Influence of CYP3A polymorphisms on tacrolimus pharmacokinetics in kidney transplant recipients.

Tacrolimus is characterized by a highly variable pharmacokinetics (PK) and a small therapeutic window. It is metabolized specifically by the CYP3A isoenzymes. This study aimed to determine, in kidney transplant patients, the influence of different genotypic clusters involving these SNPs CYP3A4*1B, CYP3A4*22, and CYP3A5*3 on Tacrolimus bioavailability during the first (PTP1) and the second (PTP2) posttransplant phase (PT). We included kidney transplant patients who received Tacrolimus and underwent drug monitoring by C0 monitoring. CYP3A4 and CYP3A5 genotyping were performed using PCR-RFLP. We classified the patients into four groups: Slow, Intermediate, rapid, and ultra-rapid metabolizers. We included 80 patients. The Tacrolimus dose-normalized C0 (C0/D ratio) was significantly decreased in intermediate, rapid, and ultra-rapid comparing with slow metabolisers. During PTP1 only CYP3A5*3 and CYP3A4*22 polymorphisms correlate significantly with C0/D ratio. Regardless of the PT phase and during the late one, only the CYP3A4 polymorphisms correlate significantly with the C0/D ratio. We identified that these SNPs are all associated independently with Tacrolimus exposure in different PT phases. Moreover, we are the first to define a genotypic cluster including the three CYP3A SNPs.

Association Between Mobile Phone Radiation Exposure and the Secretion of Melatonin and Cortisol, Two Markers of the Circadian System: A Review.

The extremely important use of mobile phones in the world, at all ages of life, including children and adolescents, leads to significant exposure of these populations to electromagnetic waves of radiofrequency. The question, therefore, arises as to whether exposure to these radiofrequencies (RFs) could lead to deleterious effects on the body's biological systems and health. In the current article, we review the effects, in laboratory animals and humans, of exposure to RF on two hormones considered as endocrine markers: melatonin, a neurohormone produced by the pineal gland and cortisol, a glucocorticosteroid synthesized by the adrenal glands. These two hormones are also considered as markers of the circadian system. The literature search was performed using PubMed, Medline, Web of Sciences (ISI Web of Knowledge), Google Scholar, and EMF Portal. From this review on RF effects on cortisol and melatonin, it appears that scientific papers in the literature are conflicting, showing effects, no effects, or inconclusive data. This implies the need for additional research on higher numbers of subjects and with protocols perfectly controlled with follow-up studies to better determine whether the chronic effect of RF on the biological functioning and health of users exists (or not). Bioelectromagnetics. 2021;42:5-17. © 2020 Bioelectromagnetics Society.

Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant.

The pharmacokinetics of Tacrolimus is characterized by a high interindividual variability that is mainly explained by pharmacogenetics biomarkers. The aims were to develop a population pharmacokinetic model (Pk pop) taking into account post-transplant phases (PTP), CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms on Tac pharmacokinetics in adult kidney transplant patients. The Pk pop study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (age, weight, sex, hematocrit and CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset. A one-compartment model (Vd: volume of distribution, CL: Tac Clearance) was found to correctly describe the evolution of the C0/D regardless of the PTP. The influence of the covariates has shown that only the CYP3A4*1B and CYP3A4*22 polymorphisms were significantly associated only with CL, regardless of PTP (p = .04 and 0.02, respectively). Only the CYP3A4*22 polymorphism influenced CL during early PTP (P1: the first three months, p = .02). During the late PTP (P2: >3 months), only CYP3A4 polymorphisms were found to affect CL (p = .03 for both). The external validation of the final model, including both CYP3A4 polymorphisms, showed an acceptable predictive performance during P1 and P2. We developed and validated a tac Pk pop model including both CYP3A4*22 and CYP3A4*1B polymorphisms, taking into account PTP. This model was very useful in the Tac dose proposal in this population on any PT day but could not be used in other organ transplants due to pharmacokinetic differences.

Effects and mechanisms of action of light-emitting diodes on the human retina and internal clock.

