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REVIEW ARTICLE
Involvement of 4-hydroxy-2-nonenal in pollution-induced skin
damage
Alessandra Pecorelli
1
| Brittany Woodby
1
| Roxane Prieux
2
| Giuseppe Valacchi
1,2,3
1
Plants for Human Health Institute,
Department of Animal Sciences, North
Carolina State University, Kannapolis,
North Carolina
2
Department of Life Sciences and
Biotechnology, University of Ferrara,
Ferrara, Italy
3
Department of Food and Nutrition, Kyung
Hee University, Seoul 02447, Korea
Correspondence
Giuseppe Valacchi, Department of Animal
Sciences, Plants for Human Health Institute,
NC Research Center, North Carolina State
University, Kannapolis, NC.
Email: gvalacc@ncsu.edu, giuseppe.
valacchi@unife.it
Funding information
Marie Sklodowska-Curie, Grant/Award
Number: 765602; European Union‘s
Horizon 2020
Abstract
The effects of environmental insults on human health are a major global concern.
Some of the most noxious pollutants that humans are exposed to include ozone (O
3
),
particulate matter (PM), and cigarette smoke (CS). Since the skin is the first line of
defense against environmental insults, it is considered one of the main target organs
for the harmful insults of air pollution. Thus, there is solid evidence that skin patholo-
gies such as premature aging, atopic dermatitis (AD), and psoriasis are associated with
pollutant exposure; all of these skin conditions are also associated with an altered
redox status. Therefore, although the mechanisms of action and concentrations of O
3
,
PM, and CS that we are exposed to differ, exposure to all of these pollutants is associ-
ated with the development of similar skin conditions due to the fact that all of these
pollutants alter redox homeostasis, increasing reactive oxygen species production and
oxidative stress. A main product of oxidative stress, induced by exposure to the afore-
mentioned pollutants, is 4-hydroxy-2-nonenal (HNE), which derives from the oxida-
tion of ω-6 polyunsaturated fatty acids. HNE is a highly reactive compound that can
form adducts with cellular proteins and even DNA; it is also an efficient cell signaling
molecule able to regulate mitogen-activated protein kinase pathways and the activity
of redox-sensitive transcription factors such as Nrf2, AP1, and NFκB. Therefore,
increased levels of HNE in the skin, in response to pollutants, likely accelerates skin
aging and exacerbates existing skin inflammatory conditions; thus, targeting HNE for-
mation could be an innovative cosmeceutical approach for topical applications.
KEYWORDS
ozone, particulate matter, cigarette smoke, peroxidation
1|INCREASING AIR POLLUTION
AND IMPLICATIONS FOR HUMAN
SKIN HEALTH
Ubiquitous exposure to environmental insults is a major
global concern for public health. Over the past 30 years, the
damaging effects of pollutants on cutaneous tissue have
become an area of growing research interest, also in view of
increased environmental pollution. Indeed, a recent search in
PubMed using the keywords “skin and pollution”reveals
Abbreviations: AD, atopic dermatitis; AhR, aryl hydrocarbon receptor;
AP1, activator protein-1; HNE, 4-hydroxy-2-nonenal; CO, carbon
monoxide; COX2, cyclooxygenase-2; CS, cigarette smoke; DEP, diethyl
phthalate; DHN, 1,4-dihydroxy-2-nonene; DnBP, di(n-butyl)phthalate;
MAPKs, mitogen-activated protein kinases; NFκB, nuclear factor “κB”;
NO
2
, nitrogen dioxide; Nrf2, nuclear factor (erythroid-derived 2)-like 2; O
3
,
ozone; PA, protein adducts; PM, particulate matter; PPARs, peroxisome-
proliferator-activated receptors; PUFA, polyunsaturated fatty acids; RHEs,
reconstituted human epidermis tissues; SC, stratum corneum; SO
2
, sulfur
dioxide; SRB1, scavenger receptor class B type I; UFPs, ultrafine
particulates; VOCs, volatile organic compounds.
Alessandra Pecorelli and Brittany Woodby contributed equally to this study.
