Endocannabinoids, endocannabinoid-like compounds and cortisone in head hair of health care workers as markers of stress and resilience during the early COVID-19 pandemic.

The pandemic caused by SARS-CoV-2 impacted health systems globally, creating increased workload and mental stress upon health care workers (HCW). During the first pandemic wave (March to May 2020) in southern Germany, we investigated the impact of stress and the resilience to stress in HCW by measuring changes in hair concentrations of endocannabinoids, endocannabinoid-like compounds and cortisone. HCW (n = 178) recruited from multiple occupation and worksites in the LMU-University-Hospital in Munich were interviewed at four interval visits to evaluate mental stress associated with the COVID-19 pandemic. A strand of hair of up to 6 cm in length was sampled once in May 2020, which enabled retrospective individual stress hormone quantifications during that aforementioned time period. Perceived anxiety and impact on mental health were demonstrated to be higher at the beginning of the COVID-19 pandemic and decreased significantly thereafter. Resilience was stable over time, but noted to be lower in women than in men. The concentrations of the endocannabinoid anandamide (AEA) and the structural congeners N-palmitoylethanolamide (PEA), N-oleoylethanolamide (OEA) and N-stearoylethanolamide (SEA) were noted to have decreased significantly over the course of the pandemic. In contrast, the endocannabinoid 2-arachidonoylglycerol (2-AG) levels increased significantly and were found to be higher in nurses, laboratory staff and hospital administration than in physicians. PEA was significantly higher in subjects with a higher resilience but lower in subjects with anxiety. SEA was also noted to be reduced in subjects with anxiety. Nurses had significantly higher cortisone levels than physicians, while female subjects had significant lower cortisone levels than males. Hair samples provided temporal and measurable objective psychophysiological-hormonal information. The hair endocannabinoids/endocannabinoid-like compounds and cortisone correlated to each other and to professions, age and sex quite differentially, relative to specific periods of the COVID-19 pandemic.

Plasticity of the human IgM repertoire in response to long-term spaceflight.

Immune dysregulation is among the main adverse outcomes of spaceflight. Despite the crucial role of the antibody repertoire in host protection, the effects of spaceflight on the human antibody repertoire are unknown. Consequently, using high-throughput sequencing, we examined the IgM repertoire of five cosmonauts 25 days before launch, after 64 ± 11 and 129 ± 20 days spent on the International Space Station (ISS), and at 1, 7, and 30 days after landing. This is the first study of this kind in humans. Our data revealed that the IgM repertoire of the cosmonauts was different from that of control subjects (n = 4) prior to launch and that two out the five analyzed cosmonauts presented significant changes in their IgM repertoire during the mission. These modifications persisted up to 30 days after landing, likely affected the specificities of IgM binding sites, correlated with changes in the V(D)J recombination process responsible for creating antibody genes, and coincided with a higher stress response. These data confirm that the immune system of approximately half of the astronauts who spent 6 months on the ISS is sensitive to spaceflight conditions, and reveal individual responses indicating that personalized approaches should be implemented during future deep-space exploration missions that will be of unprecedented durations.

Stress Related Shift Toward Inflammaging in Cosmonauts After Long-Duration Space Flight.

Space flight exerts a specific conglomerate of stressors on humans that can modulate the immune system. The mechanism remains to be elucidated and the consequences for cosmonauts in the long term are unclear. Most of the current research stems from short-term spaceflights as well as pre- and post-flight analyses due to operational limitations. Immune function of 12 cosmonauts participating in a long-duration (>140 days) spaceflight mission was monitored pre-, post-, and on two time-points in-flight. While the classical markers for stress such as cortisol in saliva where not significantly altered, blood concentrations of the endocannabinoid system (ECS) were found to be highly increased in-flight indicating a biological stress response. Moreover, subjects showed a significant rise in white blood cell counts. Neutrophils, monocytes and B cells increased by 50% whereas NK cells dropped by nearly 60% shortly after landing. Analysis of blood smears showed that lymphocyte percentages, though unchanged pre- and post-flight were elevated in-flight. Functional tests on the ground revealed stable cellular glutathione levels, unaltered baseline and stimulated ROS release in neutrophils but an increased shedding of L-selectin post-flight. In vitro stimulation of whole blood samples with fungal antigen showed a highly amplified TNF and IL-1ß response. Furthermore, a significant reduction in CD4+CD25+CD27low regulatory T cells was observed post-flight but returned to normal levels after one month. Concomitantly, high in-flight levels of regulatory cytokines TGF-ß, IL-10 and IL-1ra dropped rapidly after return to Earth. Finally, we observed a shift in the CD8+ T cell repertoire toward CD8+ memory cells that lasted even one month after return to Earth. Conclusion: Long-duration spaceflight triggered a sustained stress dependent release of endocannabinoids combined with an aberrant immune activation mimicking features of people at risk for inflammation related diseases. These effects persisted in part 30 days after return to Earth. The currently available repertoire of in-flight testing as well as the post-flight observation periods need to be expanded to tackle the underlying mechanism for and consequences of these immune changes in order to develop corresponding mitigation strategies based on a personalized approach for future interplanetary space explorations.

