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IS SUN WORSHIPPING INCREASING YOUR RISK OF MELANOMA?
Dr Anastasia BoulaisAncestral Health Symposium
Atlanta 2013
FAT MAKES YOU FAT
Dr Anastasia Boulais AHS13
FAIL!
Dr Anastasia Boulais AHS13
BUTTER CAUSES HEART ATTACKS
Dr Anastasia Boulais AHS13
FAIL!
THE EVIL ORB IN THE SKY IS OUT TO GIVE YOU LETHAL CANCER
Dr Anastasia Boulais AHS13
FAIL?
Dr Anastasia Boulais AHS13
Australia: World Leader in Melanoma
• CMM – cutaneous malignant melanoma (not “skin cancer”)• Highest incidence in the world• 10% of all cancers• 1 in 17 Australians will develop melanoma before the age of
85• 3.4% of all cancer deaths in 2010• 1980 – “Slip, slop, slap” campaign• 1986-2006 – Melanoma rates double
PRO AGAINST
1. Known cellular mechanism 1. Lower incidence in outdoor workers vs. indoor workers
2. Increased incidence with latitude 2. CMM more prevalent on less sun-exposed sites
3. Increased incidence in sunbed use 3. Negative correlation between chronic exposure and incidence of CMM
4. Association with sunburns 4. Vitamin D inhibits growth of tumours
5. Sun exposure > atypical naevi > strong risk factor for melanoma
5. Increased melanoma survival with higher sun exposure history
6. Sunscreens have not been found to decrease CMM incidence
Dr Anastasia Boulais AHS13
Does sunlight cause melanoma?
Does food cause heart disease?
Dr Anastasia Boulais AHS13
ultraviolet
visible
UVA
UVB
UVC
UVA UVB
UVC
ozone
Dr Anastasia Boulais AHS13
UVA SKIN PENETRATION
• UVA – longer wavelength with deeper skin penetration.
• Low erythema potential• Not absorbed by ozone layer• Immediate & Persistent
Pigment Darkening (IPD/PPD)• UVA tan via oxidation of
melanin precursors in basal cell layer, not an increase in melanin content.
Dr Anastasia Boulais AHS13
UVA RADIATION
• Indirect DNA damage via formation of ROS oxidative stress• No significant photoprotection• Breaks down Vitamin D bound to VDR• Induces NO¯ formation• Inhibits UVB-induced immunosuppression
Dr Anastasia Boulais AHS13
- PROTEIN DAMAGE - LIPID DAMAGE - DNA DAMAGE
Sunbeds give off 5-10x more UVA than experienced at solar noon in Southern Europe
Dr Anastasia Boulais AHS13
UVB SKIN PENETRATION
• UVB – poor skin penetration.• High erythema [burn] potential• Partially absorbed by ozone
layer• Delayed tanning (DT) 3-7 days
post exposure lasts for weeks• UVB tan via increased
synthesis of melanin and increased melanocyte density
Dr Anastasia Boulais AHS13
UVB RADIATION
• Direct DNA damage via formation of cyclobutane pyrimidine dimers [CPD] and 6-4 photoproducts [6-4PP]
• Delayed tan = photoprotection• Skin adaptations: hyperkeratosis and thickening of stratum
corneum• Vitamin D production
Source: Lester M.Davids “Recent Advances in the Biology, Therapy and Management of Melanoma” Published Feb 2013 under CC BY3.0 license
Dr Anastasia Boulais AHS13
Irradiation
Solar Zenith Angle (the
shadow rule)
Latitude
Time of the year
Time of dayElevation
Ozone concentration
UVB PARTIAL OZONE ABSORPTION
Las Cruces , NM32.6° north latitudeJune 21Clear dayMiddayCurrent ozone level
Seattle, WA47.7° north latitudeJune 21Clear dayMiddayCurrent ozone level
1.24x more UVB
Source: http://uvb.nrel.colostate.edu/UVB/publications/uvb_primer.pdf
MELANOMA ACTION SPECTRUM?
“…the available evidence points away from pyrimidine dimer formation by UVB and toward oxidative damage caused by longer [UVA] wavelengths.”
Lund et al (2007) Melanoma, long wavelength ultraviolet and sunscreens: Controversies and potential resolutions , Pharmacology and Therapeutics
UVA UVB
INDIRECT DNA DAMAGE
DIRECT DNA DAMAGE
Dr Anastasia Boulais AHS13
INNATE PROTECTION AND REPAIR
1. Delayed Tanning photon absorption2. Skin adaptation3. Melatonergic Antioxidant System4. Nucleotide Excision Repair 5. Endogenous + exogenous ROS quenchers6. Vitamin D – potent immunomodulator
Dr Anastasia Boulais AHS13
MELATONERGIC ANTIOXIDANT SYSTEM
• Melatonin is produced in pineal gland, bile fluid, BM, CSF, ovary, eyes, lymphocytes, gastric mucosa and skin
• Antioxidant – strong scavenger of UV-induced ROS
• Modulates UV-induced apoptosis• Tumour growth inhibitor
Dr Anastasia Boulais AHS13
NUCLEOTIDE EXCISION REPAIR
• XPA [Xeroderma Pigmentosum Group A]– A critical protein involved in DNA damage recognition
• XPA is a rate-limiting factor in excision repair controlled by a circadian clock
• In [nocturnal] mice: CPD + 6-4PP repaired faster in 4pm group (XPA zenith) vs. 4am group (XPA nadir)
• In humans this peak repair rate would coincide with the morning hours up to around solar noon.