Received: 21 February 2019 Revised: 19 March 2019 Accepted: 2 April 2019
DOI: 10.1002/biof.1513
© 2019 International Union of Biochemistry and Molecular Biology
BioFactors. 2019;1–12. wileyonlinelibrary.com/journal/biof 1
more than 2000 papers related to this topic (https://www.ncbi.
nlm.nih.gov/pubmed/?term=skin+pollution). Until the year
2000, only a few articles were published on this issue; how-
ever, in the last 20 years, interest in this field has grown expo-
nentially, reaching approximately 100 manuscripts per year.
This increased interest is related not only to the proven and
well-established worsening of air quality but also to the evi-
dence of a direct correlation between skin pathologies and air
pollution exposure.
1–4
Indeed, the skin is the first line of
defense because it is the interface between the environment
and our body. Therefore, cutaneous tissue is considered, along
with eyes, lung, brain, and digestive tract, as one of the main
target organs for the harmful insults of air pollution.
5
1.1 |Cutaneous tissues as a gateway for the
outdoor pollutants
Growing evidence demonstrates that the skin also constitutes
a route of entry for ambient pollutants in the human body,
promoting considerable systemic consequences in almost all
internal organs.
6–8
In a very elegant series of experiments,
Weschler et al. (2015) were able to demonstrate the ability
of volatile organic compounds (VOCs), specifically diethyl
phthalate (DEP) and di(n-butyl)phthalate (DnBP), to be
absorbed by the skin. Surprisingly, the amounts of phthalate
metabolites found in urine were similar when the subjects
were exposed to pollutants either by breathing or by dermal
exposure, suggesting that the ability of our body to absorb
pollutants from the outdoor environment by the cutaneous
tissues is similar, if not more efficient than the respiratory
tract. Even more striking is the finding that dermal absorp-
tion of VOCs increases tremendously with age; indeed, sub-
jects over 60 years old had five times higher levels of the
phthalates in urine compared to 30-year-old subjects.
8
Interestingly, a role of clothing in influencing the cutaneous
uptake of harmful compounds from polluted air has been inves-
tigated by several groups
9–11
; surprisingly, clean clothes are
only able to protect the skin by about 20–30% from pollution
absorption, eventually being a source of pollutant accumulation,
and increasing cutaneous uptake if not changed daily.
9,10
2|POLLUTION AND SKIN
PATHOLOGIES
The use of the word “pollution”can be misleading given that
there are several different pollutants that can affect our
health. In addition, not all of them have the same concentra-
tion in the air and the same mechanism of action. Based on
their chemical and physical properties as well as their
sources, the United States Environmental Protection Agency
has identified the most common air pollutants, also known as
“criteria air pollutants”, as ozone (O
3
), particulate matter
(PM), carbon monoxide (CO), lead, sulfur dioxide (SO
2
),
and nitrogen dioxide (NO
2
) (https://www.epa.gov/criteria-
air-pollutants). Clear evidence of the correlation between
each single pollutant and skin disorders has not yet been
established; however, the noxious effects of O
3
, cigarette
smoke (CS), and PM have been well demonstrated, as
described in the following section.
Overall, there is solid evidence that pathologies such as
atopic dermatitis (AD), psoriasis, acne, and, in some cases,
also skin cancer can be associated with pollutant exposure. In
particular, exposure to O
3,
PM, NO
2,
and CS has been demon-
strated to be associated with cutaneous pathologies. The semi-
nal epidemiological work by Xu et al. (2011) demonstrated
the association of these pollutants with cutaneous pathologies
by analyzing the association between emergency-room (ER)
visits for skin conditions and levels of air pollutants including
O
3
,PM
10
,SO
2
, and NO
2
. During 2 years of sampling, over
68,000 visits to the ER for skin disorders were recorded, and a
clear correlation between O
3
concentration and cutaneous
issues was demonstrated. In particular, the authors underlined
how several skin conditions such as urticaria, eczema, contact
dermatitis, rash/other nonspecific eruption, and infected skin
diseases were exacerbated when the subjects were exposed to
increased levels of this pollutant.
