7 KCCD) exhibited chronic pancreatitis and PanIN-1 (p = 1). However, KCCD mice developed higher rates of acute pancreatitis (86% vs 4%; p &amp;lt; 0.01) and PanIN-2 (43% vs 7%; p = 0.04) versus KCNC mice. PanIN-3 (14% vs 7% p = 0.48) and PDAC (29% vs 16% p = 0.6) were also increased but did not reach statistical significance. Given this phenotype, we sought a mechanism through transcriptomic analysis. In total, we found 12.8% of the protein-coding pancreatic transcriptome was cycling in either WTNC or WTCD. Pathway enrichment analysis demonstrated genes important for circadian rhythm were cycling in WTNC, while those important for catabolism and protein localization were cycling in WTCD. Only 129 genes, shared between male and female mice, exclusively cycled following circadian disruption. Of those, roughly 15% have been implicated in PDAC development, reported as prognostic biomarkers in PDAC or possibly contribute to chemotherapeutic resistance in PDAC. Conclusion: Little is known about the effects of circadian disruption on PDAC. We have demonstrated histopathologic evidence of an increased incidence of pancreatic inflammation and pathogenic lesions following circadian disruption. Transcriptomic analysis of wild-type pancreas revealed an increased number of cycling genes involved in energy production following disruption. Future work will investigate the candidate genes identified to ascertain how circadian disruption leads to increased development of pancreatic lesions. Citation Format: Patrick Beard Schwartz, Morgan Walcheck, Noah D. Carrillo, Kristina A. Matkowskyj, Christopher A. Bradfield, Sean Ronnekleiv-Kelly. Circadian disruption enhances development of pancreatic inflammation and pancreatic cancer precursors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3811.

Shift work and cancer

Circadian disruption and night-shift work have been associated with a range of acute and chronic health effects including cardiometabolic diseases, obesity, as well as breast and prostate cancer. Circadian disruption may also affect the health of the general population because of widespread mistimed lifestyle practices including mistimed eating and sleep patterns and increasing exposure to light-at-night and particularly blue light spectrum through the use of e-readers, LEDs and smartphones. New epidemiological evidence on the effects of circadian disruption and light-at-night in workers and the general population will be presented, and mechanisms of disease and potential preventive measures discussed.

Consequences of Circadian Disruption in Shift Workers on Chrononutrition and their Psychosocial Well-Being

The workers and employees in various institutions are subjected to different shifts and work schedules. The employees work not only at daytime but also during odd hours at night. The biological clock of an individual is often altered during night shifts. This affects the psychosocial well-being and circadian nutritional intake of the worker. Disturbance in circadian rhythm results in the development of metabolic disorders such as hypertension, dyslipidemia, dysglycemia, and abdominal obesity. In the present review, we discuss the nature of shift work, sleep/wake cycle of an individual, chrononutrition, dietary habits, and meal changes with regard to timing and frequency, related to shift work. We also discuss the relationship between nutritional intake and psychosocial well-being among shift workers. The review may be beneficial for prevention of metabolic disorders and maintaining sound psychological condition in shift workers.

A reductionist, in vitro model of environmental circadian disruption demonstrates SCN-independent and tissue-specific dysregulation of inflammatory responses.

Environmental circadian disruption (ECD), characterized by repeated or long-term disruption in environmental timing cues which require the internal circadian clock to change its phase to resynchronize with the environment, is associated with numerous serious health issues in humans. While animal and isolated cell models exist to study the effects of destabilizing the relationship between the circadian system and the environment, neither approach provides an ideal solution. Here, we developed an in vitro model which incorporates both elements of a reductionist cellular model and disruption of the clock/environment relationship using temperature as an environmental cue, as occurs in vivo. Using this approach, we have demonstrated that some effects of in vivo ECD can be reproduced using only isolated peripheral oscillators. Specifically, we report exaggerated inflammatory responses to endotoxin following repeated environmental circadian disruption in explanted spleens. This effect requires a functional circadian clock but not the master brain clock, the suprachiasmatic nucleus (SCN). Further, we report that this is a result of cumulative, rather than acute, circadian disruption as has been previously observed in vivo. Finally, such effects appear to be tissue specific as it does not occur in lung, which is less sensitive to the temperature cycles employed to induce ECD. Taken together, the present study suggests that this model could be a valuable tool for dissecting the causes and effects of circadian disruption both in isolated components of physiological systems as well as the aggregated interactions of these systems that occur in vivo.

