Intense solar activity reduces urinary 6-sulfatoxymelatonin in patients with COPD

Melatonin (N-acetyl-5-methoxytryptamine) is a potent nocturnal antioxidant hormone and efficient immuno-inflammatory regulator, which is primarily synthetized in the pineal gland [1]. Melatonin is also produced by other organs such as the retina and the gastrointestinal tract [1]. It is well known that pineal gland function and melatonin secretion are modulated by the environmental light/dark cycle via the suprachiasmatic nucleus (SCN) in the hypothalamus [2]. SCN is the “master clock” that regulates the 24 h-circadian rhythm, including melatonin/cortisol rhythms, gene expression, and autonomic nervous system (ANS) function [2‐8]. The disruption of 24-h circadian rhythm with concomitant reduction of melatonin synthesis and serum levels seem also to be modulated by solar and geomagnetic activity (SGA)-related visible and non-visible electromagnetic radiation [3]. This may be relevant clinically, as we have previously described reductions in pulmonary function attributable to SGA [9]. We have also observed additional adverse effects of SGA that include increases in blood pressure, atrial and ventricular arrhythmias, and increases in circulating biomarkers of systemic inflammation [10‐13]. In this study, we hypothesize that intense solar activity reduce levels of urinary 6-sulfatoxymelatonin (aMT6s), thereby providing a biologic pathway with the potential to contribute to the adverse effects of SGA.

Circulating melatonin has a short half-life (~ up to 45 min) and is rapidly metabolized in the liver with the major enzymatic metabolite of melatonin (aMT6s), which highly correlates with plasma melatonin levels [13, 14]. Studies in animals have suggested a link between seasonal rhythmicity of aMT6s levels and ~ 11-year solar cycles [8]. Melatonin levels can also be affected by genetic factors, sex, pineal gland size, and modifiable factors such as seasonal changes, latitudinal locations, medications (e.g., β-blockers and non-steroidal anti-inflammatory drugs), sleep quality, depression, smoking status, and comorbidities including diabetes and cancer [2, 13‐20]. Levels of melatonin vary throughout life, reaching highest levels in children younger than 4 years, and declining within age [2, 19]. In the lung, melatonin may mitigate respiratory disease severity by modulating pro-inflammatory cytokines such as interleukin1β and 6, and TNF-α, reducing oxidative stress [1, 13, 16]. A reduction in melatonin also can increase the risk of the development of type 2 diabetes mellitus by impairing insulin sensitivity and glucose tolerance [6, 7].

Understanding the impact of solar activity on melatonin levels is critical to understanding natural exposures that may affect health outcomes, particularly in association with oscillations of 11-solar cycles, even though the relationship between variation in solar activity and melatonin levels in humans has not been well established. To investigate this, we took advantage of previously collected urine samples in a cohort of patients with COPD [21, 22] to assess the link between short-term variation in solar activity intensity and melatonin excretion, using aMT6s concentrations to estimate melatonin levels. We also assessed effect modification of comorbidities (diabetes mellitus, obesity, and reduced pre-bronchodilator pulmonary function) on aMT6s.

To the best of our knowledge, this is the first study to demonstrate a reduction of aMT6sr during periods of intense high-energy solar particle events. The associations were stronger and more robust in patients with diabetes mellitus. Although all CME parameters are strongly correlated and represent the ejection of high energy solar material, the association between CME speed and MT6sr was greater than other parameters. As CME_speed parameter seems to play a critical role on the atmospheric photoionization processes and energetic particle precipitation, and on Earth’s magnetic field disturbances, these factors may be linked for the observed impact on melatonin levels [23]. Intense solar activity can impact human health directly, by the modulation and disruption of the 24 h-circadian rhythm, and indirectly by inducing physicochemical properties and toxicity of atmospheric aerosols [9, 12].

Solar activity continuously emits a broad-spectrum range of electromagnetic radiation that modulates changes in the solar–terrestrial environment over time scales ranging from minutes to millennia. Sun-Earth interaction plays major roles in the radioactive, physiochemical processes and dynamics of Earth systems, which affect the human health possibly by the reduction of melatonin synthesis and ANS dysregulation related to the disruption of the 24 h circadian rhythm located in the SCN [15]. While it is unclear why patients with diabetes were more susceptible to the detrimental impact of intense solar activity on aMT6sr levels, the literature describes a link between aMT6s and diabetes risk [4, 7, 17]. Reduced levels of melatonin can impair diabetes management and disrupt blood sugar control [7], which suggests that diabetic patients may experience periods of poor health during intense solar activity periods.

A bidirectional relationship between melatonin levels and insulin secretion may explain our findings in patients with diabetes. The disruption of the 24 h circadian rhythm with subsequent lower nocturnal melatonin secretion is associated with insulin secretion and resistance [4, 17], which may influence the development and progression of type 2 diabetes [4]. The circadian rhythm regulates the sleep/wake and feeding/fasting cycles through melatonin, impacting glucose homeostasis by influencing the timing of insulin secretion from pancreatic β cells, glucose production by the liver, insulin-dependent glucose GLUT 4 expression in skeletal muscles, among other effects [4]. There is a synchronization between insulin levels and melatonin during the night and day, in which melatonin action is inhibited by insulin release (and reduce glucose tolerance) through its membrane receptors MT₁ and MT₂, and the secondary messengers 3′,5′-cyclic adenosine monophosphate, 3’,5’-cyclic guanosine monophosphate, and inositol 1,4,5-trisphosphate [6]. High levels of insulin are observed when melatonin levels are low, and during the night low levels of insulin are observed with high levels of melatonin [6]. Reduction of the melatonin receptor MT₂ may play a role on the development of type 2 diabetes and metabolic diseases [6]. Concomitantly, age-related reduction levels of melatonin accompany an increase of age-related insulin resistance and type 2 diabetes risk [6]. Patients with both diabetes and COPD appear to be more susceptible to solar activity reducing circulating melatonin, and potentially antioxidant effects of melatonin. This finding suggests that differences in the response to solar activity could in part explain a greater susceptibility to effects of illnesses and environmental exposures that promote oxidative stress in patients with diabetes [25].

This study has limitations and strengths. As the original COPD study was not designed to assess effects linked to melatonin, the time of urine collection was not standardized and there is no information about melatonin determinants such as sleep habits and nocturnal light exposures, and the cohort included mainly white males. However, we improved our estimation by adjusting our models for covariates linked to impaired melatonin secretion, including urine collection time, sleep apnea history and treatment, beta blocker use, and diabetes history as covariates. As melatonin excretion is greatest at night, urine from a first morning void might be more informative, while 24-h urine collection would be ideal to assess overall impact on melatonin secretion. This limitation should bias towards a null result; therefore, the effect that we observed is likely underestimated. As melatonin was assessed at only one time of day, we are unable to comment on the effects of solar activity on circadian rhythm per se, which would require repeated measures across the day. Moreover, our findings may not be generalized to other populations. Our study strengths are the availability of this cohort with stored urine samples for every visit, extensive information regarding personal and clinical characteristics, which created a unique opportunity to test our hypotheses.

Our findings contribute to understanding relationships between solar activity and susceptibility to disruption to 24 h-circadian rhythm that result in lower levels of melatonin, a circulating anti-oxidant. These results provide evidence for a biologic pathway related to intense solar activity that may be responsible for adverse health effects. Hence, our study findings have critical relevance to understand the impact of the periodicity of solar activity intensity on aMT6sr levels in high risk patients with COPD, which impacts the progression and prognosis of the disease and comorbidities.