Abstract
Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.
Introduction
Since the development of the incandescent bulb by Thomas Alva Edison during the second half of the 19th century, light technology has experienced an accelerated advancement towards more energy-efficient technologies, such as the modern light-emitting diodes (LEDs). These improvements in light technology have led to a significant increase in illumination for both indoor and outdoor lighting, particularly during the night period. Accordingly, artificial light-at-night (ALAN) has become a defining feature of our modern lifestyle; it has also been increasingly recognized as a novel source of pollution and environmental risk factor for human health risks, including obesity and breast cancer [1]. The negative impacts of ALAN are mediated by disrupting the endogenous circadian clock, which is responsible for anticipating and tracking environmental temporal changes and accordingly regulates behavioral and physiological responses to meet environmental challenges [2]. At the cellular level, the mammalian circadian regulation is driven by a complex machinery of gene and protein crosstalk, through negative and positive transcription and translation feedback loops [3]. The circadian system is most sensitive to short wavelengths, such as the blue light (dominant at daytime) emitted from the LED lighting at nighttime [4]. Following modernization, humans have interrupted the natural light–dark cycle (the most reliable cue for entraining the biological clock) by introducing ALAN of short wavelengths, which is increasingly suggested as a possible public health problem [1], [5].
In the current paper, we first review the molecular machinery of the biological clock, which is responsible for generating circadian rhythms, and how ALAN interacts with the core machinery to disrupt these rhythms. Thereafter, we consider the association between ALAN and both obesity and cancer by discussing a possible epigenetic mechanism for mediating the adverse effects of the environmental exposure. Finally, biomarkers for obesity and cancer are suggested as a novel tool for monitoring and detecting the ALAN-induced adverse effects at the early stages in order to prevent and improve survival, particularly in hormone-dependent cancer cases.
Circadian regulation
Biological rhythms are perfectly orchestrated by environmental cues (e.g. photoperiod) to enhance survival, especially during environmental challenges [6], [7]. They also play a significant role in body homeostasis and in the temporal organization of biological responses with the changing environmental conditions [8], [9]. Photo-entrainment is a nonvisual photo-response mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) that contain the photopigment melanopsin [10]. The photoperiod signal is detected by ipRGCs and is propagated to the circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) through the retino hypothalamic tract. Consequently, the SCN invigorates the synthesis and release of melatonin (MLT) from the pineal gland during the night, to the systemic circulation primarily under dark conditions. Hence, MLT is expected to be a major component of the mechanism of action, by which the circadian clocks regulate daily and seasonal rhythms in a wide array of biological functions, including energy homeostasis [6], [11], [12].
The circadian output of the clock is defined by a network of feedback loop interactions (Figure 1) between clock genes and their protein products [13], [14]. Overall, the core of this network consists of three period genes in the mouse (Per1, Per2, and Per3) and two cyrptochrome Cry1 and Cry2, which are activated at the onset of the circadian day by a positive transcriptional feedback loop. The loop, which originates from heterodimer complexes, contains the following proteins: Circadian Locomotor Output Kaput (CLOCK), the Neuronal PAS Domain Protein 2 (NPAS2), and Brain and Muscle Arnt-like Protein 1 (BMAL1). BMAL1 hetero-dimerizes with either CLOCK or NPAS2 and acts by enhancing E-box sequences to activate the transcription of Per1, Per2, Per3, Cry1, and Cry2 [3], [15]. The day activation of Per and Cry families is terminated at the onset of the circadian night by a negative translation feedback loop comprised of their protein products PER and CRY, which conjugate heteromeric complexes to block the CLOCK/NPAS2:BMAL1-induced transcription activation at the nucleus level. Subsequently, the available PER and CRY are gradually phosphorylated by casein kinase 1-epsilon and delta, disintegrated, and completely removed from the nucleus at the end of the circadian night, thus allowing a new cycle to be regenerated [16], [17].
Simplified molecular model of the mammalian circadian clock.
Negative (−) and positive (+) transcription-translation feedback loops set the circadian rhythmicity. At the core clock (solid arrows), the transcription factors BMAL1 and CLOCK form the heterodimer to regulate their own transcription and those of other clock genes (e.g. Per and Cry families) by binding to clock E-box elements. The nuclear receptors, Rev-erb-α/β and Ror-α/β, form auxiliary (dashed arrows) feedback loops to inhibit and activate the transcription of transcription of Bmal1 and clock, respectively. Generally, these positive and negative feedback loops are synchronized by the light–dark cycle and are directly involved in the regulation of clock-controlled genes (Ccgs) that generate a wide array of circadian biological rhythms. Casein kinase 1 epsilon and delta (CK1-ε/δ) phosphorylates CRYs and PERs and finally leads to their degradation.
These primary feedback loops are supported by secondary feedback arrays involving other protein complexes, which interact with the core feedback loops at different sites of action [18], [19]. The most common secondary feedback loops involve the action of the nuclear receptors, Rev-erbα and Rorα/β, which induce the activation and inhibition of the transcription of Clock and Bmal1, respectively, by their crosstalk with the retinoid-related orphan receptors [20], [21]. The post-interactions are suggested to play an important fine-tuning role in mediating reciprocated signals between the circadian clock components and physiological responses, particularly metabolism and energy balance at the cellular levels [22]. Although the SCN is the master circadian clock, the circadian feedback loop interactions are omnipresent in eventually all cells in peripheral tissues, including the heart, spleen, lung, liver, endocrine glands, and others [23], [24]. The peripheral oscillators present a very similar molecular machinery like that of the SCN, although this is regulated in a different manner compared with the central oscillator. Peripheral oscillators are not directly entrained by light signals like the SCN and present delayed circadian responses compared with those detected in the SCN, indicating that the peripheral oscillators are modulated by central signals originating from the SCN [25], [26], [27]. Together, the central and peripheral oscillators crosstalk and eventually regulate the circadian expression of genes involved in a broad spectrum of physiological responses, such as metabolic, endocrine, and immune functions [28], [29], [30].
