Simulated Night Shift Research Articles

Night shift schedule alters endogenous regulation of circulating cytokines

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true endogenous pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t13 = -6.03, p < 0.001), without any significant differences in IL-1β, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t13 = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).

Effects of sleepiness on clinical decision making among paramedic students: a simulated night shift study

ObjectiveParamedics are at the forefront of emergency healthcare. Quick and careful decision making is required to effectively care for their patients; however, excessive sleepiness has the potential to impact on...

Alerting and Circadian Effects of Short-Wavelength vs. Long-Wavelength Narrow-Bandwidth Light during a Simulated Night Shift.

Light can be used to facilitate alertness, task performance and circadian adaptation during night work. Novel strategies for illumination of workplaces, using ceiling mounted LED-luminaires, allow the use of a range of different light conditions, altering intensity and spectral composition. This study (ClinicalTrials.gov Identifier NCT03203538) investigated the effects of short-wavelength narrow-bandwidth light (λmax = 455 nm) compared to long-wavelength narrow-bandwidth light (λmax = 625 nm), with similar photon density (~2.8 × 1014 photons/cm2/s) across light conditions, during a simulated night shift (23:00–06:45 h) when conducting cognitive performance tasks. Light conditions were administered by ceiling mounted LED-luminaires. Using a within-subjects repeated measurements study design, a total of 34 healthy young adults (27 females and 7 males; mean age = 21.6 years, SD = 2.0 years) participated. The results revealed significantly reduced sleepiness and improved task performance during the night shift with short-wavelength light compared to long-wavelength light. There was also a larger shift of the melatonin rhythm (phase delay) after working a night shift in short-wavelength light compared to long-wavelength light. Participants’ visual comfort was rated as better in the short-wavelength light than the long-wavelength light. Ceiling mounted LED-luminaires may be feasible to use in real workplaces, as these have the potential to provide light conditions that are favorable for alertness and performance among night workers.

The impact of a meal, snack, or not eating during the night shift on simulated driving performance post-shift.

Objective:The commute home following a night shift is associated with an increased risk for accidents. This study investigated the relationship between food intake during the night shift and simulated driving performance post-shift.Methods:Healthy non-shift working males (N=23) and females (N=16), aged 18–39 years (mean 24.5, standard deviation 5.0, years) participated in a seven-day laboratory study and underwent four simulated night shifts Participants were randomly allocated to one of three conditions: meal at night (N=12; 7 males), snack at night (N=13; 7 males) or no eating at night (N=14; 9 males). During the night shift at 00:30 hours, participants either ate a large meal (meal at night condition), a snack (snack at night condition), or did not eat during the night shift (no eating at night condition). During the second simulated night shift, participants performed a 40-minute York driving simulation at 20:00, 22:30, 01:30, 04:00, and 07:30 hours (similar time to a commute from work).Results:The effects of eating condition, drive time, and time-on-task, on driving performance were examined using mixed model analyses. Significant condition×time interactions were found, where at 07:30 hours, those in the meal at night condition displayed significant increases in time spent outside of the safe zone (percentage of time spent outside 10 km/hour of the speed limit and 0.8 meters of the lane center; P<0.05), and greater lane and speed variability (both P<0.01) compared to the snack and no eating conditions. There were no differences between the snack and no eating conditions.Conclusion:Driver safety during the simulated commute home is greater following the night shift if a snack, rather than a meal, is consumed during the shift.

