Accepted: 25 October 2018

DOI: 10.1111/exd.13818

REVIEW

Effects and interactions of increased

environmental temperature and UV radiation on
photoageing and photocarcinogenesis of the skin

Cheng-Che E. Lan

Department of Dermatology, Kaohsiung

Medical University Hospital, College of
Medicine, Kaohsiung Medical University,
Kaohsiung, Taiwan
Correspondence
Cheng-Che Lan, Department of Dermatology,
Kaohsiung Medical University, Kaohsiung,
Taiwan.
Email: laneric@cc.kmu.edu.tw
Abstract
Solar radiation is one of fundamental elements sustaining and maintaining life on
earth. Previous studies on health effects from the sun exposure mostly focused on
ultraviolet (UV) radiation. Although exposure to the solar radiation likely occurs in an
environment with elevated temperature, the effects and interactions of elevated en-
vironmental temperature with UV radiation on the skin, especially in the context of
ageing and carcinogenesis, have not been carefully examined. It is known that UVA
radiation results in reduced production and increased degradation of dermal colla-
gen, contributing to photoageing of the skin. Previous studies showed conflicting
results regarding the effects of increased environmental temperature on dermal col-
lagen. Additionally, we demonstrated that solar-simulated radiation and increased
environmental temperature have similar impacts on dermal fibroblasts through acti-
vation of distinct pathways. UVB radiation is well known for its carcinogenic capac-
ity. Previously, it was reported that exposure to heat treatment before UVB radiation
reduces epidermal keratinocyte cell death. We demonstrated that exposure to ele-
vated environmental temperature prior to UVB radiation reduces UVB-induced skin
tumor formation. We proposed that alterations in molecular dynamics and quantum
mechanics were involved for the observed increased environmental temperature-
induced protective effect against UVB damage. This review emphasizes that both
environmental temperature and solar radiation are important elements in nature that
have significant impacts on the human health, and future studies should focus on the
biological effects and interactions of environmental temperature and solar radiation
since this scenario is most relevant to the real-world setting.

KEYWORDS
ageing, carcinogenesis, environmental temperature, UV radiation

1 | INTRODUCTION formation and reducing skin resilience. In the context of photocar-

Human beings have intimate interactions with the environment that
has significant impacts on human health. Sun exposure is an
important environmental factor that has been well recognized to play
crucial roles in skin ageing and carcinogenesis. It is known that solar
radiation contributes to extrinsic ageing by increasing wrinkle
cinogenesis, skin cancer is an important health problem accounting
for more than 40% of all cancers in United States. In Taiwan, where
residents were mostly of Fitzpatrick’s skin types 3 and 4, the skin
cancer incidence is ranked among the top 10 malignancy within the
population (Cancer registry annual report, Taiwan, 2016). The in-
cidence rates of skin cancers are closely associated with duration