Circadian disruption
A significant disruption of the normal entrained circadian rhythms, also called circadian disruption, is a direct consequence of our modern lifestyle, such as prolonged nocturnal activity with excessive ALAN exposure, long-term and frequent shift work, sleep deprivation (activities known as 24/7 days), and flights across different time zones [31]. Circadian disruption is persistently associated with several pathological consequences, including sleep-wake disorders [32], psychiatric disorders [33], cardiovascular diseases [34], immunological disorders [35], metabolic disorders [36], obesity [37], and cancer progression [38]. Nearly a decade ago, the International Agency for Research on Cancer of the World Health Organization (WHO) stated that shift work, which involves circadian disruption is “probably carcinogenic to human” [39]. More recently, the adverse potential of circadian disruption on human health has been anchored in a resolution passed by the American Medical Association (AMA), which states that ALAN is a source of pollution that interrupts both normal sleep patterns and daily rhythms in humans [40]. ALAN, as the most prominent circadian disruptor, vigorously ceases pineal MLT synthesis and secretion and consequently disrupts circadian rhythms [31], [41]. The melanopsin-containing ipRGCs, which regulate the pineal MLT synthesis via the SCN, are extremely sensitive to short wavelength light exposure even at low irradiance [42] and for a short period [43] as they can suppress the synthesis of the pineal hormone MLT. The spectral sensitivity of MLT synthesis suppression demonstrates wavelength-dependent sensitivity with robust effects in response to short wavelength (450–500 nm) exposure [44], [45]. Accordingly, a comprehensive study on the effect of various artificial lights on MLT suppression revealed that 4000 K and 5000 K LED lights were the most effective in the suppression of the hormone compared with counterpart technologies, such as incandescent, halogen, and florescent lightening systems [46]. Furthermore, a different study demonstrated an inverse association between MLT synthesis and the irradiances of narrowband blue LED exposure (peak λ=469 nm; ½ peak bandwidth=26 nm), and the impact of this spectrum was evidently larger than that of 4000 K of white florescent at twice the energy of the former [44], [47]. Finally, the negative effects of circadian disruption on public health are expected to be exacerbated by the increasing exposure to ALAN of LED illumination emitted from variant sources, including electronic screens used by people of all ages, particularly adolescents [48]. ALAN-induced circadian disruption has been related to several health risks, including overweight, obesity, and cancer [49], [50].
Epigenetic
Epigenetic modifications regulate heritable changes without any alteration in the sequence of the DNA nucleic acids. In differentiated cells, different mechanisms of epigenetic regulation exist, including histone remodeling and DNA methylation [51]. One of the most described histone modifications in terms of post-transcriptional promotion of genes expression is the acetylation of lysine of H3 and H4 N-terminal tail domains [52]. H3 acetylation at lysine 4 activates gene expression by chromatin opening, consequently making the gene more accessible to DNA-binding transcriptional factors [53]. On the contrary, H3 histone heterochromatin protein 1 methylation at lysine 9 silences gene expression by tightening the DNA warp around the histone, thereby blocking the accessibility of the gene to transcriptional factors [54]. In mammalian cells, DNA methylation is the major epigenetic modification for regulating DNA transcription to RNA, thus controlling gene expression [55]. DNA methylation involves the conversion of cytosine nucleotide to 5-methylcytosine by the attachment of a methyl group to the C5 position of cytosine bases that occur next to guanine bases, referred to as CpG sites [56]. Typically, DNA methylation within the promotor CpG sites involves transcriptional gene silencing and consequently decreased RNA synthesis by blocking both gene accessibility to both transcriptional factors and RNA polymerase [57], [58]. DNA methylation is regulated by DNA methyltransferases (DNMTs), which are a family of enzymes that regulate all types of methylation. The mammalian cells express three types of DNMTs that differ in their activity with regards to methylation status during the cell lifespan [59]. The methyltransferases DNMT3a and DNMT3b are generally responsible for setting the patterns of methylation in the cells by regulating de novo DNA methylation, whereas the activity of DNMT1 is generally related to the maintenance of the de novo methylation patterns during DNA replication [60].
DNA methylation can occur in mammalian cells in response to a wide array of environmental factors and may represent an adaptive significance to the organism in relation to environmental challenges [61]. Conversely, epigenetic modifications, such as DNA methylation and histone protein remodeling, have been reported to be involved in the generation of several pathological alterations, including obesity [62] and cancer morbidity [63].