Rhythmic Three-Part Harmony: The Complex Interaction of Maternal, Placental and Fetal Circadian Systems

From the perspective of circadian biology, mammalian pregnancy presents an unusual biological scenario in which an entire circadian system (i.e., that of the fetus) is embodied within another (i.e., that of the mother). Moreover, both systems are likely to be influenced at their interface by a third player, the placenta. Successful pregnancy requires major adaptations in maternal physiology, many of which involve circadian changes that support the high metabolic demands of the growing fetus. A functional role for maternal circadian adaptations is implied by the effects of circadian disruption, which result in pregnancy complications including higher risks for miscarriage, preterm labor, and low birth weight. Various aspects of fetal physiology lead to circadian variation, at least in late gestation, but it remains unclear what drives this rhythmicity. It likely involves contributions from the maternal environment and possibly from the placenta and the developing intrinsic molecular clocks within fetal tissues. The role of the placenta is of particular significance because it serves not only to relay signals about the external environment (via the mother) but may also exhibit its own circadian rhythmicity. This review considers how the fetus may be influenced by dynamic circadian signals from the mother and the placenta during gestation, and how, in the face of these changing influences, a new fetal circadian system emerges. Particular emphasis is placed on the role of endocrine signals, most notably melatonin and glucocorticoids, as mediators of maternal-fetal circadian interactions, and on the expression of the clock gene in the 3 compartments. Further study is required to understand how the mother, placenta, and fetus interact across pregnancy to optimize circadian adaptations that support adequate growth and development of the fetus and its transition to postnatal life in a circadian environment.

Circadian rhythms accelerate wound healing in female Siberian hamsters

Circadian rhythms (CRs) provide temporal regulation and coordination of numerous physiological traits, including immune function. CRs in multiple aspects of immune function are impaired in rodents that have been rendered circadian-arrhythmic through various methods. In Siberian hamsters, circadian arrhythmia can be induced by disruptive light treatments (DPS). Here we examined CRs in wound healing, and the effects of circadian disruption on wound healing in DPS-arrhythmic hamsters. Circadian entrained/rhythmic (RHYTH) and behaviorally-arrhythmic (ARR) female hamsters were administered a cutaneous wound either 3h after light onset (ZT03) or 2h after dark onset (ZT18); wound size was quantified daily using image analyses. Among RHYTH hamsters, ZT03 wounds healed faster than ZT18 wounds, whereas in ARR hamsters, circadian phase did not affect wound healing. In addition, wounds healed slower in ARR hamsters. The results document a clear CR in wound healing, and indicate that the mere presence of organismal circadian organization enhances this aspect of immune function. Faster wound healing in CR-competent hamsters may be mediated by CR-driven coordination of the temporal order of mechanisms (inflammation, leukocyte trafficking, tissue remodeling) underlying cutaneous wound healing.

Consequences of Circadian Disruption on Neurologic Health

Circadian rhythms have a major role in physiology and behavior. Circadian disruption has negative consequences for physiologic homeostasis at molecular, cellular, organ-system, and whole-organism levels. The onset of many cerebrovascular insults shows circadian temporal trends. Impaired sleep-wake cycle, the most robust output rhythms of the circadian system, is significantly affected by neurodegenerative disorders, may precede them by decades, and may also affect their progression. Emerging evidence suggests that circadian disruption may be a risk factor for these neurologic disorders. This article discusses the implications of circadian rhythms in brain disorders, with an emphasis on cerebrovascular and neurodegenerative disorders.

Consequences of Circadian Disruption on Cardiometabolic Health.