Experimental Dermatology. 2019;28(Suppl. 1):23–27. wileyonlinelibrary.com/journal/exd © 2019 John Wiley & Sons A/S.  |  23
Published by John Wiley & Sons Ltd
24  |
and pattern of sun exposure. Among the solar spectrum, the span of
solar energy is approximately 7% in the ultraviolet (UV) range, 39%
[1]
in the visible range and 54% in the infrared spectrum.
region contributes significantly to the skin photoageing process due
to its abundance and depth of penetration, the UVB spectrum in-
duces direct DNA damages and abnormal immune modulations that
[2–4]
result in development of skin cancers.
Although sun exposure is closely associated with elevated en-
vironmental temperature, the effects of increased environmental
temperature on the skin have not been carefully examined. In the
subsequent sections of this paper, the effects and interactions of
solar radiation and increased environmental temperature on photo-
ageing and photocarcinogenesis of the skin will be reviewed.
2 | EFFECTS AND INTER ACTIONS OF UV R
ADIATION AND INCREASED ENVIRONMENTAL
TEMPER ATURE ON SKIN AGEING: IN VITRO
MODELS
It is well recognized that chronic sun exposure leads to enhanced age-
ing of the skin with loss of dermal collagen, either via reduced pro-
[5]
duction or increased degradation. Among the UV spectrum, UVA is
recognized to play a more important role in photoageing of the skin since
UVA has greater abundance, higher year-round and day-long av-erage
irradiance, and penetrates deeper into the dermis as compared to UVB.
[6]
This greater penetration has significant impact on photoageing since
morphologic studies indicated that the pathognomonic changes in
photoaged skin are mostly found at the dermal connective tissue.
Mechanistically, it is believed that UVA photons penetrate the dermis and
induce formation of reactive oxygen species (ROS) that modulate
[8]
photoageing process. Increased synthesis and expression of metallo-
proteinases (MMPs) by the skin dermal fibroblasts upon UV exposure is
believed to play an important role degrading the dermal collagen. .
Previously, it was demonstrated that repeated exposure to mild heat
(41°C water bath, 1 hour; twice a week) environment increased the
[10]
survival of human fibroblasts exposed to UVA radiation.
was reported that repeated mild heat (41°C incubator, 1 hour; four
treatments in 4 days) exposure increased collagen pro-duction in human
[11]
fibroblasts. On the other hand, exposure to 43°C water bath for 30
minutes induced MMP1 and MMP3 expression in cultured dermal
[12]
fibroblasts. These results suggest that exposure to different
environmental temperature may modulate the photoageing effects
imparted by solar radiation. To address this issue, we performed a series
of studies incorporating both solar radiation and increased environmental
[13]
temperature into our experimental conditions. The cultured human
dermal fibroblasts were exposed to simulated solar ra-diation (SSR) or
increased environmental temperature (incubator with temperature set at
39°C as compared to control at 37°C) for 30 min-utes. At these
experimental conditions, the viability of fibroblasts was not significantly
altered. To evaluate if these treatment conditions have an impact on skin
ageing, the expression of MMP1 was deter-mined
metalloproteinase was believed to play an important role
LAN
during photoageing by increasing degradation of type-1 and type-3
[14]
collagen that contributes to connective tissue damage which were
While UVA frequently observed in the aged skin. Accordingly, we found that both
SSR and increased temperature exposure increased the MMP1 ex-
pression of cultured fibroblasts, but the mechanisms involved in the
[15,16]
process were different. Similar to previous reports, SSR induced
MMP1 expression through increased oxidative stress. Pretreating cul-
tured fibroblasts with antioxidant abrogated MMP1 increase induced by
SSR. On the other hand, antioxidant pretreatment did not inhibit in-
creased environmental temperature-induced MMP1 expression in fi-
broblasts. Pretreatment with heat sensor transient receptor potential
vanilloid 1 (TRPV-1) antagonist was required to suppress the increased
environmental temperature-induced MMP1 expression (Figure 1).
Corroborating with these results, epidermal TRPV-1 expression was
reported to be associated with overall human skin ageing process in-
cluding intrinsic and extrinsic ageing.
[17]
These results indicate that when
investigating the biological impacts of sun exposure on human skin, the
effects and interactions of UV and environmental tempera-ture should
both be taken into consideration since these exposures are closely
associated with each other in the real-world situation but affect exposed
cells through distinct signalling cascades.
3 | EFFECTS AND INTER ACTIONS OF UV R
ADIATION AND ENVIRONMENTAL TEMPER
ATURE ON SKIN AGEING: IN VIVO STUDIES
[7]
As aforementioned, the effects of UV on skin photoageing have been
well documented. On the other hand, the effects of increased envi-
ronmental temperature on the skin in vivo in terms of ageing have not
been well studied. From historical studies, it was found that chronic
exposure to heat source may result in characteristic skin lesions recog-
[9] nized as erythema ab igne. This skin condition shares similar histologic
[18]
alterations as photoaged skin. Previously, using black cotton cloth to
block sun’s radiation, human skin exposed to the sun without ex-posure
to solar radiation demonstrated approximately 3°C increase in skin
Additionally, it
temperature after about 2.7 hours of sun exposure. Additionally, the
MMP1 expression was significantly increased by the increased skin
temperature while the expression of type procollagen I was not
[19]
significantly affected. Using animal model to examine the effects of
chronic heat treatment (43°C delivered by heating pad; trice per week, 6
weeks) on the mice skin, it was reported that this repetitive heat
treatment induced wrinkle formation and significantly increased the
[20]
MMP13 expressions in mice skin. The epidermal and dermal thick-
ness were also significantly increased by this treatment. Moreover, it was
found in the same study that this chronic heat treatment re-duced the
activities of antioxidant enzymes and increased oxidative damages of the
mice skin. Therefore, it was suggested that chronic heat exposure may
increase skin ageing. However, the interactions of environmental
temperature and UV radiation on the skin have not yet been carefully
as this examined. Recently, using an animal model, we found that exposing
hairless mice to increased environmental heat (34°C
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      25|