Circadian clock and metabolism
Currently, it is becoming clear that energy homeostasis and distinct metabolic responses are the outcomes of several integrated circadian signals [49], [64], [65]. Indeed, chronobiological studies have shown that several metabolic enzymes regulating variant metabolic processes are under circadian control [66], [67]. Peripheral circadian oscillators have been demonstrated in both white and brown adipose tissues that play a prominent role in energy conservation and adaptive metabolic responses [68], [69], [70]. Additionally, normal satiety hormone levels, such as leptin [71], ghrelin [72], insulin [73], and glucagon [74], tend to exhibit circadian oscillation. Finally, functional connections between core clock genes and metabolic processes are increasingly being characterized using mutant mice. The Per2 mutant mice exhibited severe obesity when offered a high fat diet [75]. The Clock knockout mice show significant metabolic abnormalities, such as mitigated feeding rhythms, increased appetite, obesity, hyperglycemia, and others [66]. Additionally, in Clock-deficient mice, significant increases in food intake, body mass, and body fat percentage was measured compared with counterpart normal mice [76]. Loss function of the clock gene Bmal1 affects daily rhythms of glucose and triglyceride levels in mice [77]. Nonetheless, other clock gene mutant mice (e.g. Bmal1 and mPer2) were reported to not becoming obese [78].
Meanwhile, transcriptional regulation of rate limiting-steps in energy homeostasis is a prominent factor controlling oscillated metabolic responses [79]. The conspicuous metabolic enzyme hepatic 3-hydroxy-3-methylglutarul CoA reductase (rate controlling-factor for cholesterol biosynthesis), exhibit robust diurnal variations with higher levels during the night [80]. The expression of glycogen synthase 2 (rate limiting-enzyme for glycogenesis) in the liver is under circadian control [81]. The transcriptional activation of glycogen synthase 2 is regulated by CLOCK through binding to E-box elements [82]. Moreover, the rhythmic expression of nicotinamide phosphoribosyltranferase, which regulates a significant limiting-step in the nicotinamide adenine dinucleotide (NAD+) salvage pathway (involved in oxidation-reduction reactions), is controlled by the transcriptional factors CLOCK:BMAl1 [83]. Consistently, Clock- and Bmal1-mutant mice exhibit no obvious rhythmic oscillation in the expression of Nicotinamide phosphoribosyltransferase [84]. The clock transcription components are closely involved in the regulation of several nuclear receptors, such as Retinoic acid-related orphan receptor α and Peroxisome proliferator-activated receptor [85]. These receptors are directly involved in a wide array of metabolic pathways, such as lipid, glucagon, and cholesterol metabolism [86]. Finally, the transcriptional circadian factors can interact with certain nutrient sensors that reliably reflect the cellular energetic status, such as Sirtuin 1 and Adenosine monophosphate-activated protein kinase [86], [87]. These sensors can interact jointly or independently with key clock transcriptional factors, such as CLOCK, BMAL1, and CRY1, to modulate distinct metabolic processes, including gluconeogenesis, mitochondrial biogenesis, glycogen and fatty acid metabolism, steroid synthesis, and others [86].
LAN and circadian disruption of metabolic responses
Urbanization has resulted in immense increase in the abundance of both indoor and outdoor ALAN, causing a serious light pollution that leads to adverse consequences for human health and the environment [88]. In laboratory and non-laboratory rodents, ALAN treatment has been consistently demonstrated to be associated with metabolic disorders. ALAN treatments result in a significant reduction in daily energy expenditure and body mass of social voles (Microtus socialis) and laboratory rats [89], [90]. In another mice experiment, circadian disruption by dim florescent ALAN has been reported to change feeding behavior and increased mass gain [91], [92]. This contrasting effect of ALAN on body mass could be at least partially explained by the different light intensity levels used in the comparative studies; where the direction of body mass change can be directly related to light intensity levels. Furthermore, ALAN exposure disrupts circadian clock function in the pancreatic islet, causing glucose-unresponsive insulin secretion in rats [93]. Human studies also support the association between circadian disruption and metabolic diseases. Circadian disruption by shift work is strongly associated with risk of obesity, type 2 diabetes, high blood levels of glucose and triglycerides, high blood pressure, and coronary artery disease [66], [78].
Generally, the organization of energy homeostasis expresses the relations between energy intake and energy expenditure [94]. Several human and non-human studies have demonstrated that energy intake and energy expenditure are modulated at the molecular, physiological, and behavioral levels by the SCN [78], [95], [96]. The dysregulation of the circadian transcriptional factors by environment cues, such as ALAN, could compromise daily rhythms in energy intake and energy expenditure, thus causing metabolic disorders. Indeed, a direct link between core molecular clock and energy expenditure has been established. Per2, Cry1, and Cry2 mutant mice fed with a high fat diet showed higher energy expenditure compared with wild-type mice [69]. Consistently, blocking the nuclear receptors REV-ERB-α and REV-ERB-β by synthetic agonists increases energy expenditure in mice [97].
The metabolic effects of ALAN exposure, including night shift work, are mediated by the suppression of nocturnal pineal MLT production [98], [99]. ALAN exposure prompts circadian disruption and resulted in metabolic disorders and tumor development in mice and rats, and oral MLT administration rectified the ALAN-induced adverse effects [100; Figure 2]. MLT regulates multiple clock gene expression in peripheral oscillators, such as the mouse pituitary pars tuberalis via its mt1 receptor [101], [102]. These studies demonstrated that the transcriptional factors PER1, CRY1, CLOCK, and BMAL1 are downregulated in mt1 knockout mice. Similar MLT-dependent expression sensitivity of clock genes in the SCN and pars tuberalis has also been suggested in the diurnal Soya sheep, Ovis aries [103], [104]. In animal models, MLT modifies circulating levels of insulin [105], leptin [106], ghrelin, and peptide YY [107]. In patients with chronic nonalcoholic liver disease, a significant increase in plasma levels of adiponectin, leptin, and ghrelin have been detected, in response to MLT treatment [108]. MLT can also exert its effects on metabolic processes throughout epigenetic modifications [109].