12
These data suggest a role
of O
3
in inducing inflammatory skin pathologies. Another
more recent publication has further examined the association
of short-term changes in air quality with emergency depart-
ment (ED) visits for urticaria in Canada. A total of 2905 ED
visits were analyzed, and a positive and significant correlation
was observed between air quality levels and ED visits for
urticaria, confirming that air pollution can affect skin
physiology.
13
AD is a chronic and recurrent cutaneous inflammatory dis-
ease that begins in the early stage of life. The pathogenesis of
ADisusuallylinkedtoskinbarrier alteration and immune dys-
regulation.
14,15
Indeed, changes in the stratum corneum (SC)
composition, which is the outermost layer of the skin, can facili-
tate the penetration of allergens that can then be associated with
the development of AD.
15
As opposed to the outside-in model of
AD pathogenesis,
16
the inside-out theory suggests that Th2 cyto-
kines are able to modulate the expression of proteins present in
the SC, thereby disrupting the skin barrier.
17
Although there is still existing controversy between these
two theories, one fact is clear; the perturbation of the skin
barrier plays a key role in AD, and this perturbation can be
induced by environmental pollutant exposure. For instance,
there is now evidence that air pollution influences the preva-
lence of AD. In a fairly recent study, it was shown that, in a
population of almost 5000 children from France, there was a
direct correlation between the development of eczema and
pollution levels (PM
10
and NOx).
18
In addition, a study con-
ducted in the Munich metropolitan area revealed a strong
2PECORELLI ET AL.
positive association between the distance to the nearest main
road and eczema; in particular, it was found that NO
2
was
positively associated with eczema in children exposed to
traffic-related air pollution.
19
In a more recent work, PM
10
and NO
2
exposure during the first trimester of pregnancy
was associated with the development of infantile AD.
20
It
has also been demonstrated that maternal smoking during
pregnancy and/or in the first year after birth is a major risk
factor for the development of AD among children aged
between 6 and 13 years.
21
Similarly, fetal tobacco smoke
exposure during the third trimester of pregnancy was posi-
tively associated with a higher cumulative incidence of
atopic eczema/dermatitis syndrome in exposed infants in a
Japanese study; the authors suggest that maternal smoking
might induce epigenetic changes in the fetal allergen-specific
immune responses, promoting development of AD.
22
Thus, the evidence that exposure to environmental tobacco
smoke during early childhood can predispose children to later
development of AD has been documented, but it is still not
clear whether current smokers develop AD. This point was
well clarified in the paper by Lee et al., in which, among
83 patients diagnosed with adult-onset AD, more than 50%
were current smokers, and about one-third have smoked in
the past.
23
This study strongly supports the idea of the associ-
ation between current smoking and the development of adult-
onset AD, as well as a correlation between exposure to CS
and AD in nonsmokers.
Besides eczema and AD, psoriasis is another inflammatory-
related skin disease that appears to be associated with air pollu-
tion. Indeed, it has been proposed that exposure to pollutants
such as PM,
24
CS,
25
or O
326
can activate the aryl hydrocarbon
receptor (AhR), and this can further activate Th17 cells
27
;the
main cells involved in psoriasis and present in psoriatic lesions.
Although there is controversy in the link between CS and psori-
asis, a recent study with over 17 million patients over the age of
20 years that were followed for 8 years was able to clearly show
the positive correlation between risk of psoriasis and smoking
period.
28
In addition, this correlation was stronger for subjects
that smoked more than two packs per day and much lower for
0.5 pack smokers.
28
Interestingly, CS has been also connected with the devel-
opment of acne,
4
another multifactorial skin disease. Acne is
usually characterized by increased sebum production, abnor-
mal keratinization of the pilosebaceous duct, and inflamma-
tion driven by the presence of Propionibacterium acnes. It
has been shown that these processes are induced by an
altered redox status, which pollutant exposure can gener-
ate.
