Loading...
 
Toggle Health Problems and D

Sunlight - not too much and not too little - May 2016

 Download the PDF from VitaminDWiki

Cancer Research Frontiers. 2016 May; 2(2): 156-183. doi: 10.17980/2016.156 Review

Sunlight: For Better or For Worse? A Review of Positive and Negative Effects of Sun Exposure

Han van der Rhee1, Esther de Vries2, Claudia Coomans3, Piet van de Velde4, Jan Willem Coebergh5

department of Dermatology, Hagaziekenhuis, P.O. Box 40551, Leyweg 275, 2504 Den Haag, Zuid-Holland, the Netherlands department Health, Erasmus University;Medical;Center,    P.O.    Box    2040

3000 CA Rotterdam, the Netherlands

department of Molecular Cell Biology, Laboratory for Neurophysiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

4Faculty of Archaeology, Leiden University, Postbus 9514, 2300 RA Leiden, the Netherlands department    of    Public    health,    Erasmus    University    Medical    Center,    P.O.    Box    2040

3000 CA Rotterdam, the Netherlands

Corresponding author: Han van der Rhee. Voorstraat 56, 2201 HX Noordwijk, The Netherlands Phone: 0031713617424; Email: hvdrhee@casema.nl

Citation: Han van der Rhee, et al. Sunlight: For Better or For Worse? A Review of Positive and Negative Effects of Sun Exposure. Cancer Research Frontiers. 2016 May; 2(2): 156-183. doi: 10.17980/2016.156 Copyright: @ 2016 Han van der Rhee, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing Interests: The authors declare no competing financial interests.

Received Nov 26, 2015; Revised Feb 3, 2016; Accepted Feb 13, 2016. Published Apr 22, 2016

Abstract

During the last decades new, mainly favorable, associations between sunlight and disease have been discovered, initially ascribed to vitamin D. There is, however, accumulating evidence that the formation of nitric oxide, melatonin, serotonin, endorphin, photodegradation of folic acid, immunomodulation, photoadaptation, and the effect of (sun)light on circadian clocks, are involved as well. After a systematic search in the literature, a summary is given of (recent) research on the health effects of sun exposure and the possibly involved mechanisms.

In the last 200 years our exposure to sunlight has changed radically: from a more continuous to an intermittent exposure. Our exposure to light during the day and to artificial light in the evening and at night has changed as well. The present 'epidemic' of skin cancer is mainly caused by the increase of intermittent sun exposure, coinciding with decrease of chronic exposure. Effects of chronic and occupational exposure appear to be latitude-dependent: risk of skin cancer decreases with increasing latitude. In North-western Europe chronic exposure yields a relatively low risk of melanoma and (to a lesser degree) of basal cell carcinoma and squamous cell carcinoma. There is epidemiological and experimental evidence that chronic exposure to sunlight could contribute to the prevention of colorectal-, breast-, prostate cancer, non-Hodgkin Lymphoma, multiple sclerosis, and metabolic syndrome. The possible consequences of these findings for public health messages on sun exposure are discussed. It is concluded that both too much and too little sunlight may be harmful to our health.

Keywords: skin cancer, colon cancer, breast cancer, non-Hodgkin lymphoma, metabolic syndrome, multiple sclerosis, sunlight, vitamin D, circadian clocks, nitric oxide

1. Introduction

The beginning of the 20th century saw a rise in the advocacy of ultraviolet (UV) exposure both as a prophylactic measure against rickets and infectious disease and as treatment for patients with chronic ulcers, cutaneous and other forms of tuberculosis (1,2,3). These medical opinions played a significant role in the popularity of recreational sunbathing (4).

Decades later an increase in the incidence of skin cancer was noted, starting in northern Australia, with its (sub)tropical climate and its population with a sun-sensitive skin (5-7). In 1992 the WHO concluded that solar UV radiation is the main environmental cause of skin cancer (5).

The positive and negative influence of sun exposure is well-established now for a number of diseases. (Table 1) During the last decades new associations between sunlight and disease (particularly colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, and metabolic syndrome) were discovered, initially ascribed to vitamin D. However, it became evident that vitamin D is not the only potential mechanism of action for these effects of sunlight (11-16).

This review presents the available data on the relationship between sunlight (both ultraviolet rays and visible light) and:

-the risk of skin-, colon-, breast-, prostate cancer, and non-Hodgkin lymphoma,

-the risk of multiple sclerosis, and metabolic syndrome.

Skin pigmentation and skin color are correlated strongly with UV radiation. Since pigmentation is an important factor in regulating the penetration of UV rays into the skin, it has effects on health. Migration, the rise of rapid long-distance transportation, and lifestyle changes have led to a completely different exposure to sunlight, in comparison with our ancestors. The health consequences of this change in exposure are often underestimated

Table 1. Established negative and positive effects of sunlight.

Negative effects

Positive effects

Induction of skin cancer:

Prevention and treatment of skin diseases like

- basal cell carcinoma,

- psoriasis,

- squamous cell carcinoma,

- eczema,

- melanoma

- vitiligo

Photo-ageing

- acne

Photodermatoses, like:

Photosynthesis of vitamin D, important for

- polymorphic light eruption,

bone and muscle health

- solar urticaria,

Prevention and treatment of seasonal affective

-    photo-allergic and -toxic reactions Aggravation of skin diseases like

-    rosacea

-    Chronic Discoid Lupus Erythematosus Aggravation of eye diseases:

-    cataract

-    macular degeneration

Aggravation of internal disease:

-    Systemic Lupus Erythematosus

-    Porphyrias

disorder

Sources: references 8-10

Table 2. Search strategy.

Subject

Mesh terms

Skin Cancer

Melanoma or basal cell carcinoma or cutaneous squamous cell carcinoma and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Colorectal cancer

Colonic neoplasms or rectal neoplasms or colorectal neoplasms and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Breast cancer

Breast neoplasms and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Prostate cancer

Prostatic neoplasms and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Non-Hodgkin lymphoma

Lymphoma Non-Hodgkin and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Multiple sclerosis

Multiple sclerosis and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

Metabolic syndrome

Metabolic syndrome or diabetes mellitus or hypertension and sunlight or ultraviolet rays or vitamin D or circadian rhythm or circadian clocks or light

A literature search was performed in Pubmed from 1 January 2004 until 1 October 2015. The mesh terms used are given in the right column.

(17-20). Therefore this review begins with a brief summary of the present knowledge of the relationship between (the evolution of) skin pigmentation, sun exposure, and health. Finally, the biological mechanisms activated by sunlight will be described.

2. Methods

A systematic search of the literature was performed as described in table 2. Epidemiological, experimental, and clinical studies on colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, and metabolic syndrome, were evaluated. All identified titles and abstracts were reviewed by one of the authors (Van der Rhee). The initial inclusion criteria were: studies with original data that met the following demands: investigating the effect of sunlight on the subjects mentioned above, with a clear description of methodology and containing effect estimates with P value or confidence intervals. Further details are described elsewhere (21).

For most of the topics mentioned (skin-, colon-, breast-, prostate cancer, non-Hodgkin lymphoma, and sunlight or vitamin D; metabolic syndrome and vitamin D) systematic reviews and/or meta-analyses were available. The results of these studies are presented. Consequently the original studies were excluded, with the exception of recent studies not yet included in the systematic reviews and meta-analyses. When no systematic reviews or meta-analyses were available, summaries of the literature are provided. Finally, 71 original studies, 21 meta-analyses, 6 systematic reviews, and 17 reviews were included.

3. Results

3.1.    Health effects of ultraviolet radiation

3.1.1.    Skin color and sunlight. Evolutionary biology and anthropology

The estimated degree of variation in human skin pigmentation is 88%, which is high compared to roughly 10-15% observed for genetic loci on average. Such high phenotypic differentiation, most likely, is the effect of natural selection. The variation in pigmentation markedly correlates with the latitudinal differences in annual UV radiation; therefore it is presumed that UV radiation is the selective force (17-19). UV radiation is highest at the equator and diminishes gradually with increasing latitude on both the Northern and Southern Hemispheres. In the Northern Hemisphere every 10 degrees in latitude the color of the skin gets roughly 8 % lighter (20).

Our skin color is defined by the amount of the pigment melanin. Recently, several locus-specific and genome-wide association studies, searching for signatures of positive selection, have highlighted distinct loci in the pigmentation pathways. One of the most important polymorphisms affecting skin and hair color is the rs16891982*G/C SNP on chromosome 5 in the SLC45A2 gene (22-24). In African and Asian populations the ancestral 374L allele dominates (23,25). The 374F allele dominates in Europe with a north-south decline (26). For details see Table 3.

Positive natural selection functions on genetic variability in such a way that the fittest individuals have the best chance of surviving and producing more offspring. Apparently a light skin offered the best chances for the European ancestors. The principal theories relating to variation in pigmentation and UV radiation assume that dark skin protects against sunburn and possibly folate deficiency, whereas light skin allows sufficient photosynthesis of vitamin D and other possible effects of sunlight in areas with low UV radiation (17-19,27). The importance of vitamin D as a selective force in the evolution of skin pigmentation is related to its manifold effects on fitness (18,19,28).

In the context of human evolution, the variation in pigmentation is considered a superb compromise between the positive and deleterious effects of sunlight (18,19). This is an appropriate statement for our ancestors who up to the industrial revolution mainly had outdoor occupations, whereas nowadays the vast majority of the population in developed countries works indoors. Since the Second World War developments such as automobiles, TV, computers, videogames, indoor sports etc. have promoted indoor activities. German and Danish studies revealed that indoor workers on average expose their hands and face to less than 3% of the total available amount of sunlight (29,30).

Simultaneously, the advent of widely available, rapid long-distance transportation promoted the popularity of sun-seeking vacations in areas with an UV index much higher than at home. The exposition pattern to sunlight has definitely changed from a continuous or occupational pattern to a more intermittent pattern.

Not only has the exposure of our skin to UV changed. The exposure of our eyes to bright light during daytime, and to artificial light in the evening and at night has changed as well. Our ancestors rose with the sun and went to bed at sunset. The invention of light bulbs at the end of the 19th century has had a dramatic influence on our pattern of activity and rest. At present we are exposed to numerous sources of bright light from lamps (both indoor and outdoor), television, and computer screens in the evening and at night, while our daytime exposure to (sun)light has diminished considerably (31,32). Moreover, 15-20 percent of the western population is regularly working at night in illuminated surroundings (33).

3.1.2. Skin cancer

Skin cancer results from an interaction between genetic susceptibility and environmental

Table 3. Frequency of the 374F allele of the SLC45A2 gene in 10 cities across Europe and Africa.

Location

(Europe)

Latitude(°)

Frequency

of 374F

allele

Location

(Africa)

Latitude(°)

Frequency of

374F allele

Copenhagen,

Denmark

56

0.98

Tangier, Morocco

36

0.61

Brussels,

Belgium

50

0.93

Algiers, Algeria

36

0.70

Marseille,

France

43

0.89

Tunis,

Tunisia

36

0.69

Barcelona, Spain

41

0.86

Nouakchott,

Mauritania

20

0.41

Sevilla,

Spain

37

0.73

Dakar, Senegal and Africa south of Senegal

=<15

0.00*

The 374F allele is associated with depigmented skin. *Except inhabitants of European origin.