Cardiovascular disease, diabetes and obesity are highly prevalent diseases associated with reduced quality of life and life expectancy. We discuss a novel risk factor for these cardiometabolic diseases: circadian disruption. Circadian disruption occurs when the internal circadian (∼24-hour) rhythms are not in synchrony with the environment or each other. This paper reviews (1) cardiometabolic health of shift work, which often leads to circadian disruption, (2) effects of experimentally disrupted circadian rhythms on cardiometabolic function, (3) observational studies of sleep timing and behavioral chronotype, and (4) potential mediators linking chronotype and shift work to circadian disruption and cardiometabolic health.

Effects of circadian disruption on methamphetamine consumption in methamphetamine-exposed rats.

A substantial number of clinical studies indicate associations between sleep abnormalities and drug abuse; however, the role played by the circadian system in the development of addiction is largely unknown. The aim of this study was to examine the effects of experimentally induced chronic jet lag on methamphetamine consumption in a rat model of methamphetamine drinking. Male Sprague-Dawley rats (n = 32) were housed in running wheel cages in a 12:12h light:dark cycle. One group of rats (n = 16) was given 2weeks of forced methamphetamine consumption (0.01% in drinking water; meth pre-exposed) while a second group (n = 16, not pre-exposed) received water only. This was followed by a 2-week abstinence period during which half of the animals from each group were exposed to four consecutive 6-h advancing phase shifts of the light:dark cycle, while the other half remained on the original light:dark cycle. Methamphetamine consumption was assessed in all rats following the deprivation period using a two-bottle choice paradigm. Methamphetamine consumption was initially lower in methamphetamine pre-exposed versus not pre-exposed rats. However, during the second week following abstinence, consumption was significantly higher in phase-shifted rats of the methamphetamine pre-exposed group compared to all other groups. These data reveal an effect of circadian rhythm disturbance on methamphetamine consumption and suggest that dysregulation of the circadian system be considered in the etiology of relapse and addiction.

Effects of Circadian Disruption on Mental and Physical Health

Circadian (daily) rhythms in physiology and behavior are phylogenetically ancient and are present in almost all plants and animals. In mammals, these rhythms are generated by a master circadian clock in the suprachiasmatic nucleus of the hypothalamus, which in turn synchronizes "peripheral oscillators" throughout the brain and body in almost all cell types and organ systems. Although circadian rhythms are phylogenetically ancient, modern industrialized society and the ubiquity of electric lighting has resulted in a fundamental alteration in the relationship between an individual's endogenous circadian rhythmicity and the external environment. The ramifications of this desynchronization for mental and physical health are not fully understood, although numerous lines of evidence are emerging that link defects in circadian timing with negative health outcomes. This article explores the function of the circadian system, the effects of disrupted clocks on the brain and body, and how these effects impact mental and physical health.

Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night

This review article discusses recent work on the melatonin-mediated circadian regulation and integration of molecular, dietary, and metabolic signaling mechanisms involved in human breast cancer growth and the consequences of circadian disruption by exposure to light at night (LAN). The antiproliferative effects of the circadian melatonin signal are mediated through a major mechanism involving the activation of MT(1) melatonin receptors expressed in human breast cancer cell lines and xenografts. In estrogen receptor (ERα+) human breast cancer cells, melatonin suppresses both ERα mRNA expression and estrogen-induced transcriptional activity of the ERα via MT(1) -induced activation of G(αi2) signaling and reduction of 3',5'-cyclic adenosine monophosphate (cAMP) levels. Melatonin also regulates the transactivation of additional members of the steroid hormone/nuclear receptor super-family, enzymes involved in estrogen metabolism, expression/activation of telomerase, and the expression of core clock and clock-related genes. The anti-invasive/anti-metastatic actions of melatonin involve the blockade of p38 phosphorylation and the expression of matrix metalloproteinases. Melatonin also inhibits the growth of human breast cancer xenografts via another critical pathway involving MT(1) -mediated suppression of cAMP leading to blockade of linoleic acid uptake and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Down-regulation of 13-HODE reduces the activation of growth factor pathways supporting cell proliferation and survival. Experimental evidence in rats and humans indicating that LAN-induced circadian disruption of the nocturnal melatonin signal activates human breast cancer growth, metabolism, and signaling provides the strongest mechanistic support, thus far, for population and ecological studies demonstrating elevated breast cancer risk in night shift workers and other individuals increasingly exposed to LAN.