White light-emitting diodes (LEDs) will likely become the most used lighting devices worldwide in the future because of their very low prices over the course of their long lifespans which can be up to several tens of thousands of hours. The expansion of LED use in both urban and domestic lighting has prompted questions regarding their possible health effects, because the light that they provide is potentially high in the harmful blue band (400-500 nm) of the visible light spectrum. Research on the potential effects of LEDs and their blue band on human health has followed three main directions: 1) examining their retinal phototoxicity; 2) examining disruption of the internal clock, i.e., an out-of-sync clock, in shift workers and night workers, including the accompanying health issues, most concerningly an increased relative risk of cancer; and 3) examining risky, inappropriate late-night use of smartphones and consoles among children and adolescents. Here, we document the recognized or potential health issues associated with LED lighting together with their underlying mechanisms of action. There is so far no evidence that LED lighting is deleterious to human retina under normal use. However, exposure to artificial light at night is a new source of pollution because it affects the circadian clock. Blue-rich light, including cold white LEDs, should be considered a new endocrine disruptor, because it affects estrogen secretion and has unhealthful consequences in women, as demonstrated to occur via a complex mechanism.

Light at night pollution of the internal clock, a public health issue.

Light is the major synchronizer of the internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus. Retinal ganglion cells contain melanopsin, a photoreceptor with a peak sensitivity to blue wavelength (460-480 nm). Light signal is transmitted from the eye to the clock, then to the pineal gland which produces melatonin, considered as the hand of the clock. Even a weak intensity of light (LEDs, tablets, mobile phones, computers...) is able to block the secretion of melatonin, the hormone of darkness. Light is also able to phase advance or phase delay the circadian system according to the timing of exposure. This Phase Response Curve (PRC) is used to resynchronize the clock in various situations of circadian desynchronization. Exposure to Light at Night (LAN) results in a disruption of the circadian system which is deleterious to health. In industrialized countries, including France, 75 % of the total workforce is estimated to be involved in atypical hours, far from the classical diurnal hours of work. Of interest, shift work and night work involve 15.4 % of the French workforce. A number of epidemiologic studies, peiformed mainly on nurses, showed an association between sustained night work (3 to 20 years) and an increased risk of breast cancer Health problems faced by flight attendants have also been reported, though other causes like exposure to radiations cannot be ruled out. Other deleterious effects are reported in this paper. The potential mechanisms of the deleterious effects of LAN on health are suppression of melatonin andsleep deprivation. The International Agencyfor Cancer Research (IARC) classified shift work that involves circadian disruption as ( probably carcinogenic to humans". Countermeasures (e.g melatonin, bright light, use of psychotropic drugs) have been proposed as a means to improve adaptation to shift work and night work and to fight " clock pollution " and circadian desynchronization by LAN.

Twenty-four-hour pattern in French firemen of lag time response to out-of-hospital cardiac arrest and work-related injury.

Circadian cognitive and physical rhythms plus 24 h patterns of accidents and work-related injuries (WRI) have been verified in numerous studies. However, rarely, if ever, have 24 h temporal differences in both work performance and risk of WRI been assessed in the same group of workers. We explored in a homogenous group of French firemen (FM) 24 h patterns of both lag time (LT) response duration to emergency calls for medical help (ECFM) for life-threatening out-of-hospital cardiac arrests (OHCA), used as a non-specific index of work performance, and WRI. Our studies demonstrate rather high amplitude statistically significant 24 h patterns of the two variables. The LT response duration was twice as long -0500 h (slowest response) than -1600 h (fastest response). In the same group of FM, the actual number WRI/h was greatest -1600 h and lowest in the early morning hours. However, the 24 h pattern of the relative risk (RR) of WRIs, i.e., per clock hour number of WRI/(total number of responses to emergency calls x number of FM at risk per response), was very different, the RR being greatest -0200 h and lowest in the afternoon. The 24 h pattern in LT response duration to ECMH for OHCA and RR of WRI was strongly correlated (r = +0.85, P < 0.01), with the nocturnal trough (slowest response) in LT response duration coinciding with the nocturnal peak RR of WRI. These findings indicate the requirement for circadian rhythm-based interventions to improve the nocturnal compromised work performance and elevated risk of WRI of shift-working FM.

The environment and the internal clocks: The study of their relationships from prehistoric to modern times.

