Photic Stress and Rhythmic Physiological Processes: Roles of Selenium as a Chronobiotic

Abstract

Physiological processes exhibit distinct rhythmic patterns influenced by external cues. External cues such as photic signal play an important role in the synchronization of physiological rhythms. However, excess of or indiscriminate exposure to photic signals exerts profound effects on physiological processes, disrupting normal hormonal secretory rhythms, altering sleep/wakefulness cycle, and impairing reproductive function. Alteration in sleep/wakefulness cycle, impairment in reproductive cycle, and disruption of normal hormonal secretory rhythms characterize risk groups for photic stress such as night workers, trans-meridian travelers, and night-active people. Evidence from primary studies is increasing on the tendency of selenium to reset internal biorhythms by targeting circadian proteins and melatonin. The review highlights the chronobiological roles of selenium.

1. Introduction

Virtually all physiological processes including gene expressions exhibit rhythmic patterns. These patterns are influenced by external cues such as light, temperature, metabolic activity, and diet. Indiscriminate exposure to external cues affects the pattern of the rhythms [1, 2, 3]. For instance, light is necessary as an external cue to reset circadian pacemakers situated in the suprachiasmatic nucleus; indiscriminate exposure to light and photic stress will affect the functionalities of these pacemakers, causing alteration in the rhythmic pattern of gene expressions with attendant impairments in physiological functions [4, 5]. This may cascade into a raised risk level for a number of medical conditions including cancer, diabetes mellitus, cardiovascular disorders, reproductive derangements, and sleep problems [6]. With continuous proliferation, popularization and utilization of artificial light during nighttime, night workers, trans-meridian travelers, and night-active people tend to be at a higher risk of adverse consequences of circadian misalignment and desynchronization if no precautionary measures are observed.

Besides lifestyle changes and precautionary measures to minimize and mitigate circadian disruptions occasioned by alterations in external cues, most especially light, the roles of nutritional factors cannot be overemphasized [7, 8, 9]. Selenium is one of the essential micronutrients for mammals. It is chiefly available in soil and water in variable levels. Its level the plant and animal foods is determined by the soil and water concentration of selenium [10]. It can also be added to food as a supplement. The daily recommended intake of the mineral is 55 micrograms/day for both females and males [11].

As far as its functions are concerned, selenium plays roles as a cofactor for glutathione peroxidase, an enzyme that catalyzes the peroxidation of glutathione to form water. This implies that the mineral is necessary for the regulation of oxidative stress, maintenance of oxidant/antioxidant homeostasis, and prevention of DNA oxidation [12], among others. Second, it acts as a cofactor for iodothyronine deiodinase, an enzyme that converts thyroxin to 3,6,3′-tri-iodothyronine. 3,6,3′-Tri-iodothyronine is an active form of thyroid hormone and far more active than thyroxin. Therefore, the deficiency of selenium may lead to the deficiency of thyroid function, and this can manifest as disorders in all organs where thyroid hormone is needed.

Selenium has also been reported to exhibit the tendency to synchronize biorhythms. This ability is an important corrective measure for desynchronization. A study by Zhang and Zarbi [13] indicated how selenium increased the expression of a circadian protein ‘PER2’. PER2 acts as a negative regulator of circadian rhythm, inhibiting the expression of BMAL1 proteins and CLOCK. Primary studies are available to support the roles of selenium as a therapeutic option for desynchronization. The aim of the work was to highlight the chronobiological roles of selenium.

2. Light pollution and photic stress

The quest for fortune has overwhelmed human affinity for nature and natural mechanisms, one of which is natural light/dark cycle [14]. Nowadays, prolonged exposure to light at night is one of the most common forms of light pollution, an inducer of photic stress [5]. It is characterized by alterations in photoperiod. Conditions associated with light at night include night work and insomnia [4].

The genesis of photic stress can be traced back to the discovery of electric bulb by the renowned American inventor Thomas Alva Edison, who developed a deep vacuum incandescent lamp with a carbon cotton filament [6]. However, the first successful attempt to use electricity for lighting was earlier made by Humphrey Davy in 1801, who discovered the incandescence of an energized conductor [6]. Nowadays, due to rapid electricity proliferation, electric lighting has replaced most traditional lighting sources, making human population virtually independent of natural photoperiod of 12 hour light/12 hour dark cycle. As a matter of fact, over one-third of the world population is estimated to live under light polluted areas [15].