Sources: references 25 and 26

exposure, mainly to UV. The incidence rates of skin cancer have been increasing worldwide since at least five decades (34,35). Increased risks were shown for those who have red/blonde hair, light eye color, burn easily, and tan poorly (36,37).

Intermittent sun exposure and sunburn, particularly at young age, are considered to be the main risk factors for melanoma, the most lethal form of skin cancer. Intermittent exposure is defined as: recreational activities such as sunbathing, water sports, and vacations in sunny places. Chronic exposure is usually defined as a continuous or more continuous pattern of sun exposure (38). Successive metaanalyses (38-40) found an inverse association between chronic and occupational exposure and melanoma risk. The effect of chronic and occupational sun exposure appeared to be latitude-dependent (41). Chronic and occupational exposure increases melanoma risk in Southern Europe (41), whereas in Northwestern Europe it is associated with relative low risks (41-45). In a case-control study performed in the Netherlands, it was found that leisure activities such as sunbathing and vacations in sunny countries increased the risk of melanoma in indoor workers but not in outdoor workers (42).

For basal cell carcinoma (BCC) intermittent exposure is an important risk factor as well (43,44,46,47). A meta-analysis investigating the effect of occupational exposure on the risk of BCC found a pooled odds ratio (OR) of 1.4 (95%CI:1.2-1.7) (48). The data also show that there is a decline in risk from lower to higher latitudes in Europe. The risk is robust in southern countries, whereas studies performed at or above 50 degrees north latitude show no association between occupational sun exposure and BCC risk (48). More recent studies performed in Denmark (44) and Eastern and Central Europe (49), not yet included in this meta-analysis, show a significant decrease in risk of BCC in outdoor workers; in Denmark this

Table 4. Associations between different types of skin cancer and different types of UV exposure.

Type of skin

cancer

Type of UV exposure

References

Intermittent with sunburn

Chronic

Occupational

Melanoma

Most important risk    factor*,

uninfluenced by latitude

Risk influenced by latitude.    In    sunny

regions increased risk. In moderate and cold regions: decreased risk*

Risk influenced by latitude. In sunny regions increased risk. In moderate and cold regions decreased risk*

37-44

Basal    cell

carcinoma

Most important risk factor

Probably modest risk factor. Influence of

latitude not studied

Modest risk factor. In Europe influenced by latitude.    In    southern

Europe increased risk, in Northern    Europe

decreased risk

35,42,45-47

Squamous

cell

carcinoma

Modest    risk

factor

Most important risk factor. Influence of

latitude not studied

Important    risk factor,

influenced by latitude: decreasing    risk    with

increasing latitude

35,42,43,49

Intermittent exposure is defined as: recreational activities and vacations in sunny places. Chronic exposure is defined as a continuous or more continuous pattern of sun exposure.

*For melanoma of trunk and limbs, not for head and neck melanoma

effect was even dose-dependent for men working in agriculture.

A meta-analysis of studies on the association between occupational sun exposure and squamous cell carcinoma (SCC) found an increased risk (OR 1.8;95%CI: 1.4-2.2). Metaregression analyses suggested a decreasing strength of this association with increasing latitude (50). Two Scandinavian studies found no association between occupational exposure and SCC risk (44,51).

In vitro, 1,25-dihydroxyvitamin D inhibits keratinocyte and melanocyte growth and promotes differentiation, factors that are important for skin cancer prevention (52). However, epidemiological studies do not show a consistent relationship between 25-hydroxyvitamin D levels and the risk of skin cancer (52,53). A recent meta-analysis found no association between the blood levels of 25-hydroxyvitamin D and melanoma risk, and a statistically significant positive association with increasing risk of nonmelanoma skin cancer for high values of 25-hydroxyvitamin D levels was found. An inverse relationship might exist between 25-hydroxyvitamin D blood levels and melanoma thickness at diagnosis and melanoma survival (53-55).

3.1.3. Colorectal-, breast-, prostate cancer, and non-Hodgkin lymphoma

In 1980, the hypothesis was proposed that vitamin D is a protective factor against colon cancer (56). Subsequently, for many types of cancer an inverse association between ambient solar radiation and cancer incidence and mortality rates has been described. For many

Table 5 Associations between UV exposure and colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, hypertension and diabetes.

Disease

Influence of sunlight

Reference

Epidemiology: ecological, case-control and prospective studies. High vs low UV exposure

Animal experiments with UV

Experiments in humans with UV

Colon

cancer

Mainly inverse associations with cancer

risk.

Reduction in malignant progression and growth of carcinomas

n.d.

15,16,55

57

Breast

cancer

Mainly inverse associations with cancer

risk.

Inhibition of tumor outgrowth with xenografts of breast cancer cell lines

n.d.

15,56,57,5

9

Prostate

cancer

Mainly inverse associations with cancer

risk

n.d.

n.d.

15,56,57

Non-

Hodgkin

lymphoma

Mainly inverse associations with lymphoma risk

n.d

n.d

15,56

58,135

Multiple

sclerosis

Mainly inverse associations with MS risk and mortality

Chronic UV exposure suppresses disease induction and progression

In MS patients depression, fatigue and MRI

neurodegeneration inversely associated with sun exposure

11,12,67

80,136

Hyper

tension

Towards the equator less hypertension. Hypertension shows seasonality. Higher ambient temperature associated with lower blood pressure

n.d.

Regular artificial UV exposure lowers blood pressure significantly.

81-89

Diabetes

Moderate evidence for

inverse associations

with diabetes risk

In a murine model of obesity UV significantly suppressed weight gain, glucose intolerance, insulin resistance, serum levels of fasting insulin and glucose

Regular artificial UV exposure increases glucagon-stimulated insulin secretion

90-94

n.d.=not done

types of cancer only ecologic studies are available. For colorectal-, breast, prostate cancer, and non-Hodgkin lymphoma (NHL) case-control and prospective studies were performed (15,21,57). A systematic review of 26 case-control and 19 cohort studies on these subjects, established an inverse association between chronic (not intermittent) sun exposure and colorectal-, breast-, prostate cancer and NHL. The association was consistent and persuasive (15). As to NHL, the larger studies that specifically investigated the risk in NHL subtypes, found a decreased risk mainly for B cell lymphoma, particularly diffuse large cell and follicular lymphomas, and not for T cell lymphoma (15,58).

Although in many studies the results were corrected for known risk factors, confounding with dietary and lifestyle factors cannot be excluded completely. Animal studies, however, support a causal relationship. Inhibition of tumor outgrowth by UV exposure was found with xenografts of breast cancer cell lines in mice (59). Moderate UV doses can reduce the load of primary intestinal tumors of mice. This reduction could be partly ascribed to the increase of the vitamin D status. However, a reduction in malignant progression and growth of adenocarcinomas could not be attributed to vitamin D, as these effects were only observed with moderate UV exposure and not with dietary supplementation (16).

Virtually all studies on the association between the 25-hydroxyvitamin D serum levels and colorectal cancer risk (15,57,60,61) showed inverse associations. For breast cancer, case-control studies observed inverse associations, but prospective studies found mixed results. A recent dose-response meta-analysis of prospective studies of 25-hydroxyvitamin D suggested an inverse association only in postmenopausal women with a plasma 25-hydroxyvitamin D level lower than 27 ng/mL, with flattening of effects above 35 ng/mL (62).

No epidemiological support was found for a decreased risk of prostate cancer or NHL and higher levels of serum 25-hydroxyvitamin D (15,57,60,61,63).

Animal studies support a causal relationship between vitamin D and the prevention of colon, breast-, and prostate cancer: supplementation of vitamin D and vitamin D analogues resulted in a lower incidence of tumors and a reduction of tumor outgrowth. Placebo-controlled, randomized vitamin D supplementation trials showed an inverse association for all-cause mortality, but not for cancer risk (64-66). For details see table 6.

3.1.4.    Multiple sclerosis

The prevalence of multiple sclerosis (MS) follows a latitudinal gradient (67,68). Case-control-, prospective-, and twin studies on the association between sun exposure and MS in Caucasians found reduced risks or mortality with increasing hours of sun exposure (12,6976).

Sun exposure and 25-hydroxyvitamin D levels appear to contribute independently to the reduced MS risk (11,12). Studies with an experimental autoimmune encephalomyelitis (EAE) model of MS demonstrated that vitamin D treatment leads to a modest suppression of disease induction and progression, using doses which cause vitamin D toxicity and hypercalcaemia.    However,    chronic

suberythematal UV doses, that caused only a modest increase in serum 25-hydroxyvitamin D, led to a greater disease suppression than vitamin D without side effects (11,77,78).

In MS patients personal reported sun exposure was inversely associated with depression, fatigue scores (79), and MRI measures of neurodegeneration (80), independently of vitamin D.

3.1.5.    Metabolic syndrome

Metabolic syndrome is an important determinant of vascular disease, which is the major cause of morbidity and mortality worldwide. Ambient solar radiation was found to correlate well with the prevalence of coronary heart disease mortality rate in the adult population of Western Europe (81). Sun exposure is associated with beneficial effects on blood pressure and the risk of diabetes.

Levels of blood pressure (BP) vary with latitude with less hypertension towards the equator (82). The seasonality of BP, higher values in winter than in summer, was already described more than 50 years ago (83). Ambient temperature and seasonality (reflected by the number of hours between sunrise and sunset)

Table 6 Summary of the results of studies on the association between vitamin D (vit D) and colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis (MS), hypertension and diabetes.

Disease

Observational studies

Animal experiments

Vitamin D supplementa tion

References

Colon cancer

Inverse    associations

with cancer risk

Reduction of incidence and tumor growth

Insufficient

evidence

15,16,57,60,6

1, 64-66

Breast cancer

Mixed results. Inverse

associations with cancer risk mainly in postmenopausal women

Reduction of incidence and tumor growth

Insufficient

evidence

15,57,59

62,64,65

Prostate

cancer

Insufficient evidence

Reduction of incidence and tumor growth

Insufficient

evidence

15,57,60,61,6

4,65

Non-Hodgkin

lymphoma

Insufficient evidence

n.d

Insufficient

evidence

15,,57,58,61,6

3-65

Multiple sclerosis (MS)

Inverse    associations

with MS risk

Vit    D    enhances

immunotolerance    and

suppresses    disease

induction    and

progression

Insufficient

evidence

11,12,71,79,8

0

Hypertension

Inverse    associations

with hypertension risk

n.d.

Inconclusive

evidence

95,100,101,10

4

Diabetes

Inverse    associations

with diabetes risk

Vit    D    enhances

immunotolerance    and

suppresses    disease

induction

Insufficient

evidence

90,93,96

99,102,103

n.d= not done

appear to be independent predictors of BP (84,85). Pregnancy hypertension (86) and preeclampsia (87) show seasonality as well. Both increased sunlight and increased ambient temperature in the month(s) before delivery were associated with decreased rates of pregnancy hypertension. All studies on irradiation of Caucasians with physiological doses (8-20 J/cm2) of ultraviolet A (UVA) reported significant lowering of BP (88-90).