Circadian misalignment increases mood vulnerability in simulated shift work

Night shift work can associate with an increased risk for depression. As night workers experience a ‘misalignment’ between their circadian system and daily sleep–wake behaviors, with negative health consequences, we investigated whether exposure to circadian misalignment underpins mood vulnerability in simulated shift work. We performed randomized within-subject crossover laboratory studies in non-shift workers and shift workers. Simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and sleep/wake cycles (circadian misalignment), while environmental conditions and food intake were controlled. Circadian misalignment adversely impacted emotional state, such that mood and well-being levels were significantly decreased throughout 4 days of continuous exposure to circadian misalignment in non-shift workers, as compared to when they were under circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p < 0.001; well-being: p < 0.001; adjusted p-values). Similarly, in shift workers, mood and well-being levels were significantly reduced throughout days of misalignment, as compared to circadian alignment (interaction of “circadian alignment condition” vs. “day”, mood: p = 0.002; well-being: p = 0.002; adjusted p-values). Our findings indicate that circadian misalignment is an important biological component for mood vulnerability, and that individuals who engage in shift work are susceptible to its deleterious mood effects.

Circulating Exosomal miRNAs Signal Circadian Misalignment to Peripheral Metabolic Tissues

Night shift work increases risk of metabolic disorders, particularly obesity and insulin resistance. While the underlying mechanisms are unknown, evidence points to misalignment of peripheral oscillators causing metabolic disturbances. A pathway conveying such misalignment may involve exosome-based intercellular communication. Fourteen volunteers were assigned to a simulated day shift (DS) or night shift (NS) condition. After 3 days on the simulated shift schedule, blood samples were collected during a 24-h constant routine protocol. Exosomes were isolated from the plasma samples from each of the blood draws. Exosomes were added to naïve differentiated adipocytes, and insulin-induced pAkt/Akt expression changes were assessed. ChIP-Seq analyses for BMAL1 protein, mRNA microarrays and exosomal miRNA arrays combined with bioinformatics and functional effects of agomirs and antagomirs targeting miRNAs in NS and DS exosomal cargo were examined. Human adipocytes treated with exosomes from the NS condition showed altered Akt phosphorylation responses to insulin in comparison to those treated with exosomes from the DS condition. BMAL1 ChIP-Seq of exosome-treated adipocytes showed 42,037 binding sites in the DS condition and 5538 sites in the NS condition, with a large proportion of BMAL1 targets including genes encoding for metabolic regulators. A significant and restricted miRNA exosomal signature emerged after exposure to the NS condition. Among the exosomal miRNAs regulated differentially after 3 days of simulated NS versus DS, proof-of-concept validation of circadian misalignment signaling was demonstrated with hsa-mir-3614-5p. Exosomes from the NS condition markedly altered expression of key genes related to circadian rhythm in several cultured cell types, including adipocytes, myocytes, and hepatocytes, along with significant changes in 29 genes and downstream gene network interactions. Our results indicate that a simulated NS schedule leads to changes in exosomal cargo in the circulation. These changes promote reduction of insulin sensitivity of adipocytes in vitro and alter the expression of core clock genes in peripheral tissues. Circulating exosomal miRNAs may play an important role in metabolic dysfunction in NS workers by serving as messengers of circadian misalignment to peripheral tissues.

Blue-Enriched White Light Improves Performance but Not Subjective Alertness and Circadian Adaptation During Three Consecutive Simulated Night Shifts.

Use of blue-enriched light has received increasing interest regarding its activating and performance sustaining effects. However, studies assessing effects of such light during night work are few, and novel strategies for lighting using light emitting diode (LED) technology need to be researched. In a counterbalanced crossover design, we investigated the effects of a standard polychromatic blue-enriched white light (7000 K; ∼200 lx) compared to a warm white light (2500 K), of similar photon density (∼1.6 × 1014 photons/cm2/s), during three consecutive simulated night shifts. A total of 30 healthy participants [10 males, mean age 23.3 (SD = 2.9) years] were included in the study. Dependent variables comprised subjective alertness using the Karolinska Sleepiness Scale, a psychomotor vigilance task (PVT) and a digit symbol substitution test (DSST), all administered at five time points throughout each night shift. We also assessed dim-light melatonin onset (DLMO) before and after the night shifts, as well as participants’ opinion of the light conditions. Subjective alertness and performance on the PVT and DSST deteriorated during the night shifts, but 7000 K light was more beneficial for performance, mainly in terms of fewer errors on the PVT, at the end of the first- and second- night shift, compared to 2500 K light. Blue-enriched light only had a minor impact on PVT response times (RTs), as only the fastest 10% of the RTs were significantly improved in 7000 K compared to 2500 K light. In both 7000 and 2500 K light, the DLMO was delayed in those participants with valid assessment of this parameter [n = 20 (69.0%) in 7000 K light, n = 22 (78.6%) in 2500 K light], with a mean of 2:34 (SE = 0:14) and 2:12 (SE = 0:14) hours, respectively, which was not significantly different between the light conditions. Both light conditions were positively rated, although participants found 7000 K to be more suitable for work yet evaluated 2500 K light as more pleasant. The data indicate minor, but beneficial, effects of 7000 K light compared to 2500 K light on performance during night work. Circadian adaptation did not differ significantly between light conditions, though caution should be taken when interpreting these findings due to missing data. Field studies are needed to investigate similar light interventions in real-life settings, to develop recommendations regarding illumination for night workers.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03203538.

