The circadian pacemaker is responsible for organizing the timing of the entire body, spanning multiple body systems [21–24]. Light is detected by photoreceptive ganglion cells (pRGCs) in the eye. A cluster of pRGCs form the retino-hypothalamic tract that projects to and entrains a group of neurons that make up the circadian oscillators in the suprachiasmatic nuclei (SCN) , which control melatonin synthesis in the pineal gland. Melatonin is an indole-amine that is found throughout the animal kingdom and orchestrates changes in many physiological functions in response to variation in day length (reviewed in ), and the nightly duration of melatonin is the critical parameter responsible for transducing the effects of light on both the neuroendocrine axis and directly on individual body systems . Exposure to extended periods of light alters melatonin levels in many species, including humans [28–31]. Thus, exposure to light at night could result in a variety of physiological effects, potentially mediated through varying levels of melatonin (Fig. 1). In addition, direct sympathetic control of physiological processes after variation in lighting conditions has been documented independently of melatonin synthesis . Consequently, exposure to extended periods of light could alter physiological state through a variety of other mechanisms.
Disruptions of normal circadian timing can evoke a multitude of downstream effects, reorganizing the entire physiological state. Constant lighting conditions alter the rhythmicity of several hormones including prolactin , glucocorticoids [33,34], adrenocorticotropic hormone, corticotrophin releasing factor , serotonin , and melatonin . Human exposure to a low-level incandescent bulb at night requires only 39 min to suppress melatonin levels to 50% . Such changes in melatonin production and release regulates metabolism, immune function, and endocrine balances via the reproductive, adrenal, and thyroid hormone axes . The ensuing effects of disrupted melatonin rhythms by chronic exposure to light at night are countless. In addition, the effects resulting from downstream consequences, such as sleeplessness, make the web of physiological changes resulting from constant light even wider. In the interest of space, the medical implications associated with sleep deprivation will not be considered in depth here. Recent work has largely focused on the potential link between exposure to artificial light at night and the prevalence of several cancers (see below). Such links, however, would likely result from a combination of upstream physiological effects originally triggered by the alteration of the circadian system, many of which could have drastic medical implications in addition to cancer. For example, melatonin and its metabolites have the ability to protect against oxidative stress and diseases resulting from oxidative attack (see below). Depression of melatonin could thus magnify the amount and results of oxidative damage. There is a need for a full understanding of the physiological and epidemiological impacts caused by increasing exposure to light at night through light pollution and shift work.
Efficient energy metabolism is crucial to overall physiological function. Interruptions or difficulties with the efficiency of metabolic processes can result in a variety of disorders, including obesity, type II diabetes, and heart disease. There is an abundance of evidence illustrating an effect of exposure to extended levels of artificial light both directly on metabolic processes, as well as on several of these epidemiological end-points.
Long-term exposure of rats to constant light had strong regulatory effects on metabolism, specifically on carbohydrate metabolism in the liver . Experiments on broiler chickens demonstrated that constant light shifts metabolic efficiency; female broiler chickens reared in a constant light environment gained a significantly higher percentage of fat compared with controls reared on a 12 L:12 D light cycle. Male broiler chickens also gained significantly more weight when exposed to constant light, but the mechanism behind this effect differed (i.e. food intake was higher in males reared in constant light) . Constant-light induced interruption in the nightly secretion of melatonin has also been shown to exert metabolic effects. Melatonin appears to affect body mass regulation, gut efficiency, metabolic rate, and nonshivering thermogenesis in some mammalian species (reviewed in ), and also improves ATP synthesis in the heart . Thus, the basic processes associated with acquisition and utilization of energy are functionally altered after exposure to extended periods of artificial lighting.
Several studies suggest that humans are experiencing similar effects in response to artificial light exposure at night. For example, detrimental effects of shift work have been observed in carbohydrate and lipid metabolism, insulin resistance, hypertension, coronary heart disease, and myocardial infarction (reviewed in ). Such influences could result from either direct physiological effects of light exposure or indirect effects associated with a lack of sleep . Sleep deprivation significantly alters endocrine and metabolic parameters associated with diabetes, obesity, and a cascade of other disorders . On the other hand, melatonin levels, which reflect changes in light environment more directly, have been associated with coronary heart disease. For example, in a correlative study, patients with coronary heart disease had significantly lower melatonin concentrations at night compared with patients without heart disease . Melatonin reduces the activity of the sympathetic nervous system and significantly reduces norepinephrine turnover in the heart, a potentially beneficial effect because norepinephrine and epinephrine accelerate the uptake of LDL cholesterol . Because exposure to extended periods of low-level artificial night-time lighting decrease melatonin production in rodents [28,45] and humans (reviewed in ), the potential for a direct link between exposure to night-time light and metabolic disorders, such as heart disease, become clear. It remains to be determined the extent to which metabolic disorders reflect direct effects of light on circadian organizations or down-stream processes such as sleep disruption.