Incidence rates of diabetes mellitus (DM), particularly DM type 1, follow a latitudinal gradient, inverse with the global distribution of ultraviolet rays (91,92). A systematic review reported moderate evidence to support a role of recreational sun exposure in reducing DM type 2 incidence (93). In a small study with young French adults an UV treatment of 2 weeks was found to increase glucagon-stimulated insulin secretion (94). In a murine model of obesity UV significantly suppressed weight gain, glucose intolerance, insulin resistance, serum levels of fasting insulin, and glucose (95).

Meta-analyses and (systematic) reviews of observational studies indicate that high serum 25-hydroxyvitamin D concentration is associated with a lower risk of hypertension, DM type 2, metabolic syndrome, and cardiovascular disease (96-103).

The evidence that vitamin D supplementation has a positive effect on BP is inconclusive (103,104). There is currently insufficient evidence of a beneficial effect of vitamin D supplementation in diabetes (105,106). A metaanalysis of observational trials in chronic kidney disease patients, treated with vitamin D or vitamin D analogues, reported a significant reduction of all-cause mortality (relative risk (RR) 0.73; 95% CI 0.65-0.82) and cardiovascular mortality (RR 0.63; 95% CI 0.44-0.92) (107). (Table 6)

3.2. Health effects of visible light

Most organisms exhibit daily rhythms in physiology and behavior, organized by a clock mechanism. The circadian clock consists of a central clock, localized in the hypothalamic suprachiasmatic nucleus (SCN) and peripheral clocks in virtually every tissue and organ system. The SCN clock is mainly entrained and synchronized by light via the retinohypothalamic tract, whereas the peripheral clocks are also regulated by the central SCN pacemaker, directly and indirectly, by virtue of multiple neural, humoral, and other signals from the SCN clock (108-110). The decrease of outdoor jobs, the increase of indoor activities, and the widespread adoption of electrical lighting since the 19th century has led to unnaturally disrupted cycles, with less light during daytime and more light at night. Exposure to unnatural light cycles may increase the risk of cancer (108,111-114), sleep disturbances (115), mood disorders (116,117), MS (118), cardiovascular disease, and metabolic changes (110,119-121). The International Agency for Research on Cancer (IARC) categorized shiftwork that involves circadian disruption as "probably carcinogenic to humans" in 2007 (33).

During the day light intensities of 3000 lux or more (e.g. direct or indirect sunlight) are needed to reinforce the circadian rhythm and to influence its phase, while at night light sources of 100 lux or less (comparable to the light of a bedside lamp) can lead to disturbances of the circadian rhythm (121-124).

Genetic association studies support the relation between circadian rhythm and the risk of several types of cancer, particularly breast cancer, prostate cancer, and NHL (108,125-129). Alterations of the circadian rhythm have been related to modulations of tumor growth in animal models and differences in recurrence rate, stage, and prognosis in human cancers (108).

Shift workers exposed to less bright daylight and experiencing sustained night-time illumination are at increased risk for elevated body mass index, diabetes, and cardiovascular disease (110,119,130,131). Increases in night-time light exposure at home are associated with increased body mass, waist circumference, triglyceride levels, and poor cholesterol balance in elderly individuals (132).

3.3. Biological mechanisms of action of sunlight

3.3.1.    DNA damage

A large number of molecules (chromophores) in different layers of the skin interact with and absorb UV (10). Ultraviolet B (UVB) reaches the epidermis where it is absorbed by DNA leading to the formation of photoproducts, primarily cyclobutane pyrimidine dimers (CPDs). They interfere with both replication and transcription and hence are potentially toxic and mutagenic to cells. UVA penetrates more deeply into the skin and exerts DNA damage, mainly through photo-oxidative mechanisms. UV also can induce carcinogenesis by suppressing the immune system (as reviewed in 10,133).

3.3.2.    Photoadaptation

Human epidermis adapts to chronic UV exposure by increasing the amount of melanin pigment, epidermal hyperplasia, and thickening of the horny layer. Stronger pigmentation leads to an increased absorption of UVA and UVB, while epidermal thickening mainly increases the absorption of UVB. UVB-induced (delayed) pigmentation results in a protection, which amounts to a sun protection factor of 2 to 3 against DNA damage and burning. The thickened epidermis and horny layer obstruct transmission of UV to the vulnerable cells of the basal and suprabasal layers. The protecting effect of thickening is found to be of more importance than the increase of pigmentation (134).

Regular exposure to suberythematal doses of solar-simulating artificial UV for 3 weeks decreases the ultraviolet sensitivity for erythema on average by 75%. CPD formation was reduced on average by 60%. More importantly, virtually no CPDs were found in the basal and suprabasal layers. DNA damage of basal and suprabasal cells with their proliferative capacity is likely to have far more consequences than damage of the cells of higher epidermal layers that are already committed to terminal differentiation (135137).

3.3.3.    Immunomodulation

Immunomodulation by UV radiation involves multiple pathways associated with the formation of vitamin D, cis-urocanic acid, and oxidation products of DNA, lipids and proteins. These initiate signaling pathways, leading to the release of a number of secondary mediators capable of regulating cell-mediated immunity through multiple mechanisms. UV stimulates T-regulatory cells and secretion of IL-10, reduces levels of the proinflammatory cytokine IL-17, and dampens T-helper (Th-1) immune function (as reviewed in 13). This leads to both local and systemic immunosuppression, thereby eliminating natural defense mechanisms (10,13). On the other hand, they might provide biologically plausible pathways for the reduction of MS, diabetes type 1, and NHL risk (11,13,138-143).

3.3.4.    Vitamin D

Most of our vitamin D stems from photosynthesis in the skin. Vitamin D (in its active form: 1,25-hydroxyvitamin D) has been known for its important role in regulating levels of calcium and phosphate as well as in bone mineralization. Moreover vitamin D appears to be involved in a large number of different pathophysiological processes. Many cell types are known to express vitamin D receptors and to produce 1,25-hydroxyvitamin D. Activation of the vitamin D receptor by 1,25-dihydroxy-vitamin D induces or inhibits transcription of a number of genes that influence proliferation, differentiation, invasiveness, metastatic potential, angiogenesis, and apoptosis (as reviewed in 64). Many reviews have been written about the manifold effects of vitamin D (e.g. 28,64). These effects are summarized in table 7.

3.3.5. Nitric oxide

Human skin can be considered as the largest human storage organ for nitric oxide (NO) and NO-derivatives such as nitrite and nitrosothiols. The biological effects of NO are mediated through its reaction with targets, like haem groups, cysteine residues, and iron and zinc clusters. These targets help to explain the multiple roles NO plays, including vasodilatation,    immune    defense,

neurotransmission, apoptosis, and cell motility (as reviewed in 14).

Irradiation with biologically relevant doses UVA induces in the skin release of NO from a preformed store and induces NO translocation from the skin to the circulation. This results in a significantly enhanced concentration of plasma nitroso compounds, strongly correlated with vasodilatation, a decreased vascular resistance, and a sustained reduction in BP (89,90). Intravenous slow infusion of NO in healthy volunteers increases plasma levels of nitroso thiols and elicits a simultaneous and significant drop in mean BP (90). Irradiation of Caucasians with physiological doses of UVA (8-20 J/cm2) was found to vasodilate arterial vasculature and to lower BP (88-90).

Independently of vitamin D, UV significantly suppressed weight gain, glucose intolerance, insulin resistance, serum levels of fasting insulin, glucose, and cholesterol in a murine model of obesity. NO reproduced many of these effects of UV (95).

3.3.6. Serotonin and endorphins

In a blinded experiment frequent tanners instinctively prefer a tanning bed with UV to a seemingly identical tanning bed with an acrylic filter in place that prevented the transmission of UV light (i.e. sham light). Sunbed-users feel more relaxed and less tense than non-users. This has been ascribed to an increase in the production of serotonin and endorphins (144).

Serotonin is a neurotransmitter involved not only in mood, but also in cognition, regulation of feeding behavior, anxiety, aggression, pain, sexual activity, and sleep. It is synthesized in many organs such as the intestines, CNS, thyroid gland, ovaries, breasts, and skin and then released into the blood (145). Production of serotonin can be increased by sunlight through the eyes and the skin. Blood samples from internal jugular veins showed that the production of serotonin by the brain was directly related to duration of exposure of the eyes to sunlight, rising rapidly with increased luminosity (146). UVA exposure of the skin of blinded individuals can lead to a slight increase of serum serotonin levels as well (147).

Serotonin was reported to have a risk-lowering effect on diabetes and a risk-increasing effect on hypertension (148-152).

Exposure of keratinocytes to UV radiation leads to production of an opioid 3-endorphin. This 3-endorphin, released into the blood during UV exposure, may reach the brain in sufficient concentrations to induce mood enhancement and relaxation. Some, but not all, studies in humans have demonstrated increased 3-endorphin levels in the blood after UV exposure (14). Administration of the opioid antagonist naltrexone, used for treatment of opioid dependence, reduced UV preference and even induced withdrawal symptoms in frequent tanners (153).

3.3.7.    Circadian clocks

Proper circadian clock function is essential for the coordination of cellular functions in response to light and dark cycles. Exposure to light is the most important stimulus for the circadian rhythm, and an unnatural exposure to light can weaken and/or disturb the circadian rhythm.

The circadian rhythms of both central and peripheral clocks are regulated by feedback loops generated by interplaying clock proteins (108,109). The positive limb of the clock machinery comprises CLOCK and BMAL1, which heterodimerize and induce expression of clock-controlled genes. The cryptochrome (CRY1 and CRY2) and period (PER1, PER2 and PER3) families are clock-controlled genes and encode proteins that regulate negatively the circadian machinery (108,109). The circadian clock regulates key aspects of cell growth and survival, including cell cycle, DNA damage responses, and metabolism (108-110). Animal experiments have established convincing links between some clock genes and carcinogenesis, and also between clock genes and metabolic syndrome (108,110).

3.3.8.    Melatonin

Melatonin is produced predominantly in the pineal gland, and, in lesser amounts, in the brain and extracranial sites. The melatonin precursor serotonin is normally produced during the day and only converted to melatonin in darkness. Pineal production and release of melatonin is controlled by the biologic clock in the SCN and by exposure to light. It is secreted at a daily rhythm, peaking near the middle of the night, while concentrations remain very low during daytime (145). The phase and amplitude of the nocturnal peak are controlled by exposure to light. A robust exposure to light during the day increases the amplitude, and the timing of the exposure determines the phase of the nocturnal peak. In contrast, small amounts of light during the evening and at night can reduce circulating melatonin levels (122,123,145,154).

Melatonin has a potent anti-oxidant effect and is potentially anti-metastatic, anti-angiogenic, and capable of the induction of apoptosis and cell-cycle arrest. Animal experiments and studies with cultured cancer cells have shown that melatonin has a potential for inhibition of colon-, breast-, and prostate cancer (155-158). Studies in humans reported an inverse association between high levels of the primary urinary metabolite of melatonin, 6-sulfatoxymelatonin and the risk of prostate cancer in men and breast cancer in women (159163). In vitro melatonin increases the sensitivity of a rat breast cancer cell line to vitamin D (164).

Melatonin may play a role in the regulation of BP and glucose homeostasis (145,154,165-168).