29
Indeed, the ability of PM, CS, and even O
3
to increase
reactive oxygen species (ROS) production and activate a
cascade of events, leading to increased OxInflammation, has
been well proven. In a recent work, our laboratory was able
to show that CS-induced OxInflammation hampers the
ability of sebocytes to uptake cholesterol via oxidation of an
important skin receptor, the scavenger receptor class B type
I (SRB1).
30
This pathway has also been observed in other
skin models, such as keratinocytes and 3D skin equivalents,
and is related not only to CS but also to PM and O
3
exposure
31–33
(GV unpublished data).
In addition to the aforementioned skin conditions, environ-
mental changes, due to rapid industrialization and urbanization
of the last few decades, are suspected to be the main drivers of
the increased incidence of skin pigmentation in geographic
regions with very heavy pollution, such as India and South
East Asia. Indeed, pollutants, such as PM and polycyclic aro-
matic hydrocarbons (PAH), due to their ability to enter the skin
via nanoparticles, also appear to be important risk factors for
facial hyperpigmentation disorders, specifically melasma.
34
Exposure to PM has also been implicated in the development,
persistence, and exacerbation of other cutaneous conditions,
such as AD, acne, psoriasis, skin aging, androgenetic alopecia,
and skin cancer.
35
In conclusion, ambient air pollutants, such as PM, CS, or
O
3
, seem to be involved in the pathogenesis of inflammatory
skin diseases (e.g., AD, acne, and psoriasis) via a common
denominator, that is, through enhancing oxidative stress and
proinflammatory mediators (OxInflammation phenomena)
36
(Figure 1).
3|MECHANISMS INVOLVED IN
POLLUTION AFFECT CUTANEOUS
TISSUES
3.1 |Atmospheric skin damage
Although all pollutants are able to induce OxInflammation as
the final outcome of their harmful effects, it is interesting to
note that each of them can affect human skin physiology
through different mechanisms of action. Based on their chem-
ical and physical characteristics, only some air contaminants
are able to penetrate through the layers of the skin, reaching
the dermis. Therefore, the potential damaging effects and the
way by which each pollutant impacts skin structure and func-
tion differs substantially.
O
3
is a small molecule and strong oxidizing agent that
directly acts on the surface of cutaneous tissue, disseminating
its detrimental effects into the deeper epidermal layers through
the generation of a cascade of ozonation products. Although it
is not a radical species per se, O
3
is able to oxidize compo-
nents of the cell membrane, mainly lipids, generating classical
radical species such as hydroxyl radicals that, in turn, drive
the production of cytotoxic, nonradical species including alde-
hydes. Due to its high reactivity and chemical and physical
properties of low aqueous solubility within the skin, O
3
is not
able to reach and directly damage live epidermal and dermal
PECORELLI ET AL.3
cells. In fact, it is well proven that this pollutant is entirely
consumed through reaction with skin surface lipids and the
intercellular lipids of the SC.
37
As a mechanically protective and flexible structure mainly
constituted of anucleated “dead”corneocytes, the outermost
stratum of our skin is enriched by sebaceous and intercellular
lipids including squalene, triglycerides, ceramides, free fatty
acids, wax monoesters, and cholesterol. Since all of these
lipids are easily prone to oxidation, as a natural consequence,
their reaction with O
3
can generate several secondary messen-
gers able to trigger signaling cascades across the different
layers of skin, leading to prooxidative and proinflammatory
processes.
38–40
For instance, in a recent study, it has been shown that O
3
exposure increased levels of HNE in human skin, and this
correlated with increased proinflammatory markers such as
COX2 and NFκB.
41
Interestingly, the levels of HNE followed
a clear gradient pattern, with high levels in the upper epider-
mis and lower levels in the dermis, suggesting that the effect
of O
3
on the skin is indeed mediated by oxidation products
generated mainly in the upper layers of the epidermis.
41
Therefore, it is possible to claim that the effect of O
3
on
cutaneous tissues is a consequence of its reaction with the
lipids present in the SC.
This concept was first advanced by Pryor et al.