Light exposure can also have indirect adverse effects through the promotion of oxidative stress, which can lead to a variety of other disorders, including damage to immune cells and other tissues in the body, elevated incidence of cancer, and an increase in the rate of physiological aging . Exposure of living organisms to light and oxygen results in the production of toxic molecules, reactive oxygen species, and photo-oxidants (reviewed in ). For example, rats maintained in constant light significantly increased lipid peroxidation in the liver, kidney, and brain . Similarly, rats exposed to constant light significantly elevate levels of hepatic oxidative stress . Oxidative stress is combated through numerous physiological mechanisms responsible for maintaining an oxidant:antioxidant balance within the body. Melatonin is a well-known antioxidant, playing a significant role in antioxidant defense and regulating antioxidant enzyme activity and production (reviewed in ). In humans, melatonin levels correlate with total antioxidant capacity of the blood . Constant light reduces both melatonin levels and pineal weights to a minimum  and the pro-oxidative effects of constant light were preventable through simultaneous administration of melatonin . Activity of glutathione peroxidase, an important antioxidant enzyme, decreased in rats maintained in constant light . Similarly, constant light exposure reduces glutathione levels , suggesting a decrease in glutathione production as well. It is likely that suppression of melatonin in response to constant light exposure may at least partially mediate the regulation of glutathione peroxidase activity, as previous studies have shown that melatonin stimulates glutathione synthesis  and melatonin deficiency leads to decreased tissue glutathione peroxidase activity (discussed in ). Melatonin is unique in that the free radical scavenging capability extends to its secondary, tertiary, and quaternary metabolites, making it a highly effective antioxidant even at low concentrations (see  for review). Thus, decreased levels and durations of melatonin production resulting from exposure to constant lighting conditions may result in decrease in the level and duration of this potentially important antioxidant. Alternatively, influences of changing the light environment on oxidative stress could result from downstream consequences of resulting sleep deprivation as documented in the brains of rats . Considered together, these documented reductions in melatonin concentrations in humans exposed to night-time light suggest an elevated risk of oxidative stress and many related disorders after exposure to light pollution, shift work, or both.
Exposure of an individual to chronic artificial night-time lighting could alter immune function, through some combination of oxidative, neural, or endocrine pathways. Numerous examples across taxa are available. For example, housing Japanese quail (Coturnix coturnix japonica) in constant lighting conditions significantly suppressed both cell-mediated immune responses to a challenge with phytohemaggluttinin (PHA) and humoral responses to challenges with Chukar red blood cells (RBCs) . Similarly, cockerels maintained in constant lighting conditions produced significantly fewer antibodies to a challenge with sheep RBCs and displayed significantly reduced delayed type hypersensitivity responses compared with controls maintained in 12 L:12 D lighting conditions . In a mammalian model system, nocturnal light exposure suppressed the normal increase in cytotoxic activities of natural killer cells .
Because exposure to light at night is accompanied by a significant decrease in melatonin levels (see above), it is relevant to briefly discuss the potent effects that melatonin has on the immune system. The injection of Syrian hamsters with melatonin, or maintenance of hamsters in short photoperiods which increase melatonin levels resulted in increased splenic masses, total splenic lymphocyte counts, and macrophage numbers . A number of studies have confirmed the existence of melatonin receptors in lymphatic tissue and on circulating cells of the immune system (reviewed in ). Although prevalence of splenic melatonin receptors typically fluctuate such that receptor numbers are low at night when melatonin levels are high, levels of binding sites during light at night remain high . Melatonin has been reported to counteract drug or hormone-based immunosuppression and appears to have generally immunostimulatory properties (reviewed in ). Suppression of melatonin by exposure to light pollution or during shift work could suppress such immunostimulatory properties. On the other hand, constant light generally inhibits T-cell autoimmunity by eliminating melatonin , a potentially beneficial effect. Carrillo-Vico et al. provide an excellent review of the effects of melatonin on the immune system . Based on these documented effects, the potential exists for artificial night-time light to have potent and multi-pathway modulatory effects on the immune system. Similar effects could result from decreases in sleep efficiency associated with exposure to constant levels of light. For example, in a study of humans, 40 h of wakefulness resulted in significant changes in several immune parameters, including a decrease in natural killer cell activity . Sleep deprivation also activates the HPA axis in rats and alters subsequent responses to stress , which could exert indirect effects on the immune system as well. Thus, through either direct endocrine effects or indirect sleep-related effects, exposure to light at night has the potential to significantly modulate immune function, leading to large-scale medical implications.