0025 Circadian Dysregulation of DNA Repair and Increased Endogenous and Exogenous Sensitivity to DNA Damage Precipitate Elevated Cancer Risk Associated with Night Shift Work

Abstract Introduction The elevated cancer risk associated with night shift work is poorly understood. To investigate whether circadian disruption may play a role, we assessed the circadian transcriptome and its association with hallmark cancer pathways, as well as sensitivity to endogenous and exogenous sources of DNA damage, after in-laboratory simulated shift work. Methods N=14 healthy humans (aged 22-34y; 10m, 4f) were exposed to a simulated night shift schedule (daytime sleep: 10:00-18:00) or a simulated day shift schedule (nighttime sleep: 22:00-06:00) for 3 days (n=7 in each condition). After the simulated shift schedule, subjects underwent a 24h constant routine protocol, during which blood was collected every 3h. Lymphocytes were extracted from the blood samples and subjected to transcriptome analysis using a NanoString multiplex assay. We evaluated 726 mRNA cancer hallmark targets (NanoString PanCancer Pathway Panel) and 17 circadian clock genes, with 18 arrhythmic internal controls. Gene expression was analyzed for circadian rhythmicity using mixed-effects cosinor analysis. Further, lymphocytes were investigated for DNA damage using an alkaline comet assay and immunofluorescence assessment of DNA damage response biomarkers BRCA1 and γH2AX. Lymphocytes collected at 07:30 and 19:30 were also exposed to ionizing radiation (2.5Gy) and DNA damage response assessments were repeated. Results Simulated night shift caused widespread disruption of circadian rhythmicity, as measured under constant routine, for core clock genes and the transcriptome of cancer hallmark pathways. The DNA repair pathway showed significant enrichment of rhythmic genes (p&amp;lt;0.05) after the simulated day shift schedule only. Following simulated night shift, lymphocytes showed induction of endogenous DNA damage, with extended tail in the comet assay (p&amp;lt;0.001), and higher percentage of lymphocytes with BRCA1 and γH2AX foci (p&amp;lt;0.01). Lymphocytes collected at 19:30 showed enhanced impact of ionizing radiation as indicated by increased prevalence of cells with BRCA1 and γH2AX foci (p&amp;lt;0.05). Conclusion Circadian dysregulation of DNA repair mechanisms and increased sensitivity to DNA damage following night shift work may increase genomic instability and precipitate elevated cancer risk in night shift workers. Support NIH grants ES022640 and CA227381, CDMRP award W81XWH-18-1-0100, and Pacific Northwest National Laboratory BRAVE investment under DOE contract DE-AC05-76RL01830.

Role of nocturnal light intensity on adaptation to three consecutive night shifts: a counterbalanced crossover study

ObjectivesTo investigate how a standard ceiling mounted light-emitting diode (LED)-based bright light intervention affected alertness and neurobehavioural performance during three consecutive simulated night shifts, and timing of circadian rhythm after...