Schematic representation of the connections between the circadian clock and both metabolism and cancer development in mammals under normal (gray boxes) and ALAN exposure (black boxes).
ALAN short wavelength exposure is conveyed to the circadian clock at the SCN by intrinsically photosensitive retinal ganglion cells (ipRGCs). Abnormal epigenetic modifications are suggested to mediate the ALAN-induced metabolic and carcinogenic adverse effects, which might be rectified by melatonin treatment.
Epigenetic and metabolic disorder
The functional and molecular link between epigenetic modification and energy homeostasis has been established in the literature [110]. DNA methylation and histone modification are expected to play an influential regulatory role in diabetes and obesity development by silencing the transcription of genes associated with these metabolic disorders [111]. Obesity-related epigenetic modifications occurring throughout the adult lifespan could follow encoded blueprints in the chromatin during the embryonic early stages of development [112]. Accordingly, maternal genotype and maternal environmental exposures (e.g. smoking, alcohol, drugs, ALAN and others) can affect birth weight and set the foundation for epigenetic-related obesity risk and other metabolic disorders. Furthermore, silencing genes in obesity development can be predetermined by maternal or paternal [113] epigenetic-induced genomic imprinting. For example, birth mass can be affected by paternal imprinting of gene on chromosome 11 and chromosome 6q [114]. Likewise, the development of obesity can be associated with maternal imprinting of the Gsα gene, which encodes α subunit of the Gs-protein [115].
The clock machinery comprises distinct circadian histone remodeling at the promoters of active clock genes that are regulated via clock transcriptional factors, such as CLOCK and BMAL1. The putative epigenetic control of these transcriptional factors has been suggested to interact with certain metabolic indicators, particularly Sirtuin 1, which is a key regulator of energy homeostasis [83], [116]. Sirtuin 1 is a mammalian enzyme that deacetylates histone in response to NAD+/NADH ratios, which reflect the cell metabolic status [117]. Sirtuin 1 interacts with CLOCK and BMAL1 to regulate rhythmic acetylation at the promoters of clock-associated genes in mouse liver [118] as well as to deacetylate and degrade PER2 [119]. Furthermore, Significant association between methylation levels at the CpG sites of CLOCK, BMAL1, and PER2 clock genes and obesity risk has been reported in women during the mass reduction program [120].
Circadian clock and breast cancer
The circadian clock plays a pivotal role in homeostasis maintenance, and the association between circadian-disruption with homeostasis pathologies, such as cancer, is well-established [2], [121]. The core clock genes are intimately involved in controlling diverse carcinogenic activities in cancer cells, including proliferation, apoptosis, metastatic capability, and regulation of tumor-related genes [122], [123]. Accelerated tumor development in response to circadian disruption and clock gene deregulation has been recorded. Transcription upregulation of Per1 and Per2 blocks breast-cancer cell proliferation [124] probably by induced cell apoptosis [125]. Per2 has been demonstrated to be a tumor suppressor gene in MCF-7 breast cancer epithelial cells [126] by linking the Estrogen-receptor-α (ER-α) to the circadian system regulating its degradation [127]. Single nucleotide polymorphism in the core clock genes BMAL1 and CLOCK has been suggested to be associated with high risk of breast cancer among night work-shift Norwegian nurses [128].
In vitro knocking down the gene CLOCK increases the expression of a network of cancer-related genes and decreases the activity of several tumor suppressor genes related to breast cancer [129]. In the same study, researchers also noted lower expression levels of the CLOCK gene in women free from breast cancer. Conversely, CRY2 shows lower expression levels in breast cancer cells compared with the counterpart normal cells [130]. A positive correlation between expression level of core clock genes and breast cancer risk has been reported for the gene TIMLESS in peripheral blood lymphocytes of 80 breast cancer women compared with age-matched tumor-free equal cases [131]. Researchers have also discovered a significant association between number of successive night shifts and risk of breast cancer in women who have worked night shifts with single nucleotide polymorphism in the gene BMAL1 and related orphan receptor β (ROR-β), r [128]. The association between high risk of breast cancer and single nucleotide polymorphism in other core clock genes, such as BMAL2 and PER3 has been reported [128]. The overexpression of most core clock-genes, such as PER1, PER2, PER3, CLOCK, and CRY2, has been associated with significant lower metastasis formation and longer survival rates [132]. An in vitro inhibition of the circadian transcription product cryptochrome (CRY) by synthetic product, referred to as KS15, inhibited cell proliferation and increased the sensitivity to anti-cancer drug in breast cancer cells [133]. This result suggests the important role of the clock gene CRY in breast cancer development, whereas the overexpression of this gene inhibits the growth of breast cancer cells. In Chinese women, different mutations at the core clock genes contribute differently to the level of breast cancer risk [134].
Circadian disruption and breast cancer
Breast cancer is the most prevalent malignancy among western women and has been increasingly being associated with circadian disruption provoked by shift work, jetlag, sleep deprivation, and ALAN exposures [48], [135], [136], [137]. ALAN exposure as a prevailing feature of our modern 24/7 (h/days) active society is recognized as the most powerful factor, behind circadian disruption [138–140; Figure 2]. The evidence for a causal and direct association between ALAN-induced circadian disruption and breast cancer development comes primarily from both epidemiological observations [141], [142], [143] and experimental studies [144], [145], [146].