3.3.9. Folic acid

Folic acid is essential for human health. It is involved in DNA synthesis, DNA repair, and amino acid metabolism, and, consequently, it is especially important in rapidly dividing cells, such as (pre)malignant cells and those present in the embryo and the seminiferous tubules. Deficiency is linked to birth defects and megaloblastic anemia. It may also be a risk factor for some cancers and cardiovascular disease, although the role of folate in these diseases is controversial (14,169,170). UV radiation can degrade folic acid in in-vitro studies, which was confirmed in several human studies (18,19,170-172). Consequently, photodegradation of folic acid may lead to folate deficiency. However, the degree and health consequences of such photodegradation are unknown (169,170). (Table 7)

4. Discussion

The geographic variation in human skin color is one of the best examples of natural selection, resulting in an appropriate adjustment of levels of pigmentation to levels of UV radiation (20). The most well-established explanation assumes that the optimal degree of skin pigmentation is a balance between skin dark enough to protect our cells from too much UV radiation, and yet light enough to permit sufficient penetration of UV rays in order to let them execute their beneficial effects, e.g. the photosynthesis of vitamin D. High ambient UV near the equator led to the evolution of dark photoprotective skin, in which melanin acts as natural sun block. Low UV environments led to depigmented skin (18,19,27).

In the millennia before the industrial revolution, and before fast long-distance travel and migration of lightly pigmented people to sunny climates, the skin color of a population reflected an adequate balance between the advantages and disadvantages of sunlight. In the last two centuries, however, this balance has been disturbed progressively by migration and changes in lifestyle leading to a completely different pattern of exposure to sunlight (18,19).

The 'epidemic' of skin cancer can be considered as the most striking result of this unbalance. Most skin cancers are caused by a mismatch between skin type and geography and/or sun exposure related lifestyle.

Incidence rates of melanoma have continued to rise now for several decades. Rates have been rising steadily in generations born up to the end of the 1940s, followed by a stabilization or decline in rates for more recently born cohorts in Australia, New Zealand, the U.S., Canada, and Norway (34). It is not clear whether this is mainly the result of prevention-campaigns or whether the peak of the epidemic has just been reached; possibly a combination of these two. According to an analysis of the WHO mortality database, mortality rates of melanoma increased in successive generations from 1875 until a peak year (173). Peak years were for subjects born in

Table 7. Summary of the (recently discovered) biological effects of (sun)light)

Pathways

Effects of sunlight exposure

Implications

DNA

damage

-Mutagenic

-Carcinogenic

-Increase of skin cancer risk

Photo

adaptation

-Thickening of the epidermis -Increase of pigmentation

-Protection against DNA damage and burning

Immuno-

modulation

-Stimulation of T-reg cells -Secretion of IL-10 -Reduction of IL-17 -Dampening of T-helper (Th-1) immune function

-Immunosuppression (both local and systemic)

-Increased risk of (skin) cancer

-Possibly decreased risk of MS, diabetes and NHL

Vitamin D synthesis

-Stimulation of photosynthesis in the skin

-Inhibition of proliferation, angiogenesis and metastasis, stimulation of differentiation and apoptosis; possibly decreasing cancer risk and improving prognosis

-Enhanced immuno-tolerance: possibly reducing risk of MS, diabetes and NHL - Increased insulin secretion and decreased insulin resistance: possibly reducing risk of diabetes -Maintenance of musculoskeletal health

Nitric oxide

(NO)

release

-Mobilization of NO from the skin

into the circulation

-Vasodilatation, lowering of blood pressure -Decreasing of glucose intolerance and insulin resistance, probably reducing risk of diabetes

Serotonin

production

-Increased production

-Mood improvement

-Possibly reduction of risk of diabetes

-Possibly risk increasing effect on hypertension

Endorphin

production

-Possibly increased levels of endorphins

-Mood improvement -Pain relief

Circadian

clocks

-Natural exposure to (sun)light reinforces circadian rhythm and prevents rhythm disturbances -Circadian clocks regulate key aspects of cell growth, DNA damage responses and metabolism

-Probably reduction of risk and improvement of prognosis in breast-, prostate cancer and NHL -Probably reduction of risk of weight gain and diabetes

-Mood, sleep, and cognition improvement

Melatonin

production

-Sufficient exposure to (sun)light increases nocturnal melatonin peak

-Melatonin possibly plays a role in the regulation of blood pressure and glucose homeostasis

-Possibly reduction of breast- and prostate cancer risk

-Possibly reduction of hypertension and diabetes risk

Folic acid degradation

-Lower levels of folate

-Health consequences unknown


1937-1943 in North America, 1941-1942 in Northern Europe, 1945-1953 in the United Kingdom and Ireland, and 1948 in Western

Europe. After peak years, lifetime risk of melanoma death gradually decreased in successive generations. It is expected that, as time passes, melanoma deaths will steadily rarefy in younger age groups and concentrate in older age groups (173).

After reviewing in great detail the relationship between skin cancers and sun exposure the WHO in 1992 accepted sun exposure as the main exogenous cause of cutaneous melanoma in humans (5). The available data were: observational studies in humans, experimental induction of skin cancers in animals, and other relevant data. Other relevant data considered were related to the, at that time, limited insights in the effects of UV on immunity and in the mechanisms of UV-associated DNA-damage (5). Randomized controlled trials are not available, since they are considered unfeasible and unethical. Even at present, there is discussion on the value of sunscreens in the prevention of melanoma (174-176).

The strength of the WHO conclusion was debated. The results from epidemiological studies on melanoma were considered inconsistent by some, and the relationship between sunlight exposure and melanoma risk is not a straightforward one, as is illustrated by higher incidence rates of melanoma among indoor than outdoor workers and higher incidences in the north of Europe than in the south (39,40). More convincing answers to a number of questions on effects of sun exposure were still needed at that time. Such questions included whether the pattern of sun exposure is really important, whether it acts independently of the amount of sun exposure, and whether sunburn makes a specific contribution to the risk of skin cancer. At present observational studies support the 'intermittent sun exposure hypothesis' for melanoma:    a positive

association of the latter with intermittent sun exposure and sunburn, but an inverse association with a continuous pattern of sun exposure (38). This inverse association appeared to be latitude dependent (41,45). Recently it became clear that for risk of BCC and SCC the pattern of exposure and latitude is of importance as well, particularly in Europe. Both chronic and intermittent exposure increase the risk in southern Europe, while in the north a more continuous pattern of exposure confers a relatively moderate risk (48,50).

Extensive programs for the primary prevention of skin cancer were developed, commencing in Australia in the 1980 decade with the ''Slip, Slop, Slap'' (Slip on a shirt, Slop on a sunscreen, and Slap on a hat) program, followed by the Sun Smart program. The WHO introduced the UV index: a measure of biologically effective UV radiation, designed to inform the public of UV levels. The Australian prevention programs were adopted and copied by most Western countries. They consist mainly of avoidance of the sun in the middle of the day, the use of sunlight-protective clothing, and more or less continuous use of sunscreens with a SPF of 30 or higher, that protect against UVA and UVB (7). These sun advices are more or less similar all over the world. They are without doubt useful for persons with a sun-sensitive skin living in Australia or other countries with high ambient UV. However, it is questionable whether they should be used in North-western Europe, where chronic exposure and outdoor occupations are associated with a relatively low risk of melanoma and BCC and even SCC (in Scandinavia) (44,48-51).

Regular exposure to UV leads to an almost complete disappearance of DNA damage in the basal and suprabasal layers of the epidermis, where the initiating of skin cancer occurs (135137). This might explain the 'risk-lowering' effect of regular exposure, whereby photosynthesis of extra vitamin D and/or other effects of (sun)light may contribute to this phenomenon as well. Regular exposure decreases melanoma risk in North-western Europe (with low UV indices and a short "sunny season"), whereas in Southern Europe (with relatively high UV indices and a long "sunny season") it is associated with an increased risk. Compared to inhabitants of Southern Europe, those of North-western Europe have a lesser capability of tanning, but the same capability of thickening of the epidermis, which attributes more to the protection of the skin to UV (134). Consequently, as has been suggested by Newton-Bishop and co-workers (45), regular exposure might be more important for melanoma risk in high UV environments. Additionally self-selection against outdoor work by fair-skinned people living in regions with high ambient UV could also lower the estimates of melanoma risk in those who had high occupational exposure (41).

With all these recent data in mind it is obvious that a clerk in Scandinavia with skin type 3 (sometimes mild sunburns, moderate tan) needs a different advice than a farmer in Queensland with skin type 1 (always burns, never tans). We contend that sun advices which are more individualized, both per country or climate and skin type, contribute more to human health than the present guidelines.

There are additional reasons to reconsider the present sun advice, particularly for people living in temperate climates. Present generations expose themselves less and in a more intermittent pattern to sunlight, and less to bright light during the day, and more to artificial light in the evening and at night than their ancestors. This change of exposure might not only lead to an increase of skin cancer, but to a decrease of the positive effects of (sun)light as well. These positive effects comprise both the well-established effects and the recently discovered effects. Epidemiological studies suggest that regular exposure to the sun and a natural exposure to light is inversely associated with the risk of colon-, breast-, prostate cancer, NHL, as well as MS, and metabolic syndrome (12,15,21,57,67-76,82-87,91-93,108,110).These associations are generally consistent, but the question is whether they are causal. Reverse causality cannot be excluded completely. Recent animal experiments, however, show that sunlight may indeed prevent breast-, intestinal cancer, MS and metabolic syndrome (11,16,59,95). Experiments in humans show that UV can lower blood pressure and increase insulin secretion (88-90,94). Insights into the involved mechanisms of action of sunlight are increasing gradually. In addition to the production of vitamin D, immunomodulation, the role of circadian clocks, the formation of nitric oxide, melatonin, and serotonin are important as well. Influence of formation of endorphin and the photodegradation of folic acid is more speculative. These biological effects may function simultaneously and in some instances even re-enforce each other's effect (32,164).

Thus far, the effects of too little sunlight during the daytime were studied separately from the effects of too much artificial light during the night. There is a need of studies on the combined effects of too little sunlight during the day and too much artificial light at night, a situation nowadays so prevalent almost everywhere throughout the world (32). Recent data suggest that decreased sunlight exposure during daytime can negatively affect circadian rhythmicity (177), while sufficient day-time exposure can prevent disruption of the circadian rhythm (178).

The question can be raised whether the present sun-shunning advices benefit our general health; there is no unequivocal scientific proof that they do. We could identify three prospective studies on the influence of sun exposure and sun avoidance on total mortality. Two Scandinavian studies, using personal exposure data, (179,180) found a significant negative association between sun exposure and mortality, while an American study, using ambient residential exposure data (181) found no evidence of a beneficial effect of sunlight.

At present the question "how much sunlight do we need?" is difficult to answer. Even from the viewpoint of skin cancer prevention and the avoidance of vitamin D sufficiency, the answer is complex. Regarding other biological effects of sunlight, such as immunosuppression, NO-, serotonin-, and melatonin synthesis, it is even more difficult to estimate a "healthy sun exposure" (182,183).

The present sun advices most likely lead to a decrease in the risk of skin cancer. It is obvious that excessive sun exposure and sunburn should be avoided. During sun-seeking vacations an adequate protection is needed. It is, however, unlikely that continuous protection during daily life contributes to our health, particularly in countries with a temperate climate. Both too much and too little sunlight may be harmful to our health.

