Resetting of the Human Circadian Melatonin Rhythm by Ambient Hypoxia

Circadian clocks in the body drive daily cycles in physiology and behavior. A master clock in the brain maintains synchrony with the environmental day-night cycle and uses internal signals to keep clocks in other tissues aligned. Work in cell cultures uncovered cyclic changes in tissue oxygenation that may serve to reset and synchronize circadian clocks. Here we show in healthy humans, following a randomized controlled single-blind counterbalanced crossover study design, that one-time exposure to moderate ambient hypoxia (FiO₂ ~15%, normobaric) for ~6.5 h during the early night advances the dim-light onset of melatonin secretion by 9 min (95% CI: 1-16 min). Exposure to moderate hypoxia may thus be strong enough to entrain circadian clocks to a 24-h cycle in the absence of other entraining cues. Together, the results provide direct evidence for an interaction between the body's hypoxia-sensing pathway and circadian clocks. The finding offers a mechanism through which behaviors that change tissue oxygenation (e.g., exercise and fasting/eating) can affect circadian timing and through which hypoxia-related diseases (e.g., obstructive sleep apnea and chronic obstructive pulmonary disease) can result in circadian misalignment and associated pathologies. Trial Registration: Registration number: DRKS00023387; German Clinical Trials Register: http://www.drks.de.