The effects of photic stress are of two types: image-forming effects and photoperiodic effects. While the former are characterized by discomfort and disability glare [16], the latter are characterized by disruption of the circadian rhythm, the internal clock that regulates physiological functions [17].

A major impact of exposure to light at night is the inhibition of melatonin production and shift in the circadian phase [4]. Blue light has been shown to be the most effective in the suppression of melatonin secretion [6]. Light-induced suppression of melatonin is due to reduction in postganglionic noradrenergic neural discharge to pineal glands. Since melatonin rhythm is an efferent mechanism that blends exogenous cycle (light/dark cycle) with endogenous cycle, suppressed nocturnal melatonin secretion represents impairment in synchronization [18].

The desynchronization of the circadian rhythm leads to many clinical conditions. For example, studies have shown the link between exposure to artificial light at night and fatigue [19], reduced work productivity [20], diabetes mellitus [21], many different forms of cancer [20], and derangement in female reproductive functions [22]. In humans, a shift in light/dark cycle characterizing shift work and chronic jetlag suppresses the expression of PER1 and PER2 in the suprachiasmatic nucleus and causes delay in acrophases of the circadian expression of PER1, PER2, BMAL-1, and D-site binding protein (DBP) in the liver [23]. There is a difference between the expression pattern of circadian genes in suprachiasmatic nucleus and peripheral tissues. Yamazaki et al. [24] reported that suprachiasmatic nucleus rapidly adjusts to light shifts, but peripheral tissues shift more slowly. For example, PER2 expression in the ovary peaks at light offset delayed by 4–6 hours relative to its expression in the suprachiasmatic nucleus [25]. Also, the duration of light exposure determines whether there will be shifts in the circadian rhythm in both humans and animals [26].

3. Photic stress and rhythmically controlled physiological processes

Biorhythms are periodic variations in physiologic events occurring within a time frame. Important attributes of biorhythms include orderliness, entrainability, self-sustenance, and endogeny [1, 27, 28]. Biorhythms that are completed in less than 24 hours are called ultradian rhythms (example is ultradian LH secretion). It takes more than 24 hours for infradian rhythms to be completed (example is LH surge). Those that are completed in approximately 24 hours are circadian rhythms (example is melatonin secretion).

Circadian rhythms work through a set of expressed proteins known as circadian proteins situated in the suprachiasmatic nucleus in the highest density and other nucleated cells. PER, one of the circadian proteins, interacts with other PER proteins as well as the E-box regulated, clock controlled proteins CRY1 and CRY2 to create a heterodimer, which translocate into the nucleus. At this point, it inhibits CLOCK-BMAL-1 activation [29]. The PER1 mRNA is expressed in all cells as a component of a transcription-translation negative feedback mechanism, which creates a cell autonomous molecular clock. PER1 transcription is controlled by protein interactions and with its 5 E-box and 1 D-box elements in its promoter region. Heterodimer CLOCK-BMAL1 stimulates E-box elements present in the PER1 promoter as well as activates the E-box promoters of other components of the molecular clock such as PER2, CRY1, and CRY2 (Figure 1) [5].

Figure 1.

Molecular mechanism of circadian rhythm in relation to ovulation [30].

Activators include BMAL1 (B); CLOCK (C) and repressors include period (per) and cryptochrome (cry) and are expressed rhythmically and phosphorylated by Casein kinases (CK) in granulosa cells. Transactivation by BMAL1:CLOCK is indicated by (+); repression of BMAL1:CLOCK activity by PER:CRY is indicated by (−). Arrowheads attached to sine waves indicate rhythmic transcription/translation. Curved arrows indicate nuclear translocation. Abbreviations: arachidonic acid (AA); prostaglandin E2 (PGE2); prostaglandin F2α (PGF2α); phosphorylation (P); Casein kinase 1,2 (CK1,2).

Cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis, contains E-box sequences in its promoter region. Studies by Morris and Richard [31] and Liu et al. [32] showed that CLOCK:BMAL1 heterodimers may activate COX-2 transcription. Circadian rhythms of COX-2 mRNA expression may result in rhythmic buildup of COX-2, which may then result in rhythmic synthesis and accumulation of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α). High levels of prostaglandin synthesis, particularly in response to a surge in LH secretion, orchestrate follicular rupture and ovulation.

