Effect Of Circadian Disruption Research Articles

Effect of circadian disruption on the hypothalamic control of reproduction in female mice

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.

A Computational Analysis in a Cohort of Parkinson's Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes.

Simple SummaryCancer and neurodegenerative diseases are two aging-related pathologies with differential developmental characteristics, but they share altered cellular pathways. Interestingly, dysregulations in the biological clock are reported in both diseases, though the extent and potential consequences of such disruption have not been fully elucidated. In this study, we aimed at characterizing global changes on common cellular pathways associated with Parkinson’s disease (PD) and colorectal cancer (CRC). We used gene expression data retrieved from an idiopathic PD (IPD) patient cohort and from CRC cells with unmodified versus genetically altered clocks. Our results highlight common differentially expressed genes between IPD patients and cells with disrupted clocks, suggesting a role for the circadian clock in the regulation of pathways altered in both pathologies. Interestingly, several of these genes are related to cancer hallmarks and may have an impact on the overall survival of colon cancer patients, as suggested by our analysis.Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

Genipin improves reproductive health problems caused by circadian disruption in male mice

BackgroundCircadian rhythm disruption impacts a wide range of physiological processes, including fertility. However, the effect of circadian disruption on male spermatogenesis and fertility, and treatments for these effects have been largely unexplored at the molecular level.MethodsIn this study, we examined the effects of genipin on improving the reproductive health problems caused by circadian disruption. Three groups of animals were fed under different conditions: control group (normal T cycle with saline), group of shortened T cycles (Light/Dark = 4 hours/4 hours) with saline, and a group of shortened T cycles with genipin by oral gavage. The male fertility was evaluated by fertility study and pups parameters analysis after successful sexual behavior and mating with female mice. We sacrificed the treated animals after 5 or 10 weeks and collected the testis, sperm and serum for histological analysis, sperm motility assay, and serum hormone detection, respectively. Furthermore, the effect of genipin was assessed by detection of progesterone secretion and steroidogenic key proteins expression, including StAR and CYP11A1, in mouse Leydig tumor MLTC-1 cells.ResultsMale mice exposed to shortened light-dark cycles, much shorter than 24 hours, had reduced fertility with decreased sperm concentrations and sperm motility. Male mice under circadian disruption have reduced testis size and abnormal morphology, leading to lower fertility rates, reduced litter size and pup body weight. Treatment with exogenous genipin, a natural plant-derived compound, alleviated circadian disruption-induced damage to fertility and spermatogenesis and normalized testosterone, dihydrotestosterone (DHT), and androstenedione (ASD) levels in the male mice. The levels of key proteins involved in steroidogenesis, StAR and CYP11A1, were reduced in mouse testes after the circadian disruption, but genipin treatment restored the reduction. The mRNA expression of SRD5A1, which encodes an androgen synthesis enzyme, was also upregulated by genipin treatment. Furthermore, genipin treatment showed a positive effect on steroidogenesis in MLTC-1 cells, resulting in an increase in hormone secretion and the upregulation of StAR and CYP11A1.ConclusionsOur results showed an association between circadian disruption and reproductive health problems in male mice and indicated that treatments with genipin have positive effects on the reproductive health of male mice with circadian rhythm disorders.

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.

Sleep quality and insulin resistance in adolescent subjects with different circadian preference: A cross-sectional study.

Background:Studies have shown that alterations in the sleep cycle can predispose to several disorders. Most of the previous studies were done on the adults. Hence, the aim of the study was to see the effect of circadian disruption on the health of adolescent population.Materials and Methods:In this cross-sectional study, 203 subjects were enrolled. Study subjects were divided into three groups: definite evening chronotype, intermediate chronotype, and definite morning chronotype. Sleep quality was measured by Pittsburgh Sleep Quality Index (PSQI). Daytime sleepiness and chronotype were measured by Epworth Sleepiness Score and Morningness-Eveningness Questionnaire Self-Assessment version, respectively. Two hours postprandial glucose was measured after oral glucose tolerance test. Fasting blood glucose and fasting insulin were measured. Homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated. Data were summarized as mean ± standard deviation. Crude odds ratios and Karl Pearson's correlation coefficient of metabolic parameters with poor sleep were calculated.Results:Statistically significant difference was found in the mean value of poor sleep quality, 2 h postprandial blood glucose level, and insulin resistance among subjects of three groups. Subjects of evening chronotype have more significant positive correlation of 2 h postprandial blood glucose level and HOMA-IR value with poor sleep quality when compared with subjects of intermediate and morning chronotypes.Conclusion:Subjects with evening chronotype are more prone for development of metabolic syndrome compared with subjects of intermediate and morning chronotypes if proper health policies are not adopted for adolescents.