The origin of biological rhythms goes back to the very beginning of life. They are observed in the animal and plant world at all levels of organization, from cells to ecosystems. As early as the 18th century, plant scientists were the first to explain the relationship between flowering cycles and environmental cycles, emphasizing the importance of daily light-dark cycles and the seasons. Our temporal structure is controlled by external and internal rhythmic signals. Light is the main synchronizer of the circadian system, as daily exposure to light entrains our clock over 24 hours, the endogenous period of the circadian system being close to, but not exactly, 24 hours. In 1960, a seminal scientific meeting, the Cold Spring Harbor Symposium on Biological Rhythms, brought together all the biological rhythms scientists of the time, a number of whom are considered the founders of modern chronobiology. All aspects of biological rhythms were addressed, from the properties of circadian rhythms to their practical and ecological aspects. Birth of chronobiology dates from this period, with the definition of its vocabulary and specificities in metabolism, photoperiodism, animal physiology, etc. At around the same time, and right up to the present day, research has focused on melatonin, the circadian neurohormone of the pineal gland, with data on its pattern, metabolism, control by light and clinical applications. However, light has a double face, as it has positive effects as a circadian clock entraining agent, but also deleterious effects, as it can lead to chronodisruption when exposed chronically at night, which can increase the risk of cancer and other diseases. Finally, research over the past few decades has unraveled the anatomical location of circadian clocks and their cellular and molecular mechanisms. This recent research has in turn allowed us to explain how circadian rhythms control physiology and health.

Day and night effects on the animal and plant kingdoms: The eve of chronobiology.

For a long time, cyclical changes in the body were assumed to be caused by the cyclicity of the environment (day-night, seasons). The concept of daily and seasonal changes was first documented in the 18th century by astronomer D'Ortous de Mairan, who demonstrated that plant leaf motions varied depending on the time of day, and by Linné's description of his floral clock in 1751. In 1832, De Candolle was the first to experimentally establish the endogeneity of rhythms in plants, underlining the notion of what we now term free-running rhythms. Julien-Joseph Virey made his own contribution in his thesis, published in 1814, against this backdrop, in which he examined the knowledge of his day on the daily and seasonal biological fluctuations of living matters. He emphasized the relevance of the environment's day-night cycle on plant life and created a list of plants based on their diurnality or nocturnality. He expanded on the issue of rhythmic changes in human health and sickness and provided his own data on the daily fluctuations in patient mortality he discovered at the Val-de-Grâce military hospital where he was chief pharmacist. What is crucial is his use of terms such as "living clock," "entrainment," and "innate rhythm" and the applicability of the advanced concepts Because Virey introduced the notion of temporal variations and the impact of the alternation of day and night on these variations, this thesis is a historic testimonial to understanding of biological rhythms in the first half of the 19th century. We may assume from his writings on rhythmic fluctuations that he offered the theory, followed by an experiment, however primitive, from which he drew conclusions and postulated a mechanism (the living clock) that would later prove accurate. All of these aspects indicate that this study represents an early exploration of the notion of temporal variations in humans.

[Light pollution]. / Pollution lumineuse.

LIGHT POLLUTION Artificial light can be a polluting agent deleterious for the retina, in relation to the toxicity of the blue band (380-500 nm) of the visible spectrum (380-700nm) specifically used in light-emitting diodes (LEDs). Photo-toxicity results from photochemical damage to the pigmented epithelium and retinal photoreceptors responsible for the visual function of the retina. Their photosensitive pigments, opsins for the cones and rhodopsin for the sticks, are consumed during the day and regenerated at night. Exposure to light at night seriously disrupts their metabolism. Photo-toxicity, along with heredity, is a major factor in degenerative diseases of the retina with, in addition to, the impact of age and tobacco for the most common of them, age-related macular degeneration: ARMD.Exposure to artificial light at night (LAN) has a deleterious effect on the internal clock. Intrinsically photosensitive ganglion cells (ipRGSs) are responsible for the non-visual functions of the retina, and perceive the light signal that is transmitted to the internal clock to reach the pineal gland. Light inhibits the secretion of melatonin and is able to advance or delay the clock depending on the time of exposure, causing desynchronization. Shift and night workers, like teenagers, are exposed to LAN. The incidence of breast cancer, higher in nurses exposed to LAN, is related to melatonin inhibition, sleep deprivation and desynchronization. The exposure of adolescents to screens is also questionable because the LEDs of the devices emit a blue light, the impact of which on the clock is considerable. The chronic desynchronizations of both shiftworkers and adolescents should be considered a major public health concern.