A Simulated Night Shift for Undergraduate Paramedicine Students: Lessons Learnt and the Perceived Value towards Learning

Background Ensuring undergraduate healthcare students are work ready graduates who possess real-world experiences and realistic expectations of their professional environment is essential for Australian universities. This is becoming increasingly more difficult to accomplish with ongoing difficulties on sourcing appropriate clinical placement learning opportunities. We developed and piloted a simulated paramedic night shift investigating if undergraduate paramedic students perceived the experience to be realistic and to what extent they felt it contributed toward their learning. Methods A total of 24 undergraduate paramedic students were recruited to participate in a simulated 13-hour paramedic night shift held on university campus. Student satisfaction and perceived value towards learning was measured using an online survey the day after the simulation. Results 23 of 24 participants completed the online survey. Survey data suggested 22 participants felt the simulated night shift to be realistic of real-life paramedic practice, provided a valuable learning experience and should be made a mandatory component of undergraduate paramedicine curricula. Conclusion Given the difficulties associated with providing clinical placement opportunities for students and the perception among health professionals that on entering the workforce many graduates often lack the adaptability required to undertake shift-work and the professional role of a paramedic, educators should consider the merits of providing overnight simulated experiences to undergraduate students to better prepare and acclimatise students to overnight shift work.

Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans.

Misalignment of the daily sleep-wake and fasting-feeding cycles with the endogenous circadian timing system is an inevitable consequence of night shift work and is associated with adverse metabolic health effects. However, a detailed characterisation of the effects of night shifts on 24-h rhythms in the metabolome is missing. We performed targeted metabolomic profiling on plasma samples collected every 2 h from healthy human subjects during two 24-h measurement periods at baseline and on the fourth day of a simulated night shift protocol, in which the habitual sleep-wake cycle was delayed by 10 h. Thirty-two out of the 130 detected metabolites showed a 24-h rhythm both at baseline and during the night shift condition. Among these, 75% were driven by sleep-wake and fasting-feeding cycles rather than by the endogenous circadian clock, showing an average phase delay of 8.8 h during the night shift condition. Hence, the majority of rhythmic metabolites were misaligned relative to the endogenous circadian system during the night shift condition. This could be a key mechanism involved in the increased prevalence of adverse metabolic health effects observed in shift workers. On the individual level, the response to the night shift protocol was highly diverse, with phase shifts of rhythmic metabolite profiles ranging from a 0.2-h advance in one subject to a 12-h delay in another subject, revealing an individual metabolomic signature of circadian misalignment. Our findings provide insight into the overall and individual responses of the metabolome to circadian misalignment associated with night schedules and may thereby contribute to the development of individually tailored strategies to minimise the metabolic impacts of shift work.

0191 Combining Caffeine and a Nap to Improve Alertness During a Simulated Nightshift

0191 Combining Caffeine and a Nap to Improve Alertness During a Simulated Nightshift

Effects of circadian misalignment on cognition in chronic shift workers

Shift work is associated with increased human operational errors, presumably due to the circadian timing system that inhibits optimal cognitive function during the night. Circadian misalignment, which is the misalignment between the circadian pacemaker and behavioral/environmental cycles, impairs cognitive performance in non-shift workers. However, it remains uncertain whether the adverse cognitive consequences of circadian misalignment are also observed in chronic shift workers. Thus, we investigated the effects of circadian misalignment on cognitive performance in chronic shift workers. Using a randomized, cross-over design that simulated day shift work (circadian alignment) and night shift work (circadian misalignment), we show that circadian misalignment increases cognitive vulnerability on sustained attention, information processing and visual-motor performance, particularly after more than 10 hours of scheduled wakefulness. Furthermore, their increased levels of subjective sleepiness and their decreased sleep efficiency were significantly associated with impaired sustained attention and visual-motor performance. Our data suggest that circadian misalignment dramatically deteriorates cognitive performance in chronic shift workers under circadian misalignment. This increased cognitive vulnerability may have important safety consequences, given the increasing number of nighttime jobs that crucially rely on the availability of cognitive resources.