Circadian Variation of Melatonin and Steroid Hormones and Metabolites in Male Shift Workers

Background: Night shift work has been associated with increased risk for breast and prostate cancer. The effect of circadian disruption on steroid hormone production and metabolism is a possible un...

Going beyond the limits: effect of clock disruption on human health

Synchronisation of organisms’ physiology and behaviour with the external environment is necessary for survival and reproductive fitness. This is critical for human health also. In the past, humans were exposed to predictable natural day and night cycles that allowed the internal clock to synchronise the daily rhythms in physiology and behaviour with the external environment. However, the industrial revolution has made us a 24*7 society and forced the extension of day into night via adoption of artificial light in our lives. This has altered the perception of day and night and made it difficult for the biological processes to synchronise. Such weak synchronisation can be seen in different physiological and behavioural functions that are under circadian control, such as sleep–wake behaviour, melatonin and cortisol rhythms, core body temperature cycle, etc. This also influences the regulatory mechanism at cell and gene levels. Circadian disruption has resulted in increasing incidences of certain cancers, metabolic dysfunction and mood disorders. Several evidence suggest that exposure to aberrant light alters the brain functions that regulate emotion and mood. The present discussion focuses on understanding the effect of circadian disruption on human health, and its various aspects.

Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota.

Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronic alcohol consumption—a frequent habit of majority of modern societies—increases the risk of CRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse mode of CRC. Here we assess the effect of circadian disruption—another modern life style habit—in promoting alcohol-associated CRC. Method: TS4Cre × adenomatous polyposis coli (APC)lox468 mice underwent (a) an alcohol-containing diet while maintained on a normal 12 h light:12 h dark cycle; or (b) an alcohol-containing diet in conjunction with circadian disruption by once-weekly 12 h phase reversals of the light:dark (LD) cycle. Mice were sacrificed after eight weeks of full alcohol and/or LD shift to collect intestine samples. Tumor number, size, and histologic grades were compared between animal groups. Mast cell protease 2 (MCP2) and 6 (MCP6) histology score were analyzed and compared. Stool collected at baseline and after four weeks of experimental manipulations was used for microbiota analysis. Results: The combination of alcohol and LD shifting accelerated intestinal polyposis, with a significant increase in polyp size, and caused advanced neoplasia. Consistent with a pathogenic role of stromal tryptase-positive mast cells in colon carcinogenesis, the ratio of mMCP6 (stromal)/mMCP2 (intraepithelial) mast cells increased upon LD shifting. Baseline microbiota was similar between groups, and experimental manipulations resulted in a significant difference in the microbiota composition between groups. Conclusions: Circadian disruption by Light:dark shifting exacerbates alcohol-induced polyposis and CRC. Effect of circadian disruption could, at least partly, be mediated by promoting a pro-tumorigenic inflammatory milieu via changes in microbiota.

Increased and mistimed sex hormone production in night shift workers.