POLLUTION LUMINEUSE La lumière artificielle peut être un agent polluant délétère pour la rétine, en rapport avec la toxicité de la bande bleue (380-500 nm) du spectre visible (380-700 nm), notamment utilisée dans les diodes électroluminescentes (LED). La phototoxicité résulte de lésions photochimiques au niveau de l'épithélium pigmenté et des photorécepteurs rétiniens responsables de la fonction visuelle de la rétine. Leurs pigments photosensibles, opsines pour les cônes et rhodopsines pour les bâtonnets, sont consommés le jour et régénérés la nuit. L'exposition à la lumière la nuit perturbe gravement leur métabolisme. La phototoxicité constitue, avec l'hérédité, un facteur majeur pour les maladies dégénératives de la rétine avec, en plus, l'impact de l'âge et du tabac pour la plus fréquente d'entre elles, la dégénérescence maculaire liée à l'âge (DMLA). L'exposition à la lumière artificielle la nuit (LAN) dérègle l'horloge interne. Les cellules ganglionnaires intrinsèquement photosensibles (ipRPC), responsables des fonctions non visuelles de la rétine, perçoivent le signal lumineux qui est transmis à cette l'horloge interne pour aboutir à la glande pinéale. La lumière inhibe la sécrétion de mélatonine et est capable d'avancer ou de retarder l'horloge selon l'heure d'exposition, dans le cadre d'une désynchronisation. Les travailleurs postés et de nuit, comme les adolescents, sont exposés à la LAN. L'incidence de cancer du sein, plus élevée chez les infirmières exposées à la LAN, est attribuée à l'inhibition de la mélatonine, la privation de sommeil et la désynchronisation. L'exposition des adolescents aux écrans pose aussi question, car les diodes électroluminescentes (LED) des appareils émettent une lumière bleue dont l'impact sur l'horloge interne est considérable. Les désynchronisations chroniques des travailleurs postés, comme celles des adolescents, doivent être considérées comme des préoccupations importantes de santé publique.

Assessment of cortisol secretory pattern in workers chronically exposed to ELF-EMF generated by high voltage transmission lines and substations.

We investigated the effects of extremely-low frequency electromagnetic fields (ELF-EMFs; 50 Hz) on the secretion of cortisol in 14 men (mean age = 38.0 ± 0.9 years) working in extra-high voltage (EHV) substations. The workers dwelt in houses that were close to substations and high-voltage lines. Thus, they had long histories (1-20 years) of long-yerm exposure to ELF-EMFs. Magnetic field strength was recorded using Emdex dosimeters worn by the volunteers day and night for seven days; the one-week geometric mean ranged from 0.1 to 2.6 µT. Blood samples were taken hourly from 20:00 to 08:00 the next morning. Cortisol concentrations and patterns were compared to age-matched, unexposed control subjects whose exposure level was ten times lower. The comparison of the control group (n = 15) and the groups exposed to fields of 0.1-0.3 µT (n = 5) and > 0.3 µT (n = 9), respectively, revealed a significant effect of field intensity on the cortisol secretory pattern. This study strongly suggests that chronic exposure to ELF-EMFs alters the peak-time serum cortisol levels. Studies are required on the effect of this disruption in high-risk populations such as children, elderly people, and patients with cancer.

Acute exposure to 50-Hz magnetic fields increases interleukin-6 in young healthy men.

Some epidemiologic studies have suggested that extremely low frequency magnetic fields might affect human health and, in particular, that the incidence of certain types of cancer might increase among individuals living or working in environments exposed to such fields. This study is part of a broad study we conducted in humans. The study presented here was designed to look for possible effects of acute exposure to 50-Hz magnetic fields (10 µT) on the interleukin 1 beta (IL-1ß), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA), and the interleukin-2 receptor (IL-2R) production. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed or control group and exposed group) of 16 subjects each. All subjects participated in two 24-h experiments to evaluate the effects of both continuous and intermittent (1 h "off" and 1 h "on" with the field switched "on" and "off" every 15 s) exposure to linearly polarized magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800 while recumbent. Blood samples were collected during each session at 11:00, 17:00, 22:00, 01:00, 04:00, 06:00, and 08:00. Results showed that exposure to 50-Hz magnetic fields (10 µT) significantly increases IL-6 when subjects were exposed to an intermittent magnetic field. However, no effect has been observed on interleukin IL-1ß, IL-2, IL-1RA, and IL-2R.

[Internal clock desynchronization, light and melatonin]. / Désynchronisation de l'horloge interne, lumière et mélatonine.