The Phase-Shifting Effect of Bright Light Exposure on Circadian Rhythmicity in the Human Transcriptome.

Light is a potent synchronizer of the central circadian clock; however, the effect of light exposure on peripheral gene expression is largely unknown. The objective of this study was to explore the effect of bright light exposure on genome-wide peripheral gene expression levels during a 4-day simulated night shift protocol in which the habitual sleep period is delayed by 10 h. Eleven healthy participants (mean age, 24 years; range, 18-30; 10 men/1 woman) were studied under controlled laboratory conditions. Three participants were exposed to bright light (~6,500 lux) for 8 h during the nightly waking period, while the other 8 were maintained in dim-light conditions (~10 lux). At baseline and on the fourth day after the shift in the sleep period, blood samples were collected during two 24-h measurement periods. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and used to obtain transcriptomic data. Using 2 independent approaches to determine phase shifts among rhythmically expressed genes after the shifted sleep schedule compared with baseline, we found that the average phase delay in the bright light group was approximately 8 to 9 h, whereas the average phase delay in the control group was approximately 1 to 2 h, both at the group level and at the individual level. In line with these findings, further analysis using partial least squares regression indicated that the peripheral circadian transcriptome of PBMCs was predictive of the phase of the central circadian pacemaker after only 3 days of bright light exposure. These results indicate that bright light exposure exerts a phase-shifting effect on the circadian transcriptome in PBMCs with a magnitude similar to its effect on the central circadian clock.

Glucose metabolism is impacted by timing of food intake during simulated night shift

Glucose metabolism is impacted by timing of food intake during simulated night shift

The effect of multi-frequency whole-body vibration on night-shifted mouse model

The circadian rhythm controls several biological activities; therefore, a disorganized circadian rhythm may cause fatal health problems. The aim of this study was to assess the effects of circadian rhythm disturbances induced by simulated night shift activities on the abdominal adipose tissue, bone microstructures and muscle volume in the tibiae of mice. Moreover, we evaluated the effects of multi-frequency whole-body vibration as a countermeasure against the consequences of circadian rhythm disturbances. Twenty-four 5-week-old C57BL/6J male mice were equally assigned to three groups: the normal group (Nor), night shift group (NS), and night shift with multi-frequency whole-body vibration group (NS + V). The NS and NS + V groups were exposed to circadian rhythm disturbances for 4 weeks with 3-day intervals by changing the day and night cycle based on 7 o’clock. After 4 weeks, morphological changes in the adipose tissue, bone microstructures and muscle volume in the tibiae were evaluated from three-dimensional images using in vivo micro-computed tomography. As a result, the volume of the abdominal adipose tissue was significantly higher in the NS than in the Nor and NS + V groups. Also, the microstructures of the tibia were more enhanced in the NS + V than the NS group. The volume of tibial muscle was increased in all groups, while there were no significant changes in muscle volume. From these results, we can conclude that circadian rhythm disturbances induced by night shift activities may reduce bone condition and increase the accumulation of abdominal adipose tissue and these negative effects may be prevented or improved through applying multi-frequency whole-body vibration.

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome

Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

Simulated night shift work induces circadian misalignment of the human peripheral blood mononuclear cell transcriptome

Misalignment of the endogenous circadian timing system leads to disruption of physiological rhythms and may contribute to the development of the deleterious health effects associated with night shift work. However, the molecular underpinnings remain to be elucidated. Here, we investigated the effect of a 4-day simulated night shift work protocol on the circadian regulation of the human transcriptome. Repeated blood samples were collected over two 24-hour measurement periods from eight healthy subjects under highly controlled laboratory conditions before and 4 days after a 10-hour delay of their habitual sleep period. RNA was extracted from peripheral blood mononuclear cells to obtain transcriptomic data. Cosinor analysis revealed a marked reduction of significantly rhythmic transcripts in the night shift condition compared with baseline at group and individual levels. Subsequent analysis using a mixed-effects model selection approach indicated that this decrease is mainly due to dampened rhythms rather than to a complete loss of rhythmicity: 73% of transcripts rhythmically expressed at baseline remained rhythmic during the night shift condition with a similar phase relative to habitual bedtimes, but with lower amplitudes. Functional analysis revealed that key biological processes are affected by the night shift protocol, most notably the natural killer cell-mediated immune response and Jun/AP1 and STAT pathways. These results show that 4 days of simulated night shifts leads to a loss in temporal coordination between the human circadian transcriptome and the external environment and impacts biological processes related to the adverse health effects associated to night shift work.