Abbreviations:

BCC, basal cell carcinoma;

BMAL1, brain and muscle ARNT-like 1;

BP, blood pressure;

CLOCK,circadian locomotor output cycles kaput; CPD, cyclobutane pyrimidine dimer;

CRY, cryptochrome;

DM, diabetes mellitus;

EAE, experimental autoimmune encephalomyelitis;

IARC, International Agency for Research on Cancer;

MS, multiple sclerosis;

NHL, non-Hodgkin lymphoma;

NO, nitric oxide;

OCA2, oculocutaneous albinism gene2;

PER, period;

SCC, squamous cell carcinoma;

SCN, suprachiasmatic nucleus;

SLC45A2, solute carrier family 45 member 2;

UV, ultraviolet radiation;

UVA,    ultraviolet radiation of wavelength 315400 nm;

UVB,    ultraviolet radiation of wavelength 280315 nm;

References

1.    Huldschinsky K. Heilung von Rachitis durch kunstliche Hohensonne. Dtsch Med Wochenschr. 1919;14:712-13.

2.    Dietrich H. Heliotherapy with special reference to the work of Dr. Rollier at Leysin. JAMA. 1913;61:2229-32.

3.    Titus EC. The uses of light in the treatment of disease. Sci Am. 1915;79(Suppl 2050):255.

4.    Albert MR, Ostheimer KG. The evolution of current medical and popular attitudes toward ultraviolet light exposure: Part 2. J Am Acad Dermatol. 2003 Jun;48(6):909-18. DOI: 10.1067/mjd.2003.272.

5.    International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, vol.55: Solar and ultraviolet radiation. Lyon, France: IARC Press; 1992.

6.    Albert MR, Ostheimer KG. The evolution of current medical and popular attitudes toward ultraviolet light exposure: Part 3. J Am Acad Dermatol 2003 Dec;49(6):1096-1106. DOI: 10.1016/S0190-9622(03)00021-5.

7.    McCarthy WH. The Australian experience in sun protection and screening for melanoma. J Surg Oncol. 2004 Jul 1;86(4):236-45. DOI: 10.1002/jso.20086.

8.    Lim HW, Hawk JLM. In: Bolognia JL, Jorizzo JL, MD, Schaffer JV, eds. Dermatology. Philadelphia: Elsevier Saunders, 2012.

9.    Hawk JLM, Young AR, Ferguson J. In: Burns T, Breathnach S, Cox N, Griffith C, eds. Rook's Textbook of Dermatology, 8th Edition. Oxford: Wiley-Blackwell, 2013.

10.    Lucas RM, Norval M, Neale RE, Young AR, de Gruijl FR, Takizawa, et al. The consequences for human health of stratospheric ozone depletion in association with other environmental factors. Photochem Photobiol Sci. 2015 Jan;14(1):53-87. DOI: 10.1039/C4PP90033B.

11.    Becklund BR, Severson KS, Vang SV, DeLuca HF. UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proc Natl Acad Sci. 2010 Apr 6;107(14):6418-23. DOI: 10.1073/pnas.1001119107.

12.    Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, et al. Sun exposure and vitamin

D are independent risk factors for CNS demyelination. Neurology. 2011 Feb 8;76(6):540-48. DOI: 10.1212/WNL.0b013e31820af93d.

13.    Hart PH, Gorman S, Finlay-Jones JJ. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol. 2011 Aug 19;11(9):584-96. DOI: 10.1038/nri3045.

14.    Juzeniene A, Moan J. Beneficial effects of UV radiation other than via vitamin D production. Dermatoendocrinol. 2012 Apr 1;4(2)109-17. DOI: 10.4161/derm.20013.

15.    Van der Rhee HJ, Coebergh JW, de Vries E. Is prevention of cancer by sun exposure more than just the effect of vitamin D? A systematic review of epidemiological studies. Eur J Cancer. 2013 Apr;49(6):1422-36. DOI: 10.1016/j.ejca.2012.11.001.

16.    Rebel H, Dingemanse-van der Spek C, Salvatori D, van Leeuwen JP, Robanus-Maandag EC, de Gruijl FR. UV exposure inhibits tumour growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. Int J Cancer. 2015 Jan 15;136(2):271-77. DOI: 10.1002/ijc.29002.

17.    Parra EJ. Human pigmentation variation: evolution, genetic basis and implications for public health. Yearbook of Physical Anthropology 2007;134 (Suppl 45):85-105. DOI: 10.1002/ajpa.20727.

18.    Jablonski NH, Chaplin G. Human skin adaptation as an adaptation to UV radiation. Proc Natl Acad

Sci USA. 2010 May 11;107 Suppl 2:8962-68. DOI: 10.1073/pnas.0914628107.

19.    Jablonski NG, Chaplin G. Human skin pigmentation, migration and disease susceptibility. Philos Trans R Soc Lond B Biol Sci. 2012 Mar 19;367(1590):785-92. DOI: 10.1098/rstb.2011.0308.

20.    Relethford JH. Hemispheric difference in human skin color. Am J Phys Anthropol. 1997 Dec;104(4):449-57. DOI: 10.1002/(SICI)1096-8644(199712)104:4<449::AID-AJPA2>3.0.CO;2-N.

21.    Van der Rhee HJ, de Vries E, Coebergh JW. Does sunlight prevent cancer? A systemic review. Eur J Cancer. 2006 Sep;42(14):2222-32. DOI: 10.1016/j.ejca.2006.02.024.

22.    Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, et al. Genetic evidence for the convergent evolution of light skin in Europeans and East Asians. Mol Biol Evol. 2007 Mar;24(3):710-22. DOI: 10.1093/molbev/msl203.

23.    Sturm AR, Duffy DL. Human pigmentation genes under environmental selection. Genome Biology.

2012 Sep 26;13(9):248-64. DOI: 10.1186/gb-2012-13-9-248.

24.    Liu F, Visser M, Duffy DL, Hysi PG, Jacobs LC, Lao O, et al. Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up. Hum Genet. 2015 2015 Aug;134(8):823-35. DOI: 10.1007/s00439-015-1559-0.

25.    Lucotte G, Yuasa. Near fixation of 374L allele frequencies of the skin pigmentation gene SLC45A2

in Africa. Biochem Genet. 2013 Oct;51(9-10):655-65. DOI: 10.1007/s10528-013-9595-8.

26.    Lucotte G, Mercier M, Dieterlen F, Yuasa I. A decreasing gradient of 374F allele frequencies in the skin pigmentation gene SLC45A2, from the north of West Europe to North Africa. Biochem Genet. 2010 Feb;48(1-2):26-33. DOI: 10.1007/s10528-009-9289-4.

27.    Rees JL, Harding RM. Understanding the evolution of human pigmentation: recent contributions from population genetics. J Invest Dermatol. 2012 Mar;132(3 Pt 2):846-53. DOI: 10.1038/jid.2011.358.

28.    Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality. A review of recent evidence. Autoimmun Rev. 2013 Aug;12(10):976-89. DOI: 10.1016/j.autrev.2013.02.004.

29.    Thieden E. Sun exposure behaviour among subgroups of the Danish population. Based on personal electronic UVR dosimetry and corresponding exposure diaries. Dan Med Bull. 2008 2008 Feb;55(1):47-68. DOI: 10.1111/j.1600-0781.2006.00207.x.

30.    Knuschke P, Unverricht I, Ott G, Janssen M. Personenbezogene Messung der UV-Exposition von Arbeitnehmer im Freien. Dortmund, Deutschland., 2009. [http://www.baua.de/nn-11598/de/Publikationen/FachbeitraegF1777.html]

31.    Wyse CA, Selman C, Page MM, Coogan AN, Hazlerigg DG. Circadian desynchrony and metabolic dysfunction; did light pollution make us fat? Medical Hypotheses. 2011 Dec;77(6):1139-44. DOI:10.1016/j.mehy.2011.09.023.

32.    Smolensky MH, Sackett-Lundeen LL, Portaluppi F. Nocturnal light pollution and underexposure to

daytime sunlight: Complementary mechanisms of circadian disruption and related diseases. Chronobiol Int. 2015;32(8):1029-1048. DOI: 10.3109/07420528.2015.1072002.

33.    International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic

risks to humans, vol.98: Painting, Fire-Fighting and Shiftwork. Lyon, France: IARC Press; 2010.

34.    Erdmann F, Lortet-Tieulent J, Schuz J, Zeeb H, Greinert R, Breitbart EW, et al. International trends

in the incidence of malignant melanoma 1953-2008—are recent generations at higher or lower risk? Int J Cancer. 2013 Jan 15;132(2):385-400. DOI: 10.1002/ijc.27616.

35.    Xiang F, Lucas R, Hales S, Neale R. Incidence of nonmelanoma skin cancer in relation to ambient

UV radiation in white populations, 1978-2012. Empirical relationships. JAMA Dermatol. 2014 Oct;150(10):1063-71. DOI: 10.1001/jamadermatol.2014.762.

36.    Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J Photochem Photobiol B.

2001 Oct;63(1-3):8-18. DOI: 10.1016/S1011-1344(01)00198-1.

37.    Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, et al. Meta-analysis of risk factors

for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005 Sep;41(14):2040-59. DOI: 10.1016/j.ejca.2005.03.034.

38.    Gandini S, Sera F, Cattaruzza MF, Pasquini P, Picconi O, Boyle P, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005 Jan;41(1):45-60. DOI: 10.1016/j.ejca.2004.10.016.

39.    Nelemans PJ, Rampen FH, Ruiter DJ, Verbeek ALM. In addition to the controversy on sunlight exposure and melanoma risk: a meta-analytic approach. J Clin Epidemiol. 1995 Nov;48(11):1331-42. DOI: 10.1016/0895-4356(95)00032-1.

40.    Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer. Oct 9;73(2):198-203. DOI: 10.1002/(SICI)1097-0215(19971009)73:2<198::AID-IJC6>3.0.CO;2-R.

41.    Chang YM, Barrett JH, Bishop DT, Armstrong BK, Bataille V, Bergman W, et al. Sun exposure and

melanoma risk at different latitudes : a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009 Jun;38(3):814-30. DOI: 10.1093/ije/dyp166.

42.    Nelemans PJ, Groenendal H, Kiemeney LA, Rampen FH, Ruiter DJ, Verbeek AL. Effect of intermittent exposure to sunlight on melanoma risk among indoor workers and sun-sensitive individuals. Environ Health Perspect. 1993 Aug;101(3):252-55.

43.    Kennedy C, Bajdik CD, Willemze R, De Gruijl FR, Bouwes Bavinck JN. The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol. 2003 Jun;120(6):1087-93. DOI: 10.1046/j.1523-1747.2003.12246.x.

44.    Kenborg L, Jorgensen AD, Budtz-Jorgensen E, Knudsen LE, Hansen J. Occupational exposure to the sun and risk of skin and lip cancer among male wage earners in Denmark: a population-based case-control study. Cancer Causes Control. 2010 Aug;21(8):1347-52. DOI: 10.1007/s10552-010-9562-1.