Hormone secretory pattern and sleep and wakefulness cycle are rhythmic physiological processes. They are influenced by external cues such as light, temperature, and anthropogenic factors, among others. Excess of these cues may abolish these processes. For instance, a study conducted by Attarchi et al. [33] on a risk group for light pollution (night shift workers) indicated an increase in FSH levels both in daytime and in nighttime and a decrease in melatonin in daytime and nighttime. FSH secretion is known to peak in the morning and reach nadir level at night, while melatonin is known to peak at around 2.00 am at night and reach nadir during the daytime. The findings of Attarchi et al. showed derangement in the normal secretory pattern of FSH and LH. Enormous studies have reported how prolonged exposure to light including light at night affects sleep onset, sleep quality, and sleep duration [4, 5]. Exposure to light before bedtime has been known to delay sleep onset, reduce sleep duration, and impair quality of sleep [34]. Such disruption in sleep/wakefulness cycle increases the risk of individuals acquiring a disease or exacerbates the symptoms of a preexisting condition. Shift work has been associated with an increased risk of mood disorders, depression, cardiovascular disease, endometriosis, and dysmenorrhea as well as an increased incidence and risk of breast cancer [4, 35, 36].

Reproduction involves barrage of rhythmical physiological processes to come by. For instance, at puberty, it is not secretion of gonadotropin-releasing hormone (GnRH) that triggers the episode of changes characterizing the stage but pulsatile secretion of the hormone (occurs every 90 minutes). The circadian rhythms of clock-gene expression noticed in brain areas concerned with reproduction indicate that this neural timing system elicits neuroendocrine events that produce pre-ovulatory luteinizing hormone (LH) surge and ovulation [30]. Works have documented that suprachiasmatic nucleus (SCN) is essential for normal functioning of the hypothalamic pituitary gonadal (HPG) axis [30]. SCN communicates with GnRH neurons through arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) [25]. The principal afferent pathway to SCN is the photic signal-related retino-hypothalamic pathway. These photic signals are conveyed by light-sensitive retinal ganglionic cells, which do not participate in vision [4, 5], resulting in the control of melatonin production by pineal gland and shift in the circadian phase. Melatonin plays an important role in the photoperiod-induced timing of physiological functions including the cascade of reproductive functions [5, 37].

Excess exposure to light brings about adverse health and reproductive features since circadian clocks are entrained by light duration. For example, shift duty, an employment practice meant to provide service round the clock [38] that is characterized by altered photoperiod and desynchronization of circadian clock, results in health and reproductive problems [5].

Indiscriminate exposure to light has been shown to impair hormonal rhythm, most especially in the hypothalamic hypophyseal ovarian axis, which determines the reproductive cycle and fertility [39]. For instance, continuous illumination was reported to modulate normal nighttime reduction in FSH secretion in women [40]. Other studies indicate that a shift in light/dark cycle by 6 hours caused desynchronization for more than 6 days but requires 6–12 days for clock genes rhythms to completely adjust with different peripheral tissues [24]. Ovarian clock was not fully resynchronized 6 days after exposure to 6 hours shift in light/dark cycle. It took 12 days for full restoration to occur.

Shift workers and trans-meridian travelers tend to have activity, body temperature, and hormonal rhythms that are out of phase with environmental cues [4]. Such disruption may result in endometriosis, dysmenorrhea, as well as an increased incidence and risk of breast cancer [4, 35]. Women working an evening shift, night shift, or irregularly scheduled shifts showed altered menstrual cycle length, increased menstrual pain, and changes in the duration and amount of menstrual bleeding [41]. These symptoms are followed by alterations in patterns of ovarian and hypophyseal hormone secretion, such as an increase in follicular stage length and changes in follicular stimulating hormone (FSH) concentrations [41].

Shift duty is one of the risk factors for photic stress. Female shift workers have been shown to exhibit a higher risk of producing premature or low birth weight babies, spontaneous abortion, and subfecundity [4]. Photopollution has been documented to result in the prolongation of estrous cycle length [15, 42, 43, 44], increase in estrous cycle ratio [1, 15, 42, 43], depression in LH, estradiol and progesterone secretions, and increase in estradiol/progesterone ratio [15, 42, 43].

4. Selenium

Selenium is a period IV and group VI element. The major dietary origins of selenium in most countries are plants [10, 45]. Hence, soil selenium concentrations are principal determinants of the minerals in plants and humans [46]. The level of the mineral in the body also depends on state of activity, dialysis, oral contraceptive use, diurnality, pregnancy, and lactation [47, 48], among others. The daily allowance of the mineral is 55 micrograms according to the National Institute of Medicine without gender-related variation.