42
in rela-
tion to the respiratory tract, suggesting that exposure of non-
cellular constituents of surface epithelial cells to O
3
is capable
of generating potentially toxic peroxidation products. Extrap-
olation of this concept to cutaneous tissues suggests that O
3
reacts directly with the SC lipids that contribute to the cutane-
ous tissue protective barrier,
39
generating products that are
able to penetrate the SC and target keratinocytes. It is con-
cluded that O
3
not only affects cutaneous “antioxidant”levels
and oxidation markers in the SC but also induces cellular
responses in the deeper layers of the skin.
Low-molecular-weight antioxidants are present in high
concentrations, especially in the epidermis. Oxidative stress
can overwhelm skin defenses and increase the formation of
oxidized cell components. Topical exposure to tropospheric
O
3
induces oxidative imbalances in the skin. Oxidative dam-
age to the SC may result in barrier perturbation and in the
production of lipid oxidation products that can act as “sec-
ond messengers”in the deeper layers of the skin, which, in
turn, elicits repair responses and/or the induction of defense
proteins such as NRF2 and/or heat shock proteins (HSPs).
Oxidative injury to the outermost layers of the skin can
initiate localized inflammatory responses, resulting in the
recruitment of phagocytes and their tightly regulated, cell-
specific NAD(P)H-oxidase systems for generating oxidants,
further amplifying the oxidative stress damage.
41
As of today, the potential overall mechanism by which O
3
is
able to affect skin has been described. It is generally understood
that the toxic effects of O
3,
although it is not a radical species
per se, are mediated through free radical reaction either directly
by the oxidation of biomolecules to give classical radical spe-
cies (hydroxyl radical) or by driving the radical-dependent
production of cytotoxic, nonradical species (aldehydes). Fur-
thermore, the formation of oxidation products, characteristic of
damage from free radicals, has been shown to be prevented by
the addition of the vitamins E and C. O
3
is not able to penetrate
the SC, so it first interacts with the lipids present in the outer-
most layer of the skin, leading to the generation of a number of
bioreactive species. Our lab together with other recent works
has provided some evidence that these bioactive compounds are
likely to penetrate the underlying cutaneous tissues, as demon-
strated by the presence of several proinflammatory markers in
the deeper layer of the skin.
40
It can be suggested that reaction
with the well-organized interstitial lipids and protein constitu-
ents of the outermost SC barrier, and diffusion of bioreactive
products from this tissue into the viable layers of the epidermis,
may represent a contribution to the development/exacerbation
of skin disorders associated with O
3
exposure
.
Indeed, once
these “mediators”are able to reach live cells (keratinocytes,
fibroblasts, etc.), they can induce a cellular defensive and
FIGURE 1 Consequences of 4-hydroxynonenal (HNE)
production in response to pollutants. Exposure of the skin to ozone,
cigarette smoke, and particulate matter induces lipid peroxidation and
production of HNE. This product of lipid peroxidation can form
covalent bonds with the histidine, cysteine, and lysine residues of
proteins, such as cytochrome c, through Michael addition, generating
ROS and oxidative stress, which can promote/exacerbate cutaneous
conditions such as psoriasis, premature aging, and AD. ROS, reactive
oxygen species
4PECORELLI ET AL.
inflammatory response that leads to an inflammatory/oxidative
vicious cycle, OxInflammation. This, unless quenched by
endogenous or exogenous mechanisms, will damage the skin
and compromise its barrier functions, contributing to extrinsic
skin aging.
3.2 |Mechanisms involved in CS effects
on skin
CS is a highly complex aerosol composed of more than 4700
chemicals and consists of a gas phase and a particulate phase.
Mainstream smoke (the combination of inhaled and exhaled
smoke after taking a puff of a lit cigarette) includes particu-
lates suspended in a gaseous phase. It is widely recognized
that CS contains high levels of prooxidants,
43
with more than
10
14
low molecular weight carbon- and oxygen-centered rad-
icals per puff present in gas-phase smoke.