A comprehensive meta-analysis, based on several chronobiological studies evaluating the effects of different types of circadian disruptions (e.g. shift work, sleep deprivation, and ALAN exposure) demonstrated a direct association between circadian disruption and breast cancer risk. This risk showed a dose-dependent increase with the number of years devoted to shift work, in which 16% risk increase is estimated for every 10 years of shift work [147]. Additionally, covering night shift work for 20 years or more has been shown to be notably associated with increased risk of ER-α-related breast cancer [148]. Positive correlation between ALAN intensity (using satellite images) with breast cancer incidences has been clearly demonstrated among Israeli women across 147 communities [149] and also worldwide with approximately 70% and 50% higher risk, respectively, of breast cancer incidences at the highest ALAN intensity compared with the lowest exposure [150]. Furthermore, several observational studies have demonstrated a plausible association between bedroom chronic exposure to moderate levels of ALAN and increased breast cancer prevalence [151], [152], [153]. A high risk for developing breast cancer relates not only to indoor levels of ALAN, but also to outdoor levels [142]. In a recent case-control study of 93 cases and 185 controls comprising Israeli women matched by age and residential area, high risk of breast cancer has been found to be linked with substantial exposure to ALAN from outdoor illumination, whereas reduced risk has been detected among women exposed to moderate bedroom ALAN without noteworthy external exposures [154]. Finally, several studies that have assessed the relation between breast cancer risk and the degree of visual impairment suggest an inverse dose-dependent relation between the two variables, with significant decrease in breast cancer risk among completely blind women [155], [156], [157].
The experimental evidence on the effect of ALAN exposure on cancer development in animal models suggest a significant association between the light exposure and breast cancer development. In nude rats, accelerated growth of MCF-7 human breast cancer xenografts has been noted in response to constant ALAN exposure compared with the counterpart rats kept under normal alternating light–dark cycle [144], [158]. In support of this finding, ALAN exposure as low as 0.2 lux has been demonstrated to be sufficient to induce tumor growth and increase tumor lipid uptake and metabolism [159]. In female Balb/c mice 4T1 mammary carcinoma model, tumor growth clearly accelerated in response to 1X30 min/day ALAN exposure (white fluorescent, 450 Lux, 469 nm) for 21 days compared with mice maintained under the same conditions, but without ALAN [145]. ALAN affected 4T1 tumor growth in a wavelength-dependent manner. Mice exposed to blue LED (λDominant=460 nm, 350 Lux) ALAN exposure showed higher tumor growth rates and promoted lung metastasis formation compared with incandescent (λDominant=580 nm) ALAN-exposed mice at the same intensity level. Furthermore, the tumor-free interval duration, from cell inoculation to the appearance of measurable tumors, was only 3 days for LED ALAN-treated mice, compared with the 5 days in ALAN incandescent counterpart group [160]. Most of the epidemiological and experimental data provide a well-established association between circadian disruption by shift work, ALAN, and breast cancer risk. However, some other studies failed to establish a clear association [161]. This case-control study evaluated the association between variant night shift factor and breast cancer incidences in Western Australia using a self-administered questionnaire and telephone interview to obtain details about demography, lifestyle, occupational history, and shift work factors, including ALAN, phase shift, and sleep duration [161]. In this study, night shift has been found to be associated with a small but statistically significant increase risk for breast cancer, but the association with other shift work factors, such as duration of exposure to ALAN and sleep disturbance, showed inconsistent results.
Epigenetic and breast cancer
In recent years, the connection between epigenetic modifications with cancer progression has been extensively studied, particularly in breast cancer. In normal cells, the promoter region of tumor-suppressive genes generally show un-methylated CpG sites, whereas the transcriptional silencing of these genes by abnormal hyper-methylation is a common feature in cancer cells [162]. Hyper-methylation has been reported in several genes in breast cancer, including BRC1, the most commonly investigated human gene in relation to breast cancer progression [163], [164]. BRC1 promoter methylation in free peripheral blood DNA has been associated with a 3.5-fold increased risk of early developing breast cancer [165]. Hyper-methylation has also been reported at CpG promoter sites in other tumor suppressor genes (e.g. CDKN2A and PTEN) that are associated with breast cancer development [166]. Generally, these tumor suppressor genes are involved in different carcinogenic-related processes, such as cell cycle regulation, DNA repair, hormone/receptor-mediated signaling pathways (ER-α), cell apoptosis, and metastasis formation [167].
In long-term shift work, DNA samples extracted from whole blood of 117 Danish women showed an extinctive GDM modification in several genes including onco-related genes, at more than 5000 CpG sites [168]. The genome of breast cancer cells is typically characterized by global hypo-methylation, and this assumption is supported by results of a meta-analysis study, in which breast cancer risk has been found to be significantly higher for women with the lowest GDM compared with the counterpart group with the highest GDM levels [169]. Global hypo-methylation in white blood cells has also been reported to be related with increased risk of breast cancer [170], [171]. Global DNA hypo-methylation can promote breast cancer development via several signaling pathways, including triggering genomic instability, activation of oncogenes, and inducing metastasis formations [172], [173]. Furthermore, GDM levels revealed positive correlation with carcinogenic clinical characteristics including, stage of the cancer, tumor growth rates, and high grade [160], [174], [175].
Epigenetic modifications in core clock genes are linked with carcinogenic activity [176]. The hypo-methylation of promoters and hyper-methylation of the core clock genes, CLOCK and CRY2, are expected to be associated with several breast cancer types [129], [130]. The transcriptional deregulation of the clock genes PER1, PER2, and PER3, by CpG site hyper-methylation at the promoter region has been suggested to be related to breast cancer development [177], [178]. Recently, wide genome hypo-methylation in night shift workers has been demonstrated at CpG sites of several genes, including circadian core clock genes, such as PER3 [179].