5. Chronobiotic roles of selenium: Effect on circadian genes

Selenium has been known to be essential for the execution of many physiological functions. As a co-factor for glutathione peroxidase, it is essential for the regulation of oxidative stress. As an antioxidant, glutathione peroxidase helps in the membrane integrity maintenance, prostacyclin production protection, and control of oxidations of macromolecules such as lipids, lipoproteins, and deoxyribonucleic acid (DNA) [49]. As a co-factor for iodothyronine deiodinase, the mineral plays crucial roles in the conversion of tetraiodothyronine (thyroxine) to triiodothyronine, with the latter being an active form of the former [10, 45, 46]. Triiodothyronine is a metabolic hormone. Thus, it exerts its effect on virtually all body tissues. Selenoprotein P is the principal supplier of selenium to tissues [50]. Therefore, free selenium is present in gonads, adrenal gland, thyroid gland, liver, and muscles, among others, whose functions remain sketchy. Selenoprotein P is the main provider of selenium to tissues [50]. Yet low blood and tissue selenium levels have been identified in a number of pathological conditions including HIV infections, cardiomyopathy, and kidney disorder, among others [46, 51].

Another stunning function of selenium is its role in synchronization of circadian clocks. This is predicated by its ability to increase the expression of circadian genes. Synchronization of circadian clocks is essential not only in health but also in copious disease conditions. Since circadian rhythm derangements characterize shift or rotatory work schedule and jetlag and are known as an important risk factor for tumor development (in breast, colon, and prostate), the role of selenium as a chronobiotic cannot be undersized. A study by Hu et al. [52] indicated the roles of selenium on circadian gene. L-methyl-selenocysteine was shown to up-regulate BMAL1 in cultured cells and in vivo study using mice at the transcription level. As far as the cultured cells were concerned, the authors reported that selenium executed its effects by disrupting TIEG1-induced BMAL1 repression. Conversely, in CLOCK mutant mice deficient in BMAL1, selenium could not orchestrate protection. BMAL1 plays an important role in the positive regulation or activation of circadian rhythm by bringing about the expression of PERIOD genes and CRYPTOCHROME.

Circadian genes control DNA repair mechanisms, and DNA repair mechanisms are normal responses to DNA damage. Zarbl and Fang [53] reported that methyl-selenocysteine improved PER2 expression in experimentally induced mammary carcinogenesis, thus resulting in the inhibition of mammary tumor development. In an early study, Zhang and Zarbi [13] showed that methylselenocysteine dietary administration at 3 ppm caused time-related and progressive elevation in circadian controlled transcription factor DBP and PER2 gene expression in mammary gland. Conversely, rats placed on standard chow exhibited little or no circadian fluctuation. In N-nitroso-N-methylurea-induced mammary carcinogenesis, selenium administration reduced circadian controlled transcription factor DBP and PER2 gene expression over time, while no change was noticed in those that were on normal standard chow, but the proteins were more expressed in selenium-treated carcinogenic rats than in untreated carcinogenic rats.

DNA methylation, gene expression, and histone protein modification are controlled by circadian rhythms. Xiang et al. [54] observed that treatments with selenite reduced DNA methyltransferase mRNA expression and 1 and 3A and protein levels of DNA methytransferase 1 in human prostatic carcinoma cell line (LNCaP cells). The effect of selenium administrations on PER1 expression in normal and desynchronized rats has been reported [44]. In the study, rats were desynchronized through exposure to experimental model of light pollution and photic stress for 1 week and 8 weeks. Dampening of PER1 expression was observed when compared to rats maintained under a natural 12-hour light/12-hour dark cycle. Conversely, administrations of selenium to normal rats for 8 weeks increased the expression of the clock gene. There was also an increase in PER1 expression when selenium was administered for 1 week and 8 weeks to desynchronized rats. The findings of the study suggest the tendency of selenium to resynchronize rats and provide insights into potentials of using selenium as a nutritional alternative for the prevention of diverse adverse alteration induced by excessive exposure to light as occurs in shift duty workers and people who may be exposed to artificial light (Figure 2).

Figure 2.

Effect of selenium and photic stress on circadian clock. Thick black line (stimulation), thick red line (inhibition); +VE (activation), –VE (negative feedback).