Resistance to cancer is often accomplished through endocrine, antioxidant, and immunological processes. It is now apparent that all of these processes can be altered by exposure to light at night; evidence is mounting that forms links between extended exposure to light and the incidence of several cancers in both humans and animals. For example, the risk of developing breast cancer is up to five times higher in industrialized nations than in underdeveloped countries . Current evidence suggests that high levels of artificial light at night in industrialized societies may play a role in cancer risk. Multiple studies have documented a link between night shift work and an increased incidence of breast cancer (reviewed in ). In a nationwide study of 7035 Danish women with confirmed primary breast cancer, at least half a year of predominantly work during the night increased the risk of breast cancer 1.5 fold . Other studies of women involved in various types of work during the night have consistently demonstrated an up to threefold increase in the relative risk of breast cancer (, also see  for review). Although night shift work increased the incidence of breast cancer, an increased risk was also documented in individuals who reported not sleeping during the time of night when melatonin is typically elevated . Importantly, there was an indication of increased risk in patients with the brightest bedrooms . Although breast cancer is the most abundantly studied cancer type in relation to light at night and shift work, recent studies have begun examining links with other cancer types. For instance, in a study of 602 colorectal cancer cases among 78,586 women, it was determined that a rotating night shift at least three nights per month over at least 15 yr increases the risk of colorectal cancer . Considered together, abundant evidence suggests that circadian disruption, and/or the changes in melatonin and other physiological systems may increase the risk of cancers.
Specific evidence of the role of light in tumor development was demonstrated in deer mice (Peromyscus maniculatus); mice maintained in long day lengths (16 L:8 D) were significantly more likely to develop tumors induced by 9,10-dimethyl-1,2,benzanthracene (DMBA) compared with animals maintained in short day lengths (8 L:16 D) . Indeed, 90% of animals in long day lengths developed tumors, whereas animals maintained in short day lengths developed none. More recent studies have demonstrated that exposure to extended dim light can have similar effects on tumor incidence and growth. Exposure to constant dim light (0.21 lux) significantly increased the growth of MCF-7-induced tumors and significantly increased the total tumor fatty acid uptake, linoleic acid uptake, and 13-hydroxyoctadecadienoic acid (13-HODE) production (reviewed in ). Additionally, female rats with small DMBA-induced tumors were maintained in one of the four treatment groups, including a normal light cycle (12 L:12 D), a constant bright light cycle (24 h at 300 lux), a normal light cycle with a flash of bright light halfway through the dark period, and a normal cycle with low level incandescent lighting throughout the dark period . Animals maintained in the normal light cycle (12 L:12 D) had significantly lower rates of tumor growth than all other treatments, and the animals experiencing dim light at night had the lowest survival probability. In summary, extended periods of exposure to even dim levels of light impair suppression of tumor development.
Both experimental and clinical reports suggest a link between cancer development and pineal function (reviewed in ). Under a majority of in vitro conditions, physiological levels of melatonin decrease the rate of cell proliferation, whereas elevated concentrations tend to be either cytostatic or cytotoxic (reviewed in ). Melatonin may shift the cell balance from proliferation to differentiation, and thus can prevent the proliferation of tumor cells. In addition, melatonin may promote apoptosis of cancer cells (reviewed in ). Pinealectomy accelerates the growth of transplanted melanoma in hamsters  and of transplanted Yoshida sarcoma in rats . In addition, DMBA-induced mammary tumors grew more slowly in rats treated with melatonin when compared with control rats that did not receive melatonin (, reviewed in ). In a particularly elegant study, rats were implanted with either rat hepatomas or human breast cancer xenografts . Resulting tumors were subsequently perfused in situ with human blood collected from subjects during the daytime, during the night, or following exposure to 580 μW/cm2 of white fluorescent light at night. In addition, some of the blood collected from individuals exposed to night-time light was also supplemented with a synthetic form of melatonin. Proliferative activity, linoleic acid production, 13-HODE production, and tumor cAMP levels significantly decreased when tumors were exposed to blood taken from individuals during the night-time. This suppressive effect disappeared when tumors were exposed to blood from individuals who experienced night-time light, leaving proliferation levels similar to those perfused in blood from daytime individuals. Interestingly, when melatonin was added to blood from light-exposed individuals, tumor proliferation and activity was again suppressed . These data suggest that melatonin exerts a direct effect on tumor growth and proliferation.
Constant light may act on cancer through direct actions of depressed melatonin levels or through secondary endocrine modulation associated with either light exposure resulting from light exposure and/or sleep disruption [63,65]. ‘The melatonin hypothesis’ suggests that reduced pineal melatonin secretion might increase the risk of breast cancer through an interaction with high levels of estrogen, a known promoter of breast tissue proliferation . Melatonin suppresses estrogen secretion in several species of mammals . Melatonin completely blocks estradiol-induced stimulation of breast cancer cell proliferation, and melatonin loses its antiproliferative effects unless cells are co-cultured with estradiol or prolactin . As mentioned, melatonin acts as a potent antioxidant, and thus may normally protect against estradiol-induced oxidative damage that could result in cancer (reviewed in ). Alternatively, melatonin may prevent the estradiol-induced suppression of the cell-mediated immune response, providing immunological protection against cancer development (reviewed in ). Estradiol is also responsible for upregulating telomerase activity, and melatonin may inhibit these effects. Thus, suppression of melatonin after exposure to constant light would inhibit these anti-cancer effects. Despite this evidence, rats exposed to constant light did not increase serum estradiol concentrations [62,68]. Furthermore, ovariectomy and estrogen treatment did not affect tumor formation . Thus, although the ‘melatonin hypothesis’ seems plausible, current evidence suggests that light exposure likely acts on tumor formation and growth through one or more alternative mechanisms.