ALAN, obesity, and cancer – the epigenetic nexus to melatonin
Melatonin and obesity
ALAN exposure, particularly of short wavelength (i.e. blue-white LED illumination) is a highly effective inhibitor of N-acetyltransferase, the rate-limiting enzyme in MLT synthesis, thus resulting in markedly lower MLT levels and increased human health risk [180; Figure 2]. In humans, ALAN-induced suppression of MLT is suggested to be associated with obesity development intermediated by reduced metabolic activity in brown adipose tissue (BAT) [181], [182]. BAT specializes in heat production, particularly in small rodents and infants, by uncoupling oxidative phosphorylation in mitochondria, mainly during cold exposure [183]. Until recently, BAT has been thought to fulfil marginal role in adult humans, but a new line of evidence support an important role for BAT in body mass regulation [184], [185]. MLT increases BAT activity, thus boosting energy expenditure and consequently decreasing body mass [186]. Both MLT receptors MT1 and MT2 are expressed in human brown and white adipose tissues, suggesting a regulatory metabolic role for the hormone in these tissues [187]. In rats, MLT treatment in the drinking water resulted in a significant decrease in body mass [188], [189]. A past study reported that abolishing the nocturnal MLT levels by pinealectomy tends to inhibit the short-day induced body mass loss in Siberian hamsters [190]. MLT treatment consistently reduced adiposity and body mass in several rodent species [182]. Several studies have demonstrated that chronic exposure to dim light at night increases body mas gain in mice, and this effect is suggested to be mediated by the ALAN-induced MLT suppression [91], [92], [191], [192]. Finally, MLT has been reported to influence several metabolic factors, such as insulin, insulin-like growth factor, growth hormone, glucose metabolism, and others, which could directly control body mass homeostasis [193].
MLT and cancer
The relationship between MLT and malignancy has been extensively studied in human and non-human models, showing an extraordinarily consistent oncostatic property of the pineal hormone. In premenopausal and postmenopausal women, urinary 6-sulfatoxymelatonin (6-SMT) levels, the major urinary metabolite of MLT [194], show an inverse relation with risk of breast cancer [195], [196]. Additionally, the inverse relationship between 6-SMT and breast cancer risk has been confirmed by other case-control studies in women [197]. In breast cancer patients, nocturnal 6-SMT levels were 48% lower compared with counterpart controls, and the metabolite levels significantly correlated negatively with tumor size [198]. An oral dose of MLT at 20 mg/day has been demonstrated to stabilize the disease progression and improve 1-year survival compared with patients treated with supportive care alone. Furthermore, MLT treatment improved the tumor response to chemotherapy and ameliorated the clinical side effect of the chemotherapy treatment [199]. In metastatic colorectal cancer, the efficiency of the chemotherapeutic drug irinotecan, enhanced by a concomitant nocturnal administration of MLT [200].
In mice inoculated with 4T1 breast cancer cells, ALAN exposure has been associated with the promotion of tumor growth compared with unexposed mice [145], [160]. In these recent studies, the addition of MLT to the drinking water blocked the accelerated tumor growth effects of ALAN. In rodent models of tumorigeneses, the metastasis formation of solid tumors increased in response to pinealectomy and induced-metastatic surgery effect, whereas pharmacological MLT administration reversed the formation [201]. In MCF-7 human breast-cancer cell lines, MLT administration reduced the tumor invasion potential [202], and in MCF-7 tumor-bearing mice, MLT lessened metastasis formation compared with counterpart untreated mice [203]. In rats bearing the estrogen receptor α positive (ERα+) human breast cancer, a concomitant administration of MLT and adriamycin has been shown to reduce tumor mass and increase both survival rates and life quality [204]. In Fibrosarcoma ascites and Ehrlich solid tumors, the effect of MLT administration on tumor growth rates, has been related to the time of the hormone administration, as stimulating and inhibiting effects have been detected in response to MLT injection in the morning and in the late afternoon, respectively [205]. Finally, MLT treatment suppressed the proliferation of ERα+ and ERα− human breast-cancer cell lines [206]. Two membrane G-protein associated coupled receptors, MT1 and MT2, are expressed across many tissues and cells in the body and have been found to mediate most of the oncostatic responses to MLT [207]. The MLT-induced oncostatic activities in ERα+ MCF-7 human breast-cancer cells are mediated mainly by the MT1 receptor, which is coupled with several G-proteins, including Gαi2, Gαi3, Gαq, and Gα11 [201].
At the molecular level, the involvement of MLT in tumorigenesis is mediated throughout several genes that are responsible for regulating variant cellular cancer-related activity, including apoptosis, cell cycle, cell proliferation, DNA repair, and tumor suppressor activity [208; Figure 2]. MLT can affect breast cancer cell development by blocking the linoleic acid uptake via MT1-induced cyclic adenosine monophosphate (cAMP) suppression; this promotes the downregulation of the mitogenic signaling molecule 13-hydroxyoctadecadienoic that is responsible for the activation of growth factor pathways that are essential for cells growth and survival [201]. MLT can modulate the expression patterns of different core clock genes and other circadian-related genes involved in cellular carcinogenic activities [209]. Finally, epigenetic modification is a promising molecular mechanism for metabolic and oncostatic action of MLT, in response to environmental exposure to polluting sources, such as ALAN. These reversible modifications are profoundly associated with the expression of several genes related with obesity development [112] and carcinogenic activity [210].