Environmental SSR
Heat
Fibroblasts

TRPV-1 Antioxidant
Antagonist

TRPV-1: ↑ TRPV-1: −
ROS : ↑ ROS : ↑↑

MMP1: ↑
Collagen : ↓

Aging of the skin

FI G U R E 1 Increased environmental temperature (environmental heat) and solar-simulated radiationƲ (SSR) exposure both lead to ageing of the skin. Exposure to increased environmental temperature (black line) and SSR (dashed line) leads to
activation of transient receptor potential vanilloid 1 (TRPV1) and significantƲ induction of reactive oxygen species (ROS), respectively, resulting in increased metalloproteinase-1 (MMP1) expression in treated human dermal fibroblasts. Different
inhibitors, TRPV1 antagonist and antioxidants, were required to prevent the heat and SSR induced MMP1 expression, respectively

UVB radiation (1.46 0.07 mm)

Control (0.67 0.03 mm) Ʋ

Environmental Heat 1.07 0.11 mm)

FI G U R E 2 Dermal thickness of hairless mice after indicated treatment. Exposure to increased environmental temperature (environmental
heat) and UVB radiation for 8 wk significantly increased the dermal thickness of the mice skin as compared to control
exposed through infant incubator for 30 minutes, thrice per week for
8 weeks) imparted no significant effect on epidermal thickness but
significantly increased dermal thickness (Figure 2). On the other hand,
UVB exposure (200 mJ/cm2, thrice per week for 8 weeks) significantly
increased both the epidermal and dermal thickness. Taken together,
these results indicated that chronic exposure to elevated environ-
mental temperature has significant effect on the skin (ie, dermal
thickness), and the interactions between increased
environmental
 LAN
26  |

Environmental UVB
Heat
Keratinocytes

Other potential
Molecular dynamics; Heat shock
modifications
Quantum mechanics proteins i.e. epigenetic

DNA damage
Immune regulation

Carcinogenesis of the skin

FI G U R E 3 Both elevated environmental temperature (environmental heat) and ultraviolet (UV) B exposure have significant biological
impacts on carcinogenesis of the skin. Through modulation at different levels including molecular dynamics, quantum mechanics, and heat
shock protein expressions, these two important environmental factors modify DNA damage and immune response of exposed epidermal
keratinocytes and place significant impacts on the carcinogenic process of the skin

temperature and UV radiation in the context of ageing require further [21]