45.    Newton-Bishop JA, Chang YM, Elliott F, Chan M, Leake S, Karpavicius B, et al. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate. Eur J Cancer. 2011 Mar;47(5):732-41. DOI: 10.1016/j.ejca.2010.10.008.

46.    Kricker A, Armstrong BK, English DR, Heenan PJ. Does intermittent sun exposure cause basal cell carcinoma? A case-control study in Western Australia. Int J Cancer. 1995 Feb 8;60(4):489-94. DOI: 10.1002/ijc.2910600411.

47.    Khalesi M, Whiteman DC, Rosendahl C, Johns R, Hackett T, Cameron A, et al. Basal cell carcinomas

on sun-protected vs. sun-exposed body sites: a comparison of phenotypic and environmental risk factors. Photodermatol Photoimmunol Photomed. 2015    Jul;31(4):202-11. DOI:10.1111/phpp.12170.

48.    Bauer A, Diepgen TL, Schmitt J. Is occupational solar ultraviolet radiation a relevant risk factor for

basal cell carcinoma? A systematic review and meta-analysis of the epidemiological literature. Br J Dermatol. 2011 Sep;165(3):612-25. DOI: 10.1111/j.1365-2133.2011.10425.x.

49.    Surdu S, Fitzgerald EF, Bloom MS, Boscoe FP, Carpenter DO, Haas RF, et al. Occupational exposure

to ultraviolet radiation and risk of non-melanoma skin cancer in a multinational European study. PLoS One 2013 Apr 24;8(4):e62359. DOI: 10.1371/journal.pone.0062359.

50.    Schmitt J, Seidler A, Diepgen TL, Bauer A. Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: a systemic review and metaanalysis. Br J Dermatol. 2011 Feb;164(2):291-307. DOI: 10.1111/j.1365-2133.2010.10118.x.

51.    Adami J, Gridley G, Nyren O, Dosemeci M, Linet M, Glimelius B, et al. Sunlight and non-Hodgkin's lymphoma: a population-based cohort study in Sweden. Int J Cancer. 1999 Mar 1;80(5):641-45. DOI: 10.1002/(SICI)1097-0215(19990301)80:5<641::AID-IJC1>3.0.CO;2-Z.

52.    Tang JY, Fu T, Lau C, Oh DH, Bikle DD, Asgari MM. Vitamin D in cutaneous carcinogenesis. Part II. J Am Acad Dermatol. 2012 Nov;67(5):817:e1-11. DOI: 10.1016/j.jaad.2012.07.022.

53.    Caini S, Boniol M, Tosti G, Magi S, Medri M, Stanganelli I, et al. Vitamin D and melanoma and non

melanoma skin cancer risk and prognosis: A comprehensive review and meta-analysis. Eur J Cancer. 2014 Oct;50(15):2649-58. DOI: 10.1016/j.ejca.2014.06.024.

54.    Newton-Bishop JA, Davies JR, Latheef F, Randerson-Moor J, Chan M, Gascoyne J, et al. 25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort. Int J Cancer. 2015 Jun 15;136(12);136:2890-9. DOI: 10.1002/ijc.29332.

55.    Wyatt C, Lucas RM, Hurst C, Kimlin MG. Vitamin D deficiency is associated with higher Breslow thickness. PloS One. 2015 May 13;10(5):e0126394. DOI: 10.1371/journal.pone.0126394.

56.    Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31. DOI: 10.1093/ije/9.3.227.

57.    Van der Rhee HJ, Coebergh JW, de Vries E. Sunlight, vitamin D and the prevention of cancer: a systematic review of epidemiological studies. Eur J Cancer Prev. 2009 Nov;18(6):458-75. DOI: 10.1097/CEJ.0b013e32832f9bb1.

58.    Kricker A, Armstrong BK, Hughes AM, Goumas C, Smedby KE, Zheng T, et al. Personal sun exposure and risk of non-Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium. Int J Cancer. 2008 Jan 1;122(1):144-54. DOI: 10.1002/ijc.23003.

59.    Valrance ME, Brunet AH, Welsh J. Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo. Endocrinology. 2007. Oct;148(10):4887-94. DOI: 10.1210/en.2007-0267.

60.    Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011 Mar 15;128(6):1414-24. DOI: 10.1002/ijc.25439.

61.    Ordonez Mena JM, Brenner H. Vitamin D and cancer: an overview on epidemiological studies. Adv Exp Med Biol. 2014;810:17-32.

62.    Bauer SR, Hankinson SE, Bertone-Johnson, Ding E. Plasma vitamin D levels, menopause, and risk of breast cancer. Dose-response meta-analysis of prospective studies. Medicine. 2013 May;92(3): 123-31. DOI: 10.1097/MD.0b013e3182943bc2.

63.    Lu D, Chen J, Jin J. Vitamin D status and risk of non-Hodgkin lymphoma: a meta-analysis. Cancer Causes Control. 2014 Nov;25(11):1553-63. DOI: 10.1007/s10552-014-0459-2.

64.    Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014 May;14(5):342-57. DOI: 10.1038/nrc3691.

65.    Tagliabue E, Raimondi S, Gandini S. Vitamin D, cancer risk, and mortality. Adv Food Nutr Res. 2015;75:1-52. DOI: 10.1016/bs.afnr.2015.06.003.

66.    Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, et al. A trial of calcium and vitamin D for the prevention of colorectal adenomas. N Engl J Med. 2015 Oct 15;373(16):1519-1531. DOI: 10.1056/NEJMoa1500409.

67.    Ebers GC, SadovnickAD. The geographic distribution of multiple sclerosis: a review. Neuroepidemiology. 1993;12(1):1-5. DOI: 10.1159%2F000110293.

68.    Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011 Oct;82(10):1132-41. DOI: 10.1136/jnnp.2011.240432.

69.    Freedman DM, Dosemeci M, Alavanja MC. Mortality from multiple sclerosis and exposure to residential and occupational solar irradiation: a case control study based on death certificates. Occup Environ Med. 2000 Jun;57(6):418-21. DOI: 10.1136/oem.57.6.418.

70.    Van der Mei IAF, Ponsonby Al, Dwyer T, Blizzard L, Simmons R, et al. Past exposure to sun, skin

phenotype and risk of multiple sclerosis: case control study. Br Med J. 2003 Aug 9;327(7410):316-22. DOI: 10.1136/bmj.327.7410.316.

71.    Van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, et al. Vitamin D levels in

people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol. 2007 May;254(5):581-90. DOI: 10.1007/s00415-006-0315-8.

72.    Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood sun exposure influences risk of multiple

sclerosis in monozygotic    twins. Neurology.    2007    Jul    24;69(4):381-88.    DOI:

10.1212/01.wnl.0000268266.50850.48.

73.    Tremlett H, Van der Mei IA, Pittas F, Blizzard L, Paley G, Mesaros D, et al. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-79. DOI: 10.1159/000166602.

74.    Dwyer T, van der Mei I, Ponsonby AL, Taylor BV, Stankovich J, McKay JD, et al. Melanocortin 1 receptor genotype, past environmental sun exposure, and risk of multiple sclerosis. Neurology. 2008 Aug 19;71(8):583-89. DOI: 10.1212/01.wnl.0000323928.57408.93.

75.    Westberg M, Feychting M, Jonsson F, Nise G, Gustavsson P. Occupational exposure to UV light

and mortality from multiple    sclerosis. Am J Ind    Med.    2009    May;52(5):353-57.    DOI:

10.1002/ajim.20682.

76.    Baarnhielm M, Hedstrom AK, Kockum I, Sundqvist E, Gustafsson SA, Hillert J, et al. Sunlight is associated with multiple sclerosis risk: no interaction with leukocyte antigen-DRB1*15. Eur J Neurol. 2012 Jul;19(7):955-62. DOI: 10.1111/j.1468-1331.2011.03650.x.

77.    Wang Y, Marling SJ, McKnight SM, Danielson AL, Severson KS, Deluca HF. Suppression of experimental autoimmune encephalomyelitis by 300-315 nm ultraviolet light. Arch Biochem Biophys. 2013 Aug 1;536(1):81-86. DOI: 10.1016/j.abb.2013.05.010.

78.    Wang Y, Marling SJ, Beaver EF, Severson KS, Deluca HF. UV light selectively inhibits spinal cord inflammation and demyelination in experimental autoimmune encephalomyelitis. Arch Biochem Biophys. 2015 Feb 1;567:75-82. DOI: 10.1016/j.abb.2014.12.017.

79.    Knippenberg S, Damoiseaux J, Bol Y, Hupperts R, Taylor BV, Ponsonby AL, et al. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand. 2014 Feb;129(2):123-31. DOI: 10.1111/ane.12155.

80.    Zivadinov R, Treu CN, Weinstock-Guttman B, Turner C, Bergsland N, O'Connor K, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1075-81. DOI: 10.1136/jnnp-2012-304661.

81.    Wong A. Incident solar radiation and coronary heart disease mortality rates in Europe. Eur J Epidemiol. 2008;23(9):609-14. DOI: 10.1007/s10654-008-9274-y.

82.    Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences.

Hypertension. 1997 Aug;30(2 Pt 1):150-56. DOI: 10.1161/01.HYP.30.2.150.

83.    Rose G. Seasonal variation in blood pressure in man. Nature. 1961 Jan 21;189:235. DOI: 10.1038/189235a0.

84.    Modesti PA, Morabito M, Massetti L, Orlandini S, Mancia G, Gensini GF, et al. Seasonal blood pressure changes. An independent relationship with temperature and daylight hours. Hypertension. 2013 Apr;61(4):908-14. DOI: 10.1161/HYPERTENSIONAHA.111.00315.

85.    Marti-Soler H, Gubelmann C, Aeschbacher S, Alves L, Bobak M, Bongard V, et al. Seasonality of cardiovascular risk factors: an analysis including over 230.000 participants in 15 countries. Heart. 2014 Oct;100(19):1517-23. DOI: 10.1136/heartjnl-2014-305623.

86.    Algert CS, Roberts CL, Shand AW, Morris JM, Ford JB. Seasonal variation in pregnancy hypertension is correlated with sunlight intensity. Am J Obstet Gynecol. 2010 Sep;203(3):215e1-5. DOI: 10.1016/j.ajog.2010.04.020.

87.    Immink A, Scherjon S, Wolterbeek R, Steyn DW. Seasonal influence on the admittance of preeclampsia patients in Tygerberg Hospital. Acta Obstet Gynecol Scand. 2008;87(1):36-42. DOI: 10.1080/00016340701743066.

88.    Weber KT, Rosenberg EW, Sayre RM. Suberythematal ultraviolet exposure and reduction of blood

pressure. Am J Med. 2004; Aug 15;117(4):281-83. DOI: 10.1016/j.amjmed.2004.03.016.

89.    Oplander C, Volkmar CM, Paunel-Gorgulu, van Faassen EE, Heiss C, Kelm M, et al. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res. 2009 Nov 6;105(10):1031-40. DOI: 10.1161/CIRCRESAHA.109.207019.

90.    Liu D, Fernandez BO, Hamilton A, Lang NN, Gallagher JM, Newby DE, et al. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J Invest Dermatol. 2014 Jul;134(7):1839-46. DOI: 10.1038/jid.2014.27.

