Light-at-night, circadian disruption and breast cancer: assessment of existing evidence
01 Aug 2009-International Journal of Epidemiology (Oxford University Press)-Vol. 38, Iss: 4, pp 963-970
TL;DR: If a consensus eventually emerges that LAN does increase risk, then the mechanisms for the effect are important to elucidate for intervention and mitigation and will provide for the development of lighting technologies at home and at work that minimize circadian disruption, while maintaining visual efficiency and aesthetics.
Abstract: Background Breast cancer incidence is increasing globally for largely unknown reasons. The possibility that a portion of the breast cancer burden might be explained by the introduction and increasing use of electricity to light the night was suggested >20 years ago.
Methods The theory is based on nocturnal light-induced disruption of circadian rhythms, notably reduction of melatonin synthesis. It has formed the basis for a series of predictions including that non-day shift work would increase risk, blind women would be at lower risk, long sleep duration would lower risk and community nighttime light level would co-distribute with breast cancer incidence on the population level.
Results Accumulation of epidemiological evidence has accelerated in recent years, reflected in an International Agency for Research on Cancer (IARC) classification of shift work as a probable human carcinogen (2A). There is also a strong rodent model in support of the light-at-night (LAN) idea.
Conclusion If a consensus eventually emerges that LAN does increase risk, then the mechanisms for the effect are important to elucidate for intervention and mitigation. The basic understanding of phototransduction for the circadian system, and of the molecular genetics of circadian rhythm generation are both advancing rapidly, and will provide for the development of lighting technologies at home and at work that minimize circadian disruption, while maintaining visual efficiency and aesthetics. In the interim, there are strategies now available to reduce the potential for circadian disruption, which include extending the daily dark period, appreciate nocturnal awakening in the dark, using dim red light for nighttime necessities, and unless recommended by a physician, not taking melatonin tablets.
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TL;DR: The molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC are focused on and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated bymelatonin are summarized.
Abstract: Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy-treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti-CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.
48 citations
TL;DR: The data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function and may directly link to compromised heart function and dilated cardiomyopathy in humans.
Abstract: Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.
46 citations
Cites background from "Light-at-night, circadian disruptio..."
...…mal-adjustment contributes to the pathology of various disorders, including insomnia (Flynn-Evans et al., 2017), aging (Tevy et al., 2013), cancer (Stevens, 2009), metabolic syndromes (Bray and Young, 2008), immune system imbalance (Deng et al., 2018), and cardiovascular diseases (Nonaka et al.,…...
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TL;DR: How newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts is discussed.
Abstract: The rotation of the earth and associated alternating cycles of light and dark—the basis of our circadian rhythms—are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts.
46 citations
TL;DR: The authors have shown that downregulation of Per1 or Per2 enhances cancer growth in vitro, and suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery.
Abstract: The mammalian core clock genes, Periods (Per1 and Per2), have tumor suppressor properties. Decreased expression of Per1 and Per2 has been reported in several types of human cancers. On the other hand, overexpression of Per1 or Per2 inhibits cancer cell growth in culture. The authors have shown that downregulation of Per1 or Per2 enhances cancer growth in vitro. These genes also regulate the amount of cell proliferation-related molecules, many of which are therapeutic targets. In animals, tumors grow with clear circadian organization, and Per1 and Per2 exert their tumor suppressor functions in a circadian time-dependent manner. Downregulation of Per1 or Per2 increases tumor growth only at certain specific times of the day. Per1 and Per2 differentially regulate tumor growth rhythm in vivo. These data suggest that the therapeutic efficacy of antiproliferation agents depends on the time of day of drug delivery. The optimal times of day may be shifted in tumors that have mutant Period genes.
45 citations
TL;DR: Women who reported having working at night were substantially different from those who reporting never having worked at night and many of the differences would put "ever night workers" at increased risks of cancer, vascular disease, and many other common conditions.
Abstract: Objectives The aim of this study was to compare the characteristics of women who had and had not worked at night in terms of their risk factors for common disease, indicators of general health, social activities, employment, and sleep behavior.
Methods The Million Women Study is a large prospective cohort study of women’s health in the United Kingdom with 1.3 million women recruited during 1996–2001 (aged 50–64 years) through 66 National Health Service breast screening centers. We analyzed the data from a random sample of 41 652 participants who, in 2009–2010, reported their history of night work.