protein. For murine keratinocytes, it was found that cell cycle
detailed investigation. arrest was not primarily responsible for the heat-induced UVB pro-
[22]
tective effects. More recently, we demonstrated that cultured
human keratinocytes exposed to increased environmental temper-
4 | EFFECTS AND INTER ACTIONS OF UV R ature (30 minutes in 40°C incubator) prior to UVB radiation (Heat-
ADIATION AND INCREASED ENVIRONMENTAL UVB) showed enhanced viability as compared to the keratinocytes
TEMPER ATURE ON SKIN CARCINOGENESIS: IN exposed to UVB radiation or equivalent environmental temperature
VITRO MODELS exposure after UVB irradiation (UVB-Heat).
[23]
Cyclopyrimidine dimer
(CPD) formation plays an important role in UVB-induced pho-
Ultraviolet B radiation from the sun is the principal factor result-ing in
tocarcinogenesis of the skin. Corroborating with results derived from
photocarcinogenesis of the skin. It was reported that UVB induces DNA
the viability experiments, the CPD levels were significantly lower in
damage by forming photoproducts that if unrepaired leads to mutations
Heat-UVB treated keratinocytes as compared to UVB or UVB-Heat
in the epidermis and results in development of skin cancers. Additionally,
treated groups. These results suggest that exposure to increased en-
UVB has immune suppressive effects that contribute significantly to the
vironmental temperature prior to UVB radiation may have protec-tive
[4]
formation of skin cancers. Previous studies demonstrated that effect against UVB-induced skin cancers. The involvement of heat
exposure to increased environmental temperature (42°C water bath for 1 shock protein (Hsp) for protection against UVB-induced dam-age
hour) before UVB radiation re-duced human and murine epidermal was considered since it has been demonstrated that fibroblasts with
[21,22] overexpressed Hsp70 showed enhanced cell survival after UVB
keratinocyte cell death. For human keratinocytes, it was
[24]
demonstrated that the heat-induced UVB protective effects require radiation. In our experimental condition, however, Hsp70 demon-
ongoing synthesis of mRNA and strated no significant increase after heat treatment. Therefore, an
LAN
alternate rationale explaining increased environmental temperature-
induced UVB protective effect against CPD formation was explored.
Applying molecular dynamics and quantum mechanics techniques to
our study, we demonstrated through computational simulation that
formation of TT dimer requires higher amount of energy at 40°C
environment as compared to 37°C environment due to changes in
molecular structure. This analysis provided a reasonable rationale
explaining lower CPD levels in cultured keratinocytes exposed to
environment with elevated temperature prior to UVB irradiation as
compared to keratinocytes treated with UVB irradiation alone in ac-
cordance with the “Law of Conservation of Energy.”
5 | EFFECTS AND INTER ACTIONS OF UV R
ADIATION AND INCREASED ENVIRONMENTAL
TEMPER ATURE ON SKIN CARCINOGENESIS: IN
VIVO STUDIES
Animal studies were performed to examine the effects and interac-tions
of UVB radiation and increased environmental temperature in the context
of skin carcinogenesis. We found that hairless mice exposed to
increased environmental temperature (34°C infant incubator for 30 min-
utes) prior to UVB irradiation (Heat-UVB; thrice per week) demonstrated
delayed tumor onset and harboured fewer skin tumors as compared to
their UVB and UVB-Heat treated counterparts. Additionally, the skin
specimens obtained from Heat-UVB treated mice harboured significantly
lower levels of mutant p53 as compared to the specimens obtained from
UVB-treated mice. No significant difference was found between UVB and
UVB-Heat treated groups. The results obtained from animal stud-ies
supported the notion that exposure to increased environmental tem-
perature prior to UVB radiation modifies the biological effects of UVB
radiation in the context of photocarcinogenesis. A schematic diagram
summarizing the effects and interactions of environmental heat and and
UVB on carcinogenesis of the skin is shown in Figure 3.
6 | CONCLUSION
Sun exposure is an important environmental factor associated with
human health. While the biological effects of solar radiation have been
extensively studied, the effects of elevated environmental tempera-ture,
an event that is also closely associated sun exposure, have not yet been
carefully examined. More importantly, the interaction between increased
environmental temperature and solar radiation, the scenario that is
relevant to the real-world situation, has rarely been explored. Previous
studies focusing on the biological effects of increased en-vironmental
temperature have used different experimental settings, including different
temperatures, different exposure durations and frequencies, as well as
different modes to increase environmental temperature (ie, heating pad,
water bath, incubator). For future studies focusing on the effects and
interactions of solar radiation and environ-mental temperature, the
experimental protocol should demonstrate relevance to the real-world
settings. By doing so, the results derived
     |  27
from laboratory studies will have timely impacts on establishing the
optimal strategies to promote better human health under the sun.
AC K N OW L E D G E M E N T S
This work was supported by Ministry of Health and Welfare, Taiwan
(MOHW106-TDU-B-212-113006;MOHW107-TDU-B-212-1230061).
CONFLICT OF INTERESTS
The authors have declared no conflicting interests.
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How to cite this article: Lan C-CE. Effects and interactions of
increased environmental temperature and UV radiation on
photoageing and photocarcinogenesis of the skin. Exp Dermatol.
2019;28(Suppl. 1):23‐27. https://doi.org/10.1111/exd.13818