Night shift work has been associated with an increased risk for breast and prostate cancer. The effect of circadian disruption on sex steroid production is a possible underlying mechanism, underinvestigated in humans. We have assessed daily rhythms of sex hormones and melatonin in night and day shift workers of both sexes. We recruited 75 night and 42 day workers, ages 22 to 64 years, in different working settings. Participants collected urine samples from all voids over 24 hours on a working day. Urinary concentrations of 16 sex steroid hormones and metabolites (estrogens, progestagens, and androgens) and 6-sulfatoxymelatonin were measured in all samples. Mean levels and peak time of total and individual metabolite production were compared between night and day workers. Night workers had higher levels of total progestagens [geometric mean ratio (GMR) 1.65; 95% confidence intervals (CI), 1.17-2.32] and androgens (GMR: 1.44; 95% CI, 1.03-2.00), compared with day workers, after adjusting for potential confounders. The increased sex hormone levels among night shift workers were not related to the observed suppression of 6-sulfatoxymelatonin. Peak time of androgens was significantly later among night workers, compared with day workers (testosterone: 12:14 hours; 10:06-14:48 vs. 08:35 hours; 06:52-10:46). We found increased levels of progestagens and androgens as well as delayed peak androgen production in night shift workers compared with day workers. The increase and mistiming of sex hormone production may explain part of the increased risk for hormone-related cancers observed in night shift workers.

Diagnostic Reasoning for ST-Segment Elevation Myocardial Infarction (STEMI) Interpretation Is Preserved Despite Fatigue.

Fatigue and sleepiness contribute to medical errors, although the effect of circadian disruption and fatigue on diagnostic reasoning skills is largely unknown. To determine whether circadian disruption and fatigue negatively affect the emergency medicine (EM) resident's ability to make important clinical decisions based on electrocardiogram (ECG) interpretation. Senior EM residents at 2 programs completed a questionnaire consisting of various measures of fatigue followed by an ECG test packet of ST-segment elevation myocardial infarction (STEMI) and STEMI mimics. Participants were asked to examine each ECG and determine whether cardiac catheterization laboratory activation (CLA) was indicated, and to report their confidence in their decision making on an 11-point, numeric rating scale. The primary outcome measured was a pairwise difference in accuracy of CLA between daytime and overnight testing. A total of 23 residents were enrolled in 2011 and 2012. Subjects demonstrated significant differences in multiple measures of sleepiness and fatigue during overnight periods. The median (interquartile range [IQR]) accuracy of CLA was not significantly different between daytime and overnight (70% [IQR, 50-80] versus 70% [IQR, 60-70], P = .82). There were no significant differences in the median number of overcalls (CLA when not a STEMI) and undercalls (no CLA when a STEMI was present; P = .57 and .37, respectively). Diagnostic confidence and confidence in CLA were not statistically different between daytime and overnight. Despite a measurable degree of fatigue, senior EM residents experienced no decrease in their ability to accurately make CLA decisions based on ECG interpretation.

Evidence for Possible Period 2 Gene Mediation of the Effects of Alcohol Exposure During the Postnatal Period on Genes Associated with Maintaining Metabolic Signaling in the Mouse Hypothalamus

Animals exposed to alcohol during the developmental period develop circadian disturbances and metabolic problems that often persist during their adult period. In order to study whether alcohol and the circadian clock interact to alter metabolic signaling in the hypothalamus, we determined whether postnatal alcohol feeding in mice permanently alters metabolic sensing in the hypothalamus. Furthermore, we evaluated whether the effect of circadian disruption via Period 2 (Per2) gene mutation prevents alcohol's effects on metabolic signaling in the hypothalamus. Per2 mutant and wild-type male and female mice of the same genetic background were given a milk formula containing ethanol (EtOH; 11.34% vol/vol) from postnatal day (PD) 2 to 7 and used for gene expression and peptide level determinations in the hypothalamus at PD7 and PD90. We report here that postnatal alcohol feeding reduces the expression of proopiomelanocortin (Pomc) gene and production of β-endorphin and α-melanocyte stimulating hormone (α-MSH) in the hypothalamus that persists into adulthood. In addition, expressions of metabolic sensing genes in the hypothalamus were also reduced as a consequence of postnatal alcohol exposure. These effects were not sex-specific and were observed in both males and females. Mice carrying a mutation of the Per2 gene did not show any reductions in hypothalamic levels of Pomc and metabolic genes and β-endorphin and α-MSH peptides following alcohol exposure. These data suggest that early-life exposure to alcohol alters metabolic sensing to the hypothalamus possibly via regulating Per2 gene and/or the cellular circadian clock mechanism.