Results Of the participants, 1 in 8 women (13%) reported that they had ever worked at night and 1 in 50 (2%) reported working at night for ≥20 years. For 33 sociodemographic, behavioral, reproductive, and hormonal factors examined, 20 showed highly significant differences between “ever” and “never” night workers (P<0.0001); 12 showed significant trends by duration of night work (P<0.01). In particular, compared to women who had never worked at night, women who had worked at night were more likely to (i) be of lower socioeconomic status [the odds ratio (OR) for ever versus never night workers of being in the lowest third of socioeconomic status was 1.15, 99% confidence interval (95% CI) 1.06–1.25]; (ii) have ever used hormone replacement therapy (HRT) for the menopause (OR 1.43, 99% CI 1.33–1.55); (iii) be current smokers (OR 1.37, 99% CI 1.19–1.58); and (iv) be obese (OR 1.26, 99% CI 1.15–1.37). Compared to women who had never worked at night, women who had worked at night for ≥20 years were more likely to be (i) of lower socioeconomic status (OR 1.28, 99% CI 1.04–1.57); (ii) nulliparous (OR 1.47, 99% CI 1.12–1.91); (iii) current smokers (OR 1.63, 99% CI 1.18–2.25); and (iv) obese (OR 1.55, 99% CI 1.25–1.93). Former night workers were more likely than never night workers to report a range of sleep disturbances, including poor quality of sleep (OR 1.15, 99% CI 1.01–1.31) and having to take medication to sleep (OR 1.35, 99% CI 1.15–1.60).
Conclusions Women who reported having worked at night were substantially different from those who reporting never having worked at night and many of the differences would put “ever night workers” at increased risks of cancer, vascular disease, and many other common conditions.
45 citations
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TL;DR: The criteria outlined in "The Environment and Disease: Association or Causation?" help identify the causes of many diseases, including cancers of the reproductive system.
Abstract: In 1965, Austin Bradford Hill published the article "The Environment and Disease: Association or Causation?" in the Proceedings of the Royal Society of Medicine. In the article, Hill describes nine criteria to determine if an environmental factor, especially a condition or hazard in a work environment, causes an illness. The article arose from an inaugural presidential address Hill gave at the 1965 meeting of the Section of Occupational Medicine of the Royal Society of Medicine in London, England. The criteria he established in the article became known as the Bradford Hill criteria and the medical community refers to them when determining whether an environmental condition causes an illness. The criteria outlined in "The Environment and Disease: Association or Causation?" help identify the causes of many diseases, including cancers of the reproductive system.
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TL;DR: This paper contrasts Bradford Hill’s approach with a currently fashionable framework for reasoning about statistical associations – the Common Task Framework – and suggests why following Bradford Hill, 50+ years on, is still extraordinarily reasonable.
Abstract: In 1965, Sir Austin Bradford Hill offered his thoughts on: “What aspects of [an] association should we especially consider before deciding that the most likely interpretation of it is causation?” He proposed nine means for reasoning about the association, which he named as: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. In this paper, we look at what motivated Bradford Hill to propose we focus on these nine features. We contrast Bradford Hill’s approach with a currently fashionable framework for reasoning about statistical associations – the Common Task Framework. And then suggest why following Bradford Hill, 50+ years on, is still extraordinarily reasonable.
5,542 citations
TL;DR: It is shown that retinal ganglion cells innervating the SCN are intrinsically photosensitive, and depolarized in response to light even when all synaptic input from rods and cones was blocked.
Abstract: Light synchronizes mammalian circadian rhythms with environmental time by modulating retinal input to the circadian pacemaker-the suprachiasmatic nucleus (SCN) of the hypothalamus. Such photic entrainment requires neither rods nor cones, the only known retinal photoreceptors. Here, we show that retinal ganglion cells innervating the SCN are intrinsically photosensitive. Unlike other ganglion cells, they depolarized in response to light even when all synaptic input from rods and cones was blocked. The sensitivity, spectral tuning, and slow kinetics of this light response matched those of the photic entrainment mechanism, suggesting that these ganglion cells may be the primary photoreceptors for this system.
3,052 citations
TL;DR: Findings establish that the human response to light is qualitatively similar to that of other mammals.
Abstract: Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity, which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results of previous experiments in which ordinary room light was used, these findings establish that the human response to light is qualitatively similar to that of other mammals.
1,776 citations
TL;DR: The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cellphotopigments for vision.
Abstract: The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 +/- 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects' pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R(2) = 0.81-0.95). The action spectrum constructed from these data fit an opsin template (R(2) = 0.91), which identifies 446-477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.
1,708 citations