91.    Mohr SB, Garland CF, Gorham ED, Garland FC. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia. 2008 Aug;51(8):1391-98. DOI: 0.1007/s00125-008-1061-5.

92.    Elliott JC, Lucas RM, Clements MS, Bambrick HJ. Population density determines the direction of the association between ambient ultraviolet radiation and type 1 diabetes incidence. Pediatric Diabetes. 2010 Sep;11(6):394-402. DOI: 10.1111/j.1399-5448.2009.00620.x.

93.    Shore-Lorenti C, Brennan SL, Sanders KM, Neale RE, Lucas RM, Ebeling PR. Shining the light on sunshine: a systematic review of the influence of sun exposure on type 2 diabetes mellitus-related outcomes. Clin Endocrinol. 2014 Dec;81(6):799-811. DOI: 10.1111/cen.12567.

94.    Colas C, Garabedian M, Fontbonne A, Guillozo H, Slama G, Desplanque, et al. Insulin secretion and plasma 1,25-(OH)2D after UV-B irradiation in healthy adults. Hormon Metabol Res. 1989 Mar;21(3):154-55. DOI: 10.1055/s-2007-1009178.

95.    Geldenhuys S, Hart PH, Endersby R, Jacoby P, Feelisch M, Weller RB, et al. Ultraviolet radiation suppresses obesity an symptoms of metabolic syndrome independently of vitamin D in mice fed a high-fat diet. Diabetes. 2014 Nov;63(11):3759-69. DOI: 10.2337/db13-1675.

96.    Wallis DE, Penckofer S, Sizemore GW. The "sunshine deficit" and cardiovascular disease. Circulation. 2008 Sep 30;118(14):1476-85. DOI: 10.1161/CIRCULATIONAHA.107.713339.

97.    Zittermann A, Gummert JF. Sun, vitamin D, and cardiovascular disease. J Photochem Photobiol B.

2010 Nov 3;101(2):124-9. DOI: 10.1016/j.jphotobiol.2010.01.006.

98.    Burgaz A, Orsini N, Larsson SC, Wolk A. Blood 25-hydroxyvitamin D concentration and

hypertension:a meta-analysis. J Hypertens. 2011    Apr;29(4):636-45. DOI:

10.1097/HJH.0b013e32834320f9.

99.    Poel YH, Hummel P, Lips P, Stam F, van der Ploeg T, Simsek S. Vitamin D and gestational diabetes: a systematic review and meta-analysis. Eur J Int Med. 2012 Jul;23(5):465-69. DOI: 10.1016/j.ejim.2012.01.007.

100.    Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr Soc. 2013 Feb;72(1):89-97. DOI: 10.1017/S0029665112002765.

101.    Afzal S, Bojesen SE, Nordestgaard BG. Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and meta-analysis. Clin Chem. 2013 Feb;59(2):381-91. DOI: 10.1373/clinchem.2012.193003.

102.    Ju SY, Jeong HS, Kim DH. Blood vitamin D status and metabolic syndrome in the general adult population: a dose-response meta-analysis. J Clin Endocrinol Metabol. 2014 Mar;99(3):1053-63. DOI: 10.1210/jc.2013-3577.

103.    Kienreich K, Tomaschitz A, Verheyen N, Pieber T, Gaksch M, Grubler MR, et al. Vitamin D and cardiovascular disease. Nutrients. 2013 Jul 31;5(8):3005-21. DOI: 10.3390/nu5083005.

104.    Beveridge LA, Struthers AD, Khan F, Jorde R, Scragg R, Macdonald HM, et al. Effect of vitamin D

supplementation on blood pressure: A systematic review and meta-analysis incorporating individual patient data. JAMA Intern Med.    2015    May;175(5):745-54    DOI:

10.1001/jamainternmed.2015.0237.

105.    George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med. 2012 Aug;29(8):e142-e150. DOI: 10.1111/j.1464-5491.2012.03672.x.

106.    Mitchell DM, Leder BZ, Cagliero E, Mendoza N, Henao MP, Hayden DL, et al. Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial. Am J Clin Nutr. 2015 Aug;102(2):385-92. DOI: 10.3945/ajcn.115.111682.

107.    Duranton F, Rodriguez-Ortiz M.E, Duny Y, Rodriguez M, Daures JP, Argiles A. Vitamin D treatment and mortality in chronic kidney disease: A systematic review and meta-analysis. Am J Nephrol. 2013;37(3):239-48. DOI: 10.1159/000346846.

108.    Sahar S, Sassone-Corsi P. Metabolism and cancer: the circadian clock connection. Nat Rev Cancer. 2009 Dec;9(12):886-96. DOI: 10.1038/nrc2747.

109.    Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Ann Rev Neurosci. 2012;35:445-62. DOI: 10.1146/annurev-neuro-060909-153128.

110.    Sahar S, Sassone-Corsi. Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab. 2012 Jan;23(1):1-8. DOI: 10.1016/j.tem.2011.10.005.

111.    Stevens RG. Working against our endogenous circadian clock: Breast cancer and electric lighting

in the modern world. Mutat Res. 2009    Nov-Dec;680(1-2):106-8. DOI:10.1016/j.mrgentox.2009.08.004.

112.    Stevens RG, Brainard GC, Blask DE, Lockley SW, Motta ME. Breast cancer and circadian disruption from electric lighting in the modern world. CA Cancer J Clin. 2014 May-Jun;64(3):207-18. DOI: 10.3322/caac.21218.

113.    Sigurdardottir LG, Valdimarsdottir UA, Fall K, Rider JR, Lockley SW, Schernhammer E, et al. Circadian disruption, sleep loss, and prostate cancer risk: a systematic review of epidemiologic studies. Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1002-11. DOI: 10.1158/1055-9965.EPI-12-0116.

114.    Flynn-Evans EE, Mucci L, Stevens RG, Lockley SW. Shiftwork and Prostate-Specific Antigen in National Health and Nutritional Examination Survey. J Natl Cancer Inst. 2013 Sep 4;105(17);105:1292-97. DOI: 10.1093/jnci/djt169.

115.    Kohyama J. A newly proposed disease condition produced by light exposure during night: asynchronization. Brain Dev. 2009 Apr;31(4):255-73. DOI: 10.1016/j.braindev.2008.07.006.

116.    Driesen K, Jansen NW, van Amelsvoort LG, Kant I. The mutual relationship between shift work and depressive complaints - a prospective study. Scand J Work Environ Health. 2011 Sep;37(5):402-10. DOI: 10.5271/sjweh.3158.

117.    Gonzalez R. The relationship between bipolar disorder an biological rhythms. J Clin Psychiatry. 2014 Apr;75(4):e323-31. DOI: 10.4088/JCP.13r08507.

118.    Hedstrom AK, Akerstedt T, Hillert J, Olsson T, Alfredsson L. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011 Nov;70(5):733-41. DOI: 0.1002/ana.22597.

119.    Scheer FAJL, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci USA. 2009 Mar 17;106(11):4453-58. DOI: 10.1073/pnas.0808180106.

120.    Maury E, Ramsey KM, Bass J. Circadian rhythms and metabolic syndrome: from experimental

genetics to    human disease. Circ Res. 2010 Feb    19;106(3):447-62.    DOI:

10.1161/CIRCRESAHA.109.208355.

121.    Bailey SM, Udoh US, Young ME. Circadian regulation of metabolism. J Endocrinol. 2014 Aug;222(2):R75-R96. DOI: 10.1530/JOE-14-0200.

122.    Cajochen C, Chellapa S, Schmidt C. What keeps us awake? The role of clocks and hourglasses, and melatonin. Int Rev Neurobiol. 2010;93:57-90. DOI: 10.1016/S0074-7742(10)93003-1.

123.    Kozaki T, Toda N, Noguchi H, Yasukouchi A. Effect of different light intensities in the morning on dimlight melatonine onset. J Physiol Anthropol. 2011;30(3):97-102. DOI: 10.2114/jpa2.30.97.

124.    Wright KP, McHill AW, Birks BR, Griffin BR, Rusterholz T, Chinoy ED. Entrainment of the human circadian clock to the natural dark-light cycle. Curr Biol. 2013 Aug 19;23(16):1554-58. DOI: 10.1016/j.cub.2013.06.039.

125.    Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):268-70. DOI:

126.    Zhu Y, Leaderer D, Guss C, Brown HN, Zhang Y, Boyle P, et al. Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma. Int J Cancer. 2007 Jan 15;120(2):432-35. DOI: 10.1002/ijc.22321.

127.    Hoffman AE, Zheng T, Stevens RG, Ba Y, Zhang Y, Leaderer D, et al. Clock-cancer connection in non-Hodgkin lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome2. Cancer Res. 2009 Apr 15;69(8):3605-13. DOI: 10.1158/0008-5472.CAN-08-4572.

128.    Truong T, Liquet B, Menegaux F, Plancoulaine S, Laurent-Puig P, Mulot C, et al. Breast cancer risk, nightwork, and circadian clock gene polymorphisms. Endocr Relat Cancer. 2014 Aug;21(4):629-38. DOI: 10.1530/ERC-14-0121.

129.    Rabstein S, Harth V, Justenhoven C, Pesch B, Heinze E, et al. Polymorphisms in circadian genes, night work and breast cancer: results from the GENICA study. Chronobiol Int. 2014 Dec;31(10):1115-22. DOI: 10.3109/07420528.2014.957301.

130.    Van Amelsvoort LG, Schouten EG, Kok FJ. Duration of shiftwork in relation to body mass index and waist to hip ratio. Int J Obes Relat Metab Disord. 1999 Sep;23(9):973-78.

131.    Parkes KR. Shift work and age as interactive predictors of body mass index among offshore workers. Scand J Work Environ Health. 2002 Feb;28(1):64-71. DOI: 10.5271/sjweh.648.

132.    Obayashi K, Saeki K, Iwamoto J, Okamoto N, Tomioka K, Nezu S, et al. Exposure to light at night, nocturnal urinary melatonin excretion, and obesity/dyslipidemia in the elderly: a cross-sectional analysis of the HEIJO-KYO study. J Clin Endocrinol Metab. 2013 Jan;98(1):337-44. DOI: 10.1210/jc.2012-2874.

133.    Elmets CA, Athar M. Milestones in photocarcinogenesis. J Invest Dermatol. 2013 Jul 1;133(E1):E13-17. DOI: 10.1038/skinbio.2013.179.

134.    Meinhardt M, Krebs R, Anders A, Heinrich U, Tronnier H. Effect of ultraviolet adaptation on the absorption spectra of human skin in vivo. Photodermatol Photoimmunol Photomed. 2008 Apr;24(2):76-82. DOI: 10.1111/j.1600-0781.2008.00342.x.

135.    De Winter S, Vink AA, Roza L, Pavel S. Solar-simulated skin adaptation and its effect on subsequent UV-induced epidermal DNA damage. J Invest Dermatol. 2001 Sep;117(3):678-82. DOI: 10.1046/j.0022-202x.2001.01478.x.

136.    Narbutt J, Lesiak A, Sysa-Jedrezejowska A, Wozniacka A, Cierniewska-Cieslak A, Boncela J, et al. Repeated low-dose ultraviolet (UV) exposures of humans induce limited photoprotection against the immune effects of erythemal UVB radiation. Br J Dermatol. 2007 Mar;156(3):539-47. DOI: 10.1111/j.1365-2133.2006.07670.x.