6. Chronobiotic roles of selenium: Effect on melatonin synthesis

Another important facet of chronobiology has to do with the regulation of melatonin rhythms. Melatonin is a renowned chronobiotic; it shifts in circadian phase [55], thereby affecting sleep–wake timing, blood pressure regulation, and reproduction [56]. Melatonin synthesis regulation is one of the principal outputs of light-related retino-hypothalamic pathway. During daytime, light rays enter the superior cervical ganglion through the retino-hypothalamic tract and reduce the expression of arylakylamine N acetyl transferase (ANAT), a rate-limiting enzyme that converts serotonin to melatonin. Hence, serotonin, a mood and alertness chemical messenger, becomes high in the day. Reverse occurs in the night. Epinephrine induces the expression of ANAT, raising melatonin level. Melatonin then binds with its receptors in the hypothalamus, retina, and anterior pituitary gland and reduces cAMP. This culminates into reduction in metabolic activities and sleep.

Administration of melatonin to subjects with impaired sleep/wakefulness cycle leads to resynchronization and normalization of the sleep/wakefulness cycle. Any underlying mechanism may include the influence of melatonin on clock gene expression. A study by Adeniyi et al. [44] indicated a positive correlation between nocturnal melatonin secretion and ovarian PER1 expression.

Works have shown the influence of selenium on melatonin secretion in living organisms. Adeniyi et al. [28] reported that selenium supplementation increased melatonin secretion when compared with rats that were not administered selenium. But when rats were maintained under prolonged dark condition and concomitantly treated with selenium, there was reduction in melatonin secretion. Selenite administered exogenously increased the endogenous secretion of melatonin. This occurs through the control of melatonin synthesis genes such as TDC, T5H, SNAT, and COMT [57]. In a similar pattern, Sun et al. [58] reported that selenite at a dose of 96 micrograms/kg increased melatonin synthesis. At 100 micrograms/kg and 150 micrograms/kg of selenium administrations, there was an increase in melatonin secretion in rats. In rats that were exposed to excess light, selenium administration at 150 micrograms/kg increased melatonin secretion after 1 week and 8 weeks of treatments [44].

7. Discussion

Suprachiasmatic nucleus of the hypothalamus is known as a master clock as it contains the largest amounts of circadian proteins PERIODS, CRYPTOCHROME, BMAL1, and CLOCK [25]. These proteins are also present in peripheral tissues in the body, where they regulate the timing and oscillation of gene expressions and biological events. Suprachiasmatic nucleus receives input signals through many pathways, but the principal is the light-mediating retino-hypothalamic tract, which regulates melatonin secretion and rhythmic proteins and synchronizes the body’s endogenous rhythms with external rhythms [30].

Night workers, trans-meridian travelers, and night active people are at a risk of desynchronization, a mismatch between external rhythms, especially light/dark cycle and endogenous rhythms. This mismatch also implies alteration in gene expressions and protein synthesis and variations in physiological processes, thereby aggravating the likelihood of sleep problems, endocrine disorders, reproductive derangements, and cancers [3, 6, 15, 34, 42, 43]. Specifically, breast cancer development likelihood has been reported in observers of night duty [4, 6]. In view of the necessity of night work in a teeming and ever-demanding world, the need for diverse palliatives is inevitable.

Selenium is a possible nutritional palliative for chronobiological problems in view of its ability to increase circadian genes and melatonin. Circadian proteins and melatonin determine the characteristics of rhythms and control gene expressions in nearly all body tissues. Insights into the possibility of selenium retarding tumor development stemmed from an observation that experimental rats administered selenium-enriched garlic exhibited declined cancer development [59, 60]. Although more primary studies are needed to authenticate the doses of different forms of selenium required to achieve this chronobiological effects not only in experimental animals but also in humans, the increase in PER2 expression by mammary tissue by selenium as reported by Zhang and Zarbi [13] and an increase in the expression of the clock gene in selenium-treated carcinogenic rats when compared with untreated N nitroso N methylurea-induced mammary carcinogenesis indicate that PER2 is a target of selenium. In a similar development, selenium administrations at 100 micrograms/kg and 150 micrograms/kg increased the PER1 expression in the ovaries of female rats exposed to photic stress via prolonged lighting period [15, 42, 43].

Melatonin has been used to treat sleep disorders for years as a chronobiotic. That selenium, a naturally occurring element, present in plant and animal foods can increase melatonin is quite remarkable and may reduce abusive use of melatonin for sleep induction. Evidence of its tendency to alleviate and mitigate circadian disruptions and reproductive derangements in animal studies [28, 44] is also thrilling. However, more studies are required to prove the level of safety associated with the use and prolonged use of selenium in human beings.

8. Conclusion

The review has highlighted biorhythmic effects of photic stress and the chronobiological roles of selenium.