The internal clock is synchronized by environmental factors. In humans the main factors are the light-dark alternation, the sleep-wake cycle, and social life. Rhythm desynchronization occurs when the clock is no longer in phase (harmony) with the environment, resulting in a phase shift (phase advance or phase delay) which can produce fatigue, sleep disorders and mood disorders. Clock desynchronization is related to a a loss of adaptation between the clock and synchronizers, to an inability of the clock to be entrained, or to a dysfunction of the clock itself Shiftwork and nightwork, transmeridian flights, depressive states and other psychiatric disorders, as well as blindness, aging and intake in some medications and psychoactive agents like alcohol are among the numerous causes of rhythm desynchronization. Melatonin and light exposure are able to control and resynchronize the clock. The phase response curve (PRC) clearly demonstrates that light exposure and/or melatonin administration are able to shift (advance or delay, depending on their timing) and thereby reset the clock.

Sleep and rhythm consequences of a genetically induced loss of serotonin.

BACKGROUND: A genetic deficiency in sepiapterin reductase leads to a combined deficit of serotonin and dopamine. The motor phenotype is characterized by a dopa-responsive fluctuating generalized dystonia-parkinsonism. The non-motor symptoms are poorly recognized. In particular, the effects of brain serotonin deficiency on sleep have not been thoroughly studied. OBJECTIVE: We examine the sleep, sleep-wake rhythms, CSF neurotransmitters, and melatonin profile in a patient with sepiapterin reductase deficiency. PATIENT: The patient was a 28-year-old man with fluctuating generalized dystonia-parkinsonism caused by sepiapterin reductase deficiency. METHODS: A sleep interview, wrist actigraphy, sleep log over 14 days, 48-h continuous sleep and core temperature monitoring, and measurement of CSF neurotransmitters and circadian serum melatonin and cortisol levels before and after treatment with 5-hydroxytryptophan (the precursor of serotonin) and levodopa were performed. RESULTS: Before treatment, the patient had mild hypersomnia with long sleep time (704 min), ultradian sleep-wake rhythm (sleep occurred every 11.8 +/- 5.3 h), organic hyperphagia, attentionlexecutive dysfunction, and no depression. The serotonin metabolism in the CSF was reduced, and the serum melatonin profile was flat, while cortisol and core temperature profiles were normal. Supplementation with 5-hydroxytryptophan, but not with levodopa, normalized serotonin metabolism in the CSF, reduced sleep time to 540 min, normalized the eating disorder and the melatonin profile, restored a circadian sleep-wake rhythm (sleep occurred every 24 +/- 1.7 h, P < 0.0001), and improved cognition. CONCLUSION: In this unique genetic paradigm, the melatonin deficiency (caused by a lack of its substrate, serotonin) may cause the ultradian sleep-wake rhythm.

Propofol anesthesia significantly alters plasma blood levels of melatonin in rats.

BACKGROUND: General anesthesia combined with surgery has been shown to decrease the nocturnal peak of melatonin in patients. However, the role of anesthesia itself on melatonin secretion remains unknown. We previously showed that anesthesia induced by propofol modifies the circadian time structure in both rats and humans and phase advances the circadian rest-activity rhythm in rats. In this study, we examined the secretion of melatonin during 24 h after a 30-min propofol anesthesia in rats. METHODS: Rats were exposed to 12-h light/12-h dark alteration conditions and anesthetized with propofol (120 mg/kg intraperitoneally) around their peak of melatonin secretion (Zeitgeber time 16). Trunk blood samples were collected at seven subsequent Zeitgeber times to assess the effects of propofol on circadian melatonin secretion. RESULTS: Propofol modifies the peripheral melatonin by significantly decreasing its concentration ( approximately 22-28%) during the immediate 3 h after the wake up from anesthesia and then significantly increasing melatonin secretion 20 h after anesthesia ( approximately 38%). Cosinor analysis suggests that propofol induces a phase advance of the circadian secretion of peripheral melatonin. CONCLUSIONS: The results demonstrate the disturbing effects of propofol anesthesia on the circadian rhythm of plasma melatonin in rats under normal light conditions. These results parallel the desynchronization of the circadian rhythms of locomotor activity and temperature previously observed after propofol anesthesia.

Evaluation in humans of ELF-EMF exposure on chromogranin A, a marker of neuroendocrine tumors and stress.