How much is left in your “sleep tank”? Proof of concept for a simple model for sleep history feedback

Technology-supported methods for sleep recording are becoming increasingly affordable. Sleep history feedback may help with fatigue-related decision making – Should I drive? Am I fit for work? This study examines a “sleep tank” model (SleepTank™), which is analogous to the fuel tank in a car, refilled by sleep, and depleted during wake. Required inputs are sleep period time and sleep efficiency (provided by many consumer-grade actigraphs). Outputs include suggested hours remaining to “get sleep” and percentage remaining in tank (Tank%). Initial proof of concept analyses were conducted using data from a laboratory-based simulated nightshift study. Ten, healthy males (18–35y) undertook an 8h baseline sleep opportunity and daytime performance testing (BL), followed by four simulated nightshifts (2000 h–0600 h), with daytime sleep opportunities (1000 h–1600 h), then an 8 h night-time sleep opportunity to return to daytime schedule (RTDS), followed by daytime performance testing. Psychomotor Vigilance Task (PVT) and Karolinska Sleepiness Scale were performed at 1200 h on BL and RTDS, and at 1830 h, 2130 h 0000 h and 0400 h each nightshift. A 40-minute York Driving Simulation was performed at 1730 h, 2030 h and 0300 h on each nightshift. Model outputs were calculated using sleep period timing and sleep efficiency (from polysomnography) for each participant. Tank% was a significant predictor of PVT lapses (p < 0.001), and KSS (p < 0.001), such that every 5% reduction resulted in an increase of two lapses, or one point on the KSS. Tank% was also a significant predictor of %time in the Safe Zone from the driving simulator (p = 0.001), such that every 1% increase in the tank resulted in a 0.75% increase in time spent in the Safe Zone. Initial examination of the correspondence between model predictions and performance and sleepiness measures indicated relatively good predictive value. Results provide tentative evidence that this “sleep tank” model may be an informative tool to aid in individual decision-making based on sleep history.

The circadian clock regulates cisplatin-induced toxicity and tumor regression in melanoma mouse and human models.

Cisplatin is one of the most commonly used chemotherapeutic drugs; however, toxicity and tumor resistance limit its use. Studies using murine models and human subjects have shown that the time of day of cisplatin treatment influences renal and blood toxicities. We hypothesized that the mechanisms responsible for these outcomes are driven by the circadian clock. We conducted experiments using wild-type and circadian disrupted Per1/2−/− mice treated with cisplatin at selected morning (AM) and evening (PM) times. Wild-type mice treated in the evening showed an enhanced rate of removal of cisplatin-DNA adducts and less toxicity than the morning-treated mice. This temporal variation in toxicity was lost in the Per1/2−/− clock-disrupted mice, suggesting that the time-of-day effect is linked to the circadian clock. Observations in blood cells from humans subjected to simulated day and night shift schedules corroborated this view. Per1/2−/− mice also exhibited a more robust immune response and slower tumor growth rate, indicating that the circadian clock also influences the immune response to melanoma tumors. Our findings indicate that cisplatin chronopharmacology involves the circadian clock control of DNA repair as well as immune responses, and thus affects both cisplatin toxicity and tumor growth. This has important implications for chronochemotherapy in cancer patients, and also suggests that influencing the circadian clock (e.g., through bright light treatment) may be explored as a tool to improve patient outcomes.