MLT and epigenetic modifications
Currently, there is converging evidence supporting the notion that MLT modulates energy metabolism breast cancer- and prostate cancer-related responses throug various epigenetic modifications, particularly protein histone acetylation and DNA methylation [109], [211]. MLT can modulate histone acetylation and DNA methylation [212] to regulate a wide range of several metabolic process, including energy expenditure, adiposity, insulin, and leptin levels as well as pancreatic β-cells glucose regulation [105], [213], [214], [215]. Recently, it has been demonstrated that MLT can stimulate epigenetic modification in the rat brain via histone hyper-acetylation [216], and that this effect is mediated by its mt1 receptor [217]. MLT can also regulate epigenetic modification by inhibiting DNA methyltransferase, thereby causing global DNA hypo-methylation [212].
MLT can influence carcinogenic activity through various mechanisms, including anti-proliferative activity, inhibiting synthesis of steroids, interacting with ERα to affect cellular actions of estrogen, modulating cancer-related gene expression, mediating apoptosis, blocking tumor metabolic processes, and anti-metastatic activity [206]. In vitro MLT-treated C17.2 neural stem cells, noticeably showed both increased mRNA expression of several histone deacetylase and histone h3 acetylation [217]. In MLT-treated MCF-7 cell lines, the induced increase in DNA methylation levels has been associated with the downregulation of the oncogenes EGR3 (early growth responsive gene 3) and POU4F2/Brn-3b; in comparison, the transcription levels of the tumor and metastasis suppressor gene glypican-3 (GPC-3) increased [218]. Furthermore, in estrogen-receptor-related breast cancer, MLT has been found to decrease expression levels of the aromatase gene (CYP19), which are responsible for the activity status of estrogens plausibly via methylation of the CYP19 gene or deacetylation of CYP19 histone at the promotor level [109]. Under both blue-LED and florescent ALAN exposures, Blab/c 4T1 breast-cancer cell tumor-inoculated female mice clearly demonstrated decreased GDM levels and increased tumor growth rates, and both were reversed by the addition of MLT to the drinking water during nighttime [145], [160]. Overall, these findings suggest that MLT can induce epigenetic modifications of several metabolic- and carcinogenic-related genes, subsequently rendering them active or inactive by histone acetylation or DNA methylation.
Figure 3 proposes a signaling pathway for ALAN-induced metabolic and carcinogenic syndromes. ALAN exposure, particularly short-wavelength exposure, has been detected by iPRGCs and thereafter the exposure signal has been conveyed to the SCN. As a result, pineal MLT production is suppressed and global DNA hypo-methylation developed in several genes in response to decreased DNMTs activity. The aberrant methylation in these genes, including core clock genes, can advance their silencing or activation, and thus prompt metabolic and carcinogenic syndromes. Supportively, a recent review of the signaling pathway linking between the ALAN-induced MLT suppression and breast cancer progression in human and non-human models, has implied the occurrence of epigenetic modifications, particularly GDM as a potential molecular mechanism linking environmental exposures (e.g. ALAN) and adverse health outcomes [219]. According to this review, MLT levels are regulated by ipRGCs, which control the inhibition of the pineal hormone in response to short wavelength ALAN and consequently advance tumorigenesis mediated by epigenetic modification, such as DNA methylation. Considering the suggested association between obesity and the development of variant cancers [220], the suggested nexus between ALAN, MLT suppression, epigenetic modifications, and adverse health consequences [219] is of significant clinical importance.
ALAN signaling pathway.
ALAN exposure of short wavelength (SW) are detected by intrinsically photosensitive retinal ganglion cells that transfer the signal to the SCN and the pineal MLT levels decrease rapidly. Consequently, the activity of DNA methyltransferases (DNMTs) is inhibited, and global DNA hypomethylation occurs in several genes that control metabolic and carcinogenic activities, including core clock genes. A direct signaling of MLT to the cells is also plausible.
Circadian disruption biomarkers in obesity and cancer research
The most important step in the diagnosis of circadian disruption is to establish the daily rhythm of MLT levels. Generally, the indole hormone rhythm is highly sensitive to every type of circadian disruption, including sleep disorder, jetlag, shift work, and most important ALAN [48], [137]. MLT levels, measured as 6-SMT, have been found to be significantly reduced in night shift workers compared with counterpart day workers, and the effect correlates positively with the intensity of ALAN and the number of nights worked [221]. Changing the sleep-wake cycle and ALAN resulted in phase advance of the MLT rhythm, which also reduced the circadian amplitude of the hormone in healthy men [222]. MLT suppression by ALAN has a dose-dependent response to both irradiance level and duration of the exposure [223]. Furthermore, the phase advance and suppression in MLT rhythms are intimately wavelength-dependent with more manifested effect at short wavelengths compared with long wavelengths [44], [45], [224]. Finally, the ALAN-induced MLT suppression is not age-related [225]. MLT levels can be directly determined virtually in all body fluids, including blood, saliva, and urine, using straightforward non-invasive methods. The most pervasive protocols for determination of MLT in blood, urine, and saliva are radioimmunoassay and enzyme-linked immunoassay [194]. The major MLT metabolite in urine, 6-SMT, reliable reflects pineal MLT secretion in human and the metabolite circadian rhythm can faithfully constitute a clinical diagnosis of circadian disruption-related disorders [226].