44
Sidestream
smoke goes into the air directly from a burning cigarette and
is the main component of second-hand smoke. The chemical
constituents of sidestream smoke are different from those of
directly inhaled (mainstream) CS; it has been shown that
inhaled sidestream CS is approximately four times more
toxic per gram of total particulate matter than mainstream
CS.
45
Furthermore, sidestream condensate, compared to
mainstream, is about three times more toxic per gram and
two to six times more tumorigenic per gram. The gas/vapor
phase of sidestream smoke is responsible for most of the sen-
sory irritation and respiratory tract epithelium damage.
45
As mentioned above, the toxic effect of CS on the skin
has been well demonstrated. Exposure to CS can result in
impaired wound healing, development of squamous cell car-
cinoma, oral cancer, acne, psoriasis, eczema, hair loss, and
premature skin aging.
46
Epidemiological studies strongly
correlated CS to premature skin aging.
47–49
Moreover, the
obvious esthetic damage of the skin by CS was well docu-
mented by Dr. Model more than 30 years ago, who defined
the so-called “smoker's face,”characterized by grayskin
(smoker's melanosis) and deep wrinkles (smoker's wrin-
kle).
50
Indeed, wrinkle formation is a typical feature associ-
ated with tobacco smoking.
51
CS is able to affect skin aging
by activating MMPs in the connective tissues.
52
For instance,
MMP-1 induces the degradation of both collagen and elastic
fibers. In addition, production of the procollagen types I and
III is affected by CS, while MMP-1 and MMP-3 are strongly
induced.
53
The mechanisms involved in CS-induced skin
aging remain unresolved, although it is believed that activa-
tion of the AhR signaling pathway contributes to this effect.
CS contains water-insoluble PAHs, which have been linked
to activation of the AhR signaling pathway. AhR is involved in
the regulation of development, hypoxia signaling, and circadian
rhythms, and belongs to a family of proteins that reside in the
cytoplasm in an inactive complex with accessory proteins.
54,55
Once activated, AhR dissociates from some of the proteins in
the inactive complex and translocates to the nucleus, where it
dimerizes with Arnt.
56
The AhR/Arnt heterodimer activates the
transcription of xenobiotic-metabolizing genes
57,58
;someof
which encode proteins involved in growth control, cytokines,
nuclear transcription, and regulators of extracellular matrix pro-
teolysis.
59,60
Therefore, the AhR pathway may be involved in
the effects of tobacco smoke on skin. In support of this idea, CS
increased MMP-1 mRNA induction in primary keratinocytes
and fibroblasts, and AhR knockdown abolished this effect,
suggesting the involvement of AhR activation in extrinsic skin
aging induced by CS.
61
In addition to premature aging, CS has also been linked to
psoriasis. As previously mentioned, a recent study of over
17 million subjects demonstrated a positive correlation between
smoking and psoriasis, which correlated with how many packs
per day the subjects smoked.
28
The molecular basis of this
effect is likely due to increased oxidative stress in the skin
induced by CS. In fact, our lab has demonstrated that CS expo-
sure in keratinocytes increases NAPDH oxidase activity as
assessed via p47 and p67 membrane translocation, resulting in
increased H
2
O
2
levels and mitochondrial superoxide produc-
tion.
31
We also observed that CS exposure in keratinocytes
increases the levels of HNE and acrolein adducts.
31
We believe
that increased NAPDH oxidase activity is due to increased pro-
duction of HNE adducts in response to CS exposure, since
Yun et al. (2005) demonstrated that HNE production is able to
directly activate NOx.
62
Moreover, the increased levels of
superoxide anion or H
2
O
2
produced by NOx can regulate the
AhR signaling pathway, connecting AhR activation to oxida-
tive stress responses. It is also possible that the AhR transcrip-
tion factor itself can be modified by HNE. Since increased
oxidative stress in the skin has been associated with premature
aging,
63–65
the ability of CS to induce oxidative damage likely
contributes to premature aging.