Chromogranin A (CgA), which is a major protein in adrenal chromaffin cells and adrenergic neurons, is a clinically relevant endocrine and neuroendocrine tumor marker including pheochromocytomas, neuroblastomas, and related neurogenic tumors. In this study, we looked at the effect in humans of chronic daily exposure to a 50-Hz magnetic field. We examined in 15 men (38.0 ± 0.9 years) the effects of chronic daily exposure to a 50-Hz magnetic field for 1-20 yrs both at home and at work. EMDEX II dosimeters were used to record magnetic field all day long every 30 s. for 1 week. The weekly geometric mean of the individual exposures ranged from 0.1 to 2.6 µT. Blood samples were taken hourly between 20:00 h and 08:00 h. CgA patterns of exposed subjects were compared to age-matched controls. The results of exposed subjects were compared with those for 15 unexposed men who served as controls and whose individual exposure was ten times lower ranging from 0.004 to 0.092 µT. This work shows that in the control group the serum CgA levels exhibited a nighttime peak with a progressive decline of the serum concentrations and a nadir in the morning. Both the profile and the serum concentrations of CgA, a marker of neuroendocrine tumors and stress, did not appear to be impaired in the subjects chronically exposed over a long period (up to 20 yrs) to magnetic fields though a trend toward lower levels were found at the highest exposure (>0.3 µT). This does not rule out, however, that the potential deleterious risk of ELF-EMF on frail populations such as children and the elderly may be greater at low exposure and should hence be documented, at least for their residential exposure.

Circadian disruption of body core temperature and rest-activity rhythms after general (propofol) anesthesia in rats.

BACKGROUND: General anesthesia is commonly associated with sleep disorders, fatigue, drowsiness, and mood alterations in patients. The authors examined whether general (propofol) anesthesia can impact the circadian temporal structure by disturbing circadian rest-activity and body temperature rhythms under normal light-dark conditions (light-dark 12:12 h) in rats. METHODS: A group of rats was anesthetized with propofol, and another was injected with 10% Intralipid, which was used as a control lipidic solution. The authors examined six groups of rats according to the Zeitgeber time of intraperitoneal administration (ZT6, ZT10, ZT16) and the substance injected (propofol or Intralipid). RESULTS: On the day after anesthesia, propofol induced a significant 60- to 80-min phase advance of both rest-activity and body temperature rhythms. A significant 45- to 60-min phase advance of body temperature and a significant 20-min phase advance of rest-activity were still observed on the second day after anesthesia. The amplitudes of both rest-activity and body temperature rhythms were decreased on the first and second days after anesthesia. The 24-h mean rest-activity rhythm was decreased on the day after anesthesia, whereas the 24-h mean body temperature rhythm was not modified. CONCLUSION: The results demonstrate the disturbing effects of propofol anesthesia on the circadian time structure in rats under normal light conditions.

Hypoxia-induced changes in recovery sleep, core body temperature, urinary 6-sulphatoxymelatonin and free cortisol after a simulated long-duration flight.

Fatigue and sleep disorders often occur after long-haul flights, even when no time zones are crossed. In this controlled study, we assessed the effects of two levels of hypoxia (at 8000 ft and 12 000 ft) on recovery sleep. Core body temperature (CBT), a circadian marker, urinary 6-sulphatoxymelatonin and free cortisol were studied in 20 young healthy male volunteers exposed for 8 h (08:00-16:00 hours) in a hypobaric chamber to a simulated cabin altitude of 8000 ft and, 4 weeks later, 12 000 ft. Each subject served as his own control. Sleep was recorded by polysomnography for three consecutive nights for each exposure. CBT was monitored by telemetry during the three 24-h cycles (control, hypoxic exposure and recovery). Free urinary cortisol and 6-sulphatoxymelatonin levels were assayed twice daily between 08:00 and 20:00 hours (day) and between 20:00 and 08:00 hours (night). We showed significant changes in circadian patterns of CBT at both altitudes, suggesting a phase delay, and changes in recovery sleep but only at 12 000 ft. We observed an increase in sleep onset latency which correlated positively with the increase in CBT levels during the first recovery night and a decrease in the duration of stage N(2) (formerly S(2)), which correlated negatively with the mid-range crossing time, a reliable phase marker of CBT rhythm. This study shows clearly the impact of hypobaric hypoxia on circadian time structure during air flights leading to a phase delay of CBT, independent of jet lag and consequences on sleep during recovery.