In the last few years, epigenetic modifications have been the focus of intensive research effort due to their potential application as biomarkers for various health disorders, including obesity and cancer [227]. DNA methylation is a significant candidate for biomarker development, because the methylated CpG sites present high stability compared with high mutation variability in any given type of cancer [228]. DNA hyper-methylation can silence genes that are profoundly involved in the secretion of insulin and glucagon [229]. Patients with type 2 diabetes express altered GDM in skeletal muscles, adipose tissue, and pancreatic islets [230]. DNA methylation of one CpG site at the promotor glocagone-like-peptide-1 (GLP1R) receptor gene decreases the transcription levels of GLP1R and correlated positively with the body mass index [231]. Increased methylation at the promoter within the tumor necrosis factor-α (TNF-α) cytokine shows direct correlation with expression level and body mass lose [232]. Additionally, higher DNA methylation at the promoter of the adrenoreceptor-β-3 gene, which encodes protein belonging to the β-adrenergic receptor family and expressed mainly in adipose tissues, are associated with obesity and other related disorders [233]. In obese children, DNA methylation levels at two CpG sites within the promoter of the Fas apoptotic inhibitory molecule 2 gene are clearly associated with obesity [234].
Likewise, abnormalities in epigenetic activity are expected to be evident long before the cancer becomes asymptomatic and impose fatal health risk [235]. Therefore, epigenetic modifications, particularly DNA methylation levels, are of great clinical importance as a non-invasive tool for early detection and staging of cancer. BRC1 promoter methylation is closely associated with increased risk for early development of breast cancer [165]. In invasive ductal carcinoma, the gene GHSR (Growth hormone secretagogue receptor), a member of the G-protein coupled receptor family, which binds to gherlin to regulate energy homeostasis and body mass, exhibited higher methylation levels compared with adjacent normal tissues [236]. Few years ago, a genome-wide methylated study demonstrated MCF-7 breast-cancer cell lines that are characterized by both extensive global DNA hypo-methylation and more clustered hyper-methylation at CpG-rich specific loci [237]. In breast cancer, aberrant global methylation is associated with genomic instability and increased activity of oncogenes [238], whereas hyper methylation at promoter CpG sites advance chromatin closing and further silencing of tumor suppressor genes, cell proliferation, and tumor development [167]. Furthermore, promoter hyper-methylation of breast cancer oncogenes tends to inhibit growth regulatory genes, resulting in irregular cell division, whereas global DNA hypo-methylation can stimulate the expression of metastatic genes that are required for cancer cells dissemination [239]. Recently, a whole genome methylation analysis on cell free circulating DNA detected seven novel markers presenting frequent and high levels of methylation in both ER-positive and ER-negative cancer samples compared with low levels in counterpart normal samples [240]. These markers included AKR2B2, COL6A2, GPX7, HIST1H3C, HOXB4, RASGRF2, and TM6SF1, for which the specificity and sensitivity of the screening analysis has been found to be ~96%. We can use these novel markers as a predictive and monitoring tool in order to assess the efficiency of treatment response. In another research that studied DNA methylation in circulating free DNA, clear hyper-methylation has been demonstrated in the promoter of the tumor suppressor genes ITIH5, DKK3, and RASSF1A, with high sensitivity (50%–100%) to discriminate cancer patients from healthy and benign controls [241]. The methylation levels at the promotor of the tumor suppressor genes BCAP31 and OGG1 have been found to be inversely associated with survival rates and prognosis in breast cancer patients [242]. Finally, the association between promoter hyper-methylation of tumor suppressor genes and breast cancer development has also been demonstrated in other studies [243], [244].
Concluding remarks
Light pollution has become a defining feature of human lifestyle mainly in urban areas. ALAN and rotating shift work are increasingly becoming major sources of circadian disruption that subsequently cause serious health threats as well as ecological impacts. Currently, metabolic syndrome, diabetes, obesity, and cancer have been experimentally and observationally associated with the misregulation of the transcriptional-translational feedback loops of the mammalian clock components. MLT is a leading candidate for mediating the putative ALAN-induced circadian disruption at the molecular, hormonal, and epigenetic levels. Therefore, MLT serves as an operational biomarker for circadian disruption and a promising chronobiotic drug target for circadian disruption-related diseases [245]. Enhancement of the circadian amplitude by pharmalogical agents, such as Nobiletin, has been found to ameliorate circadian disruption-related syndromes, such as obesity and metabolic disorders [246]. The Nobiletin signal transduction is suggested to be directly mediated by retinoid, which is an acid receptor related-orphan receptor that modulates core circadian clock genes, thus enhancing the circadian amplitude to moderate the pathological consequences of disruption of the circadian rhythms. Accordingly, MLT and other proven chronobiotic compounds can be utilized to rectify circadian disruption and other related diseases, particularly cancer, obesity, and metabolic disorders.
Aberrant epigenetic modifications are increasingly being associated with both obesity and cancer development. These reversible modifications can be developed at early embryonic stages and can even continue to present during later life. Furthermore, epigenetic modifications can provide a simple and non-invasive monitoring tool for circadian disruption, which can lead to the development of public health risks. In breast cancer, improving survival rates by diagnosis at early stages seems possible, as the rates are not encouraging after metastasis formation [247]. Consequently, the early detection of metabolic disorders and breast cancer development induced by circadian disruption, particularly by ALAN, provide a promising opportunity for individuals of a risk group to control the disease development by simply changing their habitual lifestyles. Further studies are warranted to address other intervention measures to counteract circadian disruption-related health risks, such as developing environmentally friendly illumination, improving circadian adaptation in rotating shift workers, and developing chronobiotic drugs that can modulate the circadian clock and prevent circadian disruption-related diseases.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved its submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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