Dr Anastasia Boulais AHS13
CIRCADIAN RHYTHM FTW!
INCREASED UVA TO UVB RATIO
↓ erythema↑ oxidative stress↓ melanin production↓ Vitamin D production↑ Vitamin D breakdown↓ protective skin adaptation
A tan with no photoprotection
Dr Anastasia Boulais AHS13
EXOGENOUS ANTIOXIDANTS AND PRO-OXIDANTS
Antioxidants• Carotenoids
– Beta-carotene– Lutein– Lycopene
• Flavonoids and Polyphenols– Tea and cocoa polyphenols– Herbs and spices
• Ascorbic acid• Vitamin E (tocopherols)
Pro-oxidants• Increased risk with high PUFA diet (RR 2-4), high
linoleic acid (RR 2.16) and cod liver oil (RR 2.9)• Recall: Sunbed RR 1.2
In vitro studiesEpidemiological evidenceHuman RCTs (erythema)
Dr Anastasia Boulais AHS13
PHYSIOLOGICAL STRESS?
• Increased number of atypical naevi in marathon runners• Training HR, training velocity and physical strain index
• Cortisol? • Oxidative stress?• Impaired carcinogenesis repair?
Dr Anastasia Boulais AHS13
Dr Anastasia Boulais AHS13
THERE’S NOTHING HEALTHY ABOUT A TAN?
HIGH INTAKE OF PRO-OXIDANTS
LOW VITAMIN D STATUS
PHYSIOLOGICAL STRESS
CIRCADIAN RHYTHM DYSRUPTION
POOR INTAKE OF ANTIOXIDANTS
HIGH UVA/UVB RATIO
GENETICS MELANOMA RISK
Know your risk…
Eat wellSleep better
Enjoy movementManage your stressSmart sun exposure
BIBLIOGRAPHY1. Juzeniene A, Moan J (2012) Beneficial effects of UV radiation other than via vitamin D production. Dermato-Endocrinology, 4:2, 109-
1172. Desotelle J, Wiling M, Ahmad N (2012) The Circadian Control of Skin and Cutaneous Photodamage. Photochemistry and Photobiology,
88: 1037-10473. Boniol M, Autier P, Boyle P, Gandini S (2012) Cutaneous melanoma attributable to sunbed use: systemic review and meta-analysis.
BMJ 345: e47574. Gaddameedhi S, Selby C, Kaufmann W, Smart R, Sancar A (2011) Control of skin cancer by the circadian rhythm. PNAS Online5. Weinstock M (1996) Controversies in the role of sunlight in the pathogenesis of CM . Photochemistry and Photobiology 63(4)6. Vinceti M, Pellacani G, Malagoli C, Bassissi S, Sieri S, Bonvicini F, Krogh V, Seidenari S (2005) A population-based case-control study of
diet and melanoma risk in Northern Italy. Public Health Nutrition 8(8) 1307-13147. Veierod M, Helle D, Aake P (1997) Diet and risk of cutaneous malignant melanoma: a prospective study of 50,757 Norwegian men and
women. Int. J Cancer: 71, 600-6048. De Giorgi V, Gori A, Grazzini M, Rossari A, Oranges T, Longo A, Lotti T, Gandini S (2012) Epidemiology of melanoma: is it still
epidemic? What is the role of the sun, sunbeds, Vit D, betablocks, and others? Dermatologic Therapy, 25: 392-3969. Godar D, Landry R, Lucas A (2009) Increased UVA exposures and decreased cutaneous Vitamin D3 levels may be responsible for the
increasing incidence of melanoma. Medical Hypothesis, 72:434-44310. Richtig E, Ambros-Rudolph C, Trapp M, Lackner H, Hofmann-Wellenhof R, Kerl H, Schwaberger G (2008) Melanoma markers in
marathon runners: increase with sun exposure and physical strain. Dermatology 217:38-4411. Lund C, Timmins G (2007) Melanoma, long wavelength ultraviolet and sunscreens: controversies and potential resolutions.
Pharmacology and Therapeutics, 114: 198-20712. Shapira N (2010) Nutritional approach to sun protection: a suggested complement to external strategies. Nutrition Review, 68(2) 71-
8613. Rosso S, Sera F, Segnan N, Zanetti R (2008) Sun exposure prior to diagnosis is associated with improved survival in melanoma patients:
Results from a long-term follow-up study of Italian patients. European Journal of Cancer, 44: 1275-128114. Agar N, Halliday G, Barnetson R, Ananthaswamy H, Wheeler M, Jones A (2004) The basal layer in human squamous tumors harbors
more UVA than UVB fingerprint mutations: A role for UVA in human skin carcinogenesis. PNAS 101(14): 4954-495915. Miyamura Y, Coelho S, Schlenz K, Batzer J, Smuda C, Choi W, Brenner M, Passeron T, Zhang G, Kolbe L, Wolber R, Hearing V (2011) The
deceptive nature of UVA-tanning versus the modest protective effects of UVB-tanning on human skin. Pigment Cell Melanoma Res 24(1); 136-147
Dr Anastasia Boulais AHS13