137.    Miyamuri Y, Coelho S, Schlenz K, Batzer J, Smuda C, Choi W, et al. The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin. Pigm Cell Melanoma Res. 2011 Feb;24(1):136-47. DOI: 10.1111/j.1755-148X.2010.00764.x.

138.    Kelly JL, Friedberg JW, Calvi LM, van Wijngaarden E, Fisher SG. A case-control study of ultraviolet radiation exposure, vitamin D, and lymphoma risk in adults. Cancer Causes Control. 2010 Aug;21(8):1265-75. DOI: 10.1007/s10552-010-9554-1.

139.    Breuer J, Schwab N, Schneider-Hohendorf T, Marziniak M, Mohan H, Bhatia U, et al. Ultraviolet light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol. 2014 May;75(5):739-58. DOI: 10.1002/ana.24165.

140.    Gibbs NK, Norval M. Photoimmunosuppression: a brief overview. Photodermatol Photoimmunol Photomed. 2013 Apr;29(2):57-64. DOI: 10.1111/phpp.12021.

141.    Adams JS, Hewison H. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metabol. 2008 Feb;4(2):80-90. DOI: 10.1038/ncpendmet0716.

142.    Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes. 2002 May;51(5):1367-74. DOI: 10.2337/diabetes.51.5.1367.

143.    Giuletti A, Gysemans C, Stoffels K, van Etten E, Decallonne B, Overbergh L, et al. Vitamin D deficiency in early life accelerates Type 1 diabetes. Diabetologia. 2004 Mar;47(3):451-62. DOI: 10.1007/s00125-004-1329-3.

144.    Feldman SR, Liguori A, Kucenic M, Rapp SR, Fleischer AB, Lang W, et al. Ultraviolet exposure is a reinforcing stimulus in frequent indoor tanners. J Am Acad Dermatol. 2004 Jul;51(1):45-51. DOI: 10.1016/j.jaad.2004.01.053.

145.    Slominski A, Wortsman J, Tobin DJ. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun. FASEB J. 2005 Feb;19(2):176-94. DOI: 10.1096/fj.04-2079rev.

146.    Lambert GW, Reid C, Kaye DM, Jennings GL, Esler MD. Effect of sunlight and season on serotonin turnover in the brain. Lancet. 2002 Dec 7;360(9348):1840-42. DOI : 10.1016/S0140-6736(02)11737-5.

147.    Gamblicher T, Bader A, Vojvodic M, Bechara FG, Sauermann K, Altmeyer P, et al. Impact of UVA exposure on psychological parameters and circulating serotonin and melatonin. BMC Dermatol. 2002 Apr 12;2:6-13. DOI: 10.1186/1471-5945-2-6.

148.    Lam DD, Heisler LK. Serotonin and energy balance: molecular mechanisms and implications for type 2 diabetes. Expert Rev Mol Med. 2007 Feb 22;9(5):1-24. DOI: 10.1017/S1462399407000245.

149.    Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, et al. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol. 2009 Oct;7(10):e1000229. DOI: 10.1371/journal.pbio.1000229.

150.    Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev. 2012 Apr;64(2):359-88. DOI: 10.1124/pr.111.004697.

151.    Amireault P, Sibon D, Cote F. Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci. 2013 Jan 16;4(1):64-71. DOI: 10.1021/cn300154j.

152.    Versteeg RI, Serlie MJ, Kalsbeek A, la Fleur SE. Serotonin, a possible intermediate between disturbed circadian rhythms and metabolic disease. Neuroscience. 2015 Aug 20;301:155-67. DOI: 10.1016/j.neuroscience.2015.05.067.

153.    Kaur M, Liguori A, Lang W, Rapp SR, Fleischer AB, Feldman SR. Induction of withdrawal symptoms in a small randomized trial of opioid blockade in frequent tanners. J Am Acad Dermatol. 2006 May;54(5):709-11. DOI: 10.1016/j.jaad.2006.01.062.

154.    Fonken LK, Nelson RJ. The effects of light at night on circadian clocks and metabolism. Endocr Rev 2014 Aug;35(4):648-70. DOI: 10.1210/er.2013-1051.

155.    Garcia-Navarro A, Gonzalez-Puga C, Escames G, Lopez LC, Lopez A, Lopez-Cantarero M, et al. Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res. 2007 Sep;43(2):195-205. DOI: 10.1111/j.1600-079X.2007.00463.x.

156.    Rondanelli M, Faliva MA, Perna S, Antoniello N. Update on the role of melatonin in the prevention of cancer tumorigenesis and in the management of cancer correlates, such as sleep-wake and mood disturbances: review and remarks. Aging Clin Exp Res. 2013 Oct;25(5):499-510. DOI : 10.1007/s40520-013-0118-6.

157.    Paroni R, Terraneo L, Bonomini F, Finati E, Virgili E, Biancardi P, et al. Antitumour activity of melatonin in a mouse model of human prostate cancer: relationship with hypoxia signalling. J Pineal Res. 2014 Aug;57(1):43-52. DOI: 10.1111/jpi.12142.

158.    Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS, et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PloS One. 2014 Jan 9;9(1):e85311. DOI: 10.1371/journal.pone.0085311.

159.    Yang WS, Deng Q, Fan WY, Wang WY, Wang X. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies. Eur J Cancer Prev. 2014 Jul;23(4):269-76. DOI: 10.1097/CEJ.0000000000000030.

160.    Sturgeon SR, Doherty A, Reeves KW, Bigelow C, Stanczyk FZ, Ockene JK, et al. Urinary levels of melatonin and risk of postmenopausal breast cancer: women's health initiative observational cohort. Cancer Epidemiol Biomarkers. 2014 Apr;23(4):629-37. DOI: 10.1158/1055-9965.EPI-13-1028.

161.    Basler M, Jetter A, Fink D, Seifert B, Kullak-Ublick GA, Trojan A. Urinary excretion of melatonin and association with breast cancer: meta-analysis and review of the literature. Breast care. 2014 Jul;9(3):182-87. DOI: 10.1159/000363426.

162.    Brown SB, Hankinson SE, Eliassen AH, Reeves KW, Qian J, Arcaro KF, et al. Urinary melatonin concentration and the risk of breast cancer in Nurses' Health Study II. Am J Epidemiol. 2015 Feb 1;181(3):155-62. DOI: 10.1093/aje/kwu261.

163.    Sigurdardottir LG, Markt SC, Rider JR, Haneuse S, Fall K, Schernhammer ES. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. Eur Urol. 2015 Feb;67(2):191-94. DOI: 10.1016/j.eururo.2014.07.008.

164.    Bizzarri M, Cucina A, Valente MG, Tagliaferri F, Borrelli V, Stipa F, et al. Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures. J Surg Res. 2003 Apr;110(2):332-37. DOI: 10.1006/jsre.2003.6628.

165.    Forman JP, Curhan GC, Schernhammer ES. Urinary melatonin and risk of incident hypertension

among young women J Hypertens. 2010    Mar;28(3):446-51. DOI:10.1097/HJH.0b013e3283340c16.

166.    Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: metaanalysis of randomized controlled trials. Vasc Health Risk Manag. 2011;7:577-84. DOI:10.2147/VHRM.S24603.

167.    McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013 Apr 3;309(13):1388-96. DOI: 10.1001/jama.2013.2710.

168.    Sharma S, Singh H, Ahmad N, Mishra P, Tiwari A. The role of melatonin in diabetes: therapeutic

implications. Arch Endocrinol Metab 2015    Oct;59(5):391-99. DOI:    10.1590/23593997000000098.

169.    Borradale DC, Kimlin MG. Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition. Nut Rev. 2012 Jul;70(7):414-22. DOI: 10.1111/j.1753-4887.2012.00485.x.

170.    Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20. DOI: 10.1016/j.gene.2013.09.063.

171.    Juzeniene A, Thu Tam TT, Iani V, Moan J. The action spectrum for folic acid photodegradation in

aqueous solutions. J    Photochem Photobiol B. 2013    Sep 5;126:11-6.    DOI:

10.1016/j.jphotobiol.2013.05.011.

172.    Borradale D, Isenring E, Hacker E, Kimlin MG. Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age. J Photochem Photobiol B. 2014 Feb 5;131:90-5. DOI: 10.1016/j.jphotobiol.2014.01.002.

173.    Autier P, Koechlin A, Boniol M. The forthcoming inexorable decline of cutaneous melanoma mortality in light-skinned populations. Eur J Cancer. 2015 Jan 2;56(1):152-9. DOI: 10.1080/10408398.2012.718723.

174.    Gorham ED, Mohr SB, Garland CF, Chaplin G, Garland FC. Do sunscreens increase risk of melanoma in populations residing at higher latitudes? Ann Epidemiol. 2007 Dec;17(12):956-63. DOI:10.1016/j.annepidem.2007.06.008.

175.    Autier P. Sunscreen abuse for intentional sun exposure. Br J Dermatol. 2009 Nov;161 Suppl 3:405. doi: 10.1111/j.1365-2133.2009.09448.x.

176.    Berwick M. The good, the bad, and the ugly of sunscreens. Clin Pharmacol Ther. 2011 Jan;89(1):31-3. DOI: 10.1038/clpt.2010.227.

177.    Coomans CP, Lucassen EA, Kooijman S, Fifel K, Deboer T, Rensen PCN, et al. Plasticity of circadian clocks and consequences for metabolism. Diabetes, Obesity and Metabolism. 2015 Sep;17 Suppl 1:65-75. DOI: 10.1111/dom.12513.

178.    Kozaki T, Kubokawa A, Taketomi R, Hatae K. Effects of day-time exposure to different light intensities on light-induced melatonin suppression at night. J Physiol Anthropol. 2015 Jul 4;34:27-33. DOI: 10.1186/s40101-015-0067-1.

179.    Yang L, Lof M, Veierod MB, Sandin S, Adami HO, Weiderpass E. Ultraviolet exposure and mortality among women in Sweden. Cancer Epidemiol Biomarkers Prev. 2011 Apr;20(4):683-90. DOI: 10.1158/1055-9965.EPI-10-0982.

180.    Lindqvist PG, Epstein E, Landin-Olsson M, Ingvar C, Nielsen K, Stenbeck M, et al. Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort. J Intern Med. 2014 Jul;276(1):77-86. DOI: 10.1111/joim.12251.

181.    Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, et al. Prospective study of ultraviolet radiation exposure and mortality risk in the United States. Am J Epidemiol. 2013 Aug 15;178(4):521-33. DOI: 10.1093/aje/kws589.

182.    Reichrath J. Skin cancer prevention and UV-protection: how to avoid vitamin D-deficiency? Br J Dermatol. 2009 Nov;161 Suppl 3:54-60. DOI: 10.1111/j.1365-2133.2009.09450.x.

183.    Byrne SN. How much sunlight is enough? Photochem Photobiol Sci. 2014 Jun;13(6):840-52. DOI: 10.1039/c4pp00051j.

- 183 -

Attached files

ID Name Comment Uploaded Size Downloads
6628 64-Sunlight, van der Rhee.pdf admin 01 May, 2016 580.47 Kb 990