Headache under simulated microgravity is related to endocrine, fluid distribution, and tight junction changes.

Head-down-tilted bed rest (HDTBR) induces headaches similar to headaches during space flights. The objective of this investigation was to study hematological, endocrinological, fluid changes and tight junctions in HDTBR-induced headaches as a proxy for space headache. The randomized crossover HDTBR design by the European Space Agency included 12 healthy, nonheadache male subjects. Before, during, and after confined HDTBR periods, epinephrine (urine), cortisol (saliva), hematological, endothelium markers, and fluid distribution parameters were measured. Headaches were assessed with a validated headache questionnaire. Compared with baseline, HDTBR in all subjects was associated with higher hematocrit, hemoglobin, and epinephrine levels, higher erythrocyte counts, and lower relative plasma volumes (all P < 0.05). In total, 26 headache episodes occurred. In subjects with headaches during HDTBR, epinephrine levels were exaggerated (vs headache-free subjects; HDTBR day 3; 5.1 ± 1.7 vs 3.4 ± 2.4; P = 0.023), cortisol levels were decreased (vs headache-free subjects; HDTBR day 1; 0.37 ± 0.16 vs 0.50 ± 0.20; P < 0.001) and the tight junction marker zonulin was elevated (vs headache-free subjects in HDTBR days 1, 3, 5; P < 0.05). HDTBR induces hemoconcentration and fluid redistribution in all subjects. During headache episodes, endocrinological changes, fluid distribution, and tight junctions were more pronounced, suggesting an additional role in headache pathophysiology.

Influences of large sets of environmental exposures on immune responses in healthy adult men.

Environmental factors have long been known to influence immune responses. In particular, clinical studies about the association between migration and increased risk of atopy/asthma have provided important information on the role of migration associated large sets of environmental exposures in the development of allergic diseases. However, investigations about environmental effects on immune responses are mostly limited in candidate environmental exposures, such as air pollution. The influences of large sets of environmental exposures on immune responses are still largely unknown. A simulated 520-d Mars mission provided an opportunity to investigate this topic. Six healthy males lived in a closed habitat simulating a spacecraft for 520 days. When they exited their "spacecraft" after the mission, the scenario was similar to that of migration, involving exposure to a new set of environmental pollutants and allergens. We measured multiple immune parameters with blood samples at chosen time points after the mission. At the early adaptation stage, highly enhanced cytokine responses were observed upon ex vivo antigen stimulations. For cell population frequencies, we found the subjects displayed increased neutrophils. These results may presumably represent the immune changes occurred in healthy humans when migrating, indicating that large sets of environmental exposures may trigger aberrant immune activity.

The impact of chronic stress burden of 520-d isolation and confinement on the physiological response to subsequent acute stress challenge.

Collective evidence indicates that previous exposure to stressful condition might be able to induce changes in brain structure, HPA axis activity and related neurotransmission, and accordingly affect physiological responses to subsequent challenges. During long-term spaceflight, space travelers have to live under the condition of isolation and confinement in the spacecraft for a long period. It is still largely unknown if this kind of chronic stress burden can induce any long-lasting changes. To address this question, following 520-d isolation and confinement simulating a flight to Mars, the participants and a matched control group were exposed to an acute stress challenge called parabolic flight. Brain cortical activity, HPA axis activity, and sympathetic adrenal-medullary system response were monitored by EEG signal, cortisol secretion, and catecholamine production, respectively. We observed enhanced EEG signals, elevated cortisol levels and increased adrenaline productions. A group effect on cortisol output was revealed showing higher cortisol peak levels in the Mars520 group as compared to the control group, suggesting that HPA axis was to a certain extent more activated in the subjects who had chronic stress experience.