3.3 |Mechanisms involved beyond PM-
induced skin damage
PM is a complex, heterogeneous mixture of particles, which
vary in size, number, surface areas, concentrations, and chemi-
cal composition. PM particles can be emitted directly from
sources like fossil-fuel combustion as well as generated from
gases through reactions involving other pollutants. PM particles
can be either liquid, solid, or liquid surrounding a solid core
and can be composed of organic chemicals, metals, and soil or
dust particles, as well as nitrates and sulfates, which can be fur-
ther categorized into different particles based on their sizes,
such as PM
10
,PM
2.5
, and ultrafine particles (UFPs). Coarse
particles have a diameter of 2.5 to 10 μm(PM
10
) and can be
generated by farming, mining, and construction.
66
Fine parti-
cleshaveadiameterof2.5μmorless(PM
2.5
)andcanbe
PECORELLI ET AL.5
generated by power plants, oil refineries, fuel combustion, cars,
and wildfires.
66
There are also UFPs with diameters less than
0.1 μm or 100 nm that can be generated by diesel and gasoline
fuel combustion from cars, aircrafts, and ships.
66–68
These par-
ticles can differ not only in their size but also in their effects on
human health. A study conducted in 2000 demonstrated that
PM
2.5
particles that are generated by combustion sources were
associated with increased daily mortality.
69
Inhalation of PM
2.5
results in increased plaque deposits in arteries, promoting
development of atherosclerosis as well as increased risk of
heart attacks.
70,71
Most studies on the effects of PM particles on human
health have focused on the negative effects of inhaling these
particles such as asthma, lung cancer, cardiovascular disease,
premature death, and premature delivery and birth defects in
babies. However, epidemiological studies indicate that PM
can promote premature skin aging and exacerbate preexisting
skin diseases.
1
Exposure to PM is associated with progression
of AD in children,
72
and an improvement in air quality
resulted in decreased prevalence and severity of AD.
73
The mechanisms involved in PM-associated skin disor-
ders result from increased oxidative stress due to PM expo-
sure. PMs can move through the skin through hair follicles
or transdermally, generating oxidative stress. PAHs are com-
ponents of UFPs that can be absorbed through the skin and
eventually damage the mitochondria, resulting in intracellu-
lar ROS production.
74
These damaged mitochondria produce
superoxide anions, which can be converted into H
2
O
2
that
can then undergo the Fenton reaction to produce hydroxyl
radicals, resulting in increased ROS and activation of redox-
sensitive transcription factors, such as AP1 and NFκB. In
addition, interactions between PM particles and surfaces can
result in extracellular ROS production, again resulting in the
activation of redox-sensitive transcription factors AP1 and
NFκB. The consequences of oxidative stress result in antiox-
idant depletion, lipid peroxidation, and DNA damage. In
support of this idea, our lab has demonstrated that exposure
to PM particles induces nuclear translocation of NFκB,
increases levels of HNE, and promotes DNA damage in
ex vivo human biopsies.
75
The consequences of increased
oxidative stress in response to PM exposure result in the
exacerbation of preexisting skin diseases and premature skin
aging.
1
3.4 |HNE: the trigger for pollution-induced
skin OxInflammation
HNE derives from the oxidation of ω-6 polyunsaturated fatty
acids (PUFAs), essentially arachidonic and linoleic acid, that
is, the two most represented fatty acids in biomembranes; for a
more in-depth view of HNE production, see.
76
In the context
of pollutants and skin, HNE has been shown to be produced in
the cutaneous tissues after exposure to O
3,
PM, and CS. As
previously mentioned, O
3
immediately interacts with the
PUFAs present in the upper layers of the epithelium, oxidizing
these lipids and forming unstable peroxides that can then lead
to the formation of HNE.
77
The mechanism by which PM is
believed to induce the production of HNE is less direct; the
transition metal constituents of PM (Fe, Zn, Ni, etc.) are
believed to undergo Fenton or Fenton-like reactions, generating
ROS like OH
−.78
In addition, as previously mentioned, PAHs,
which are components of PM that are highly lipophilic, can
localize to the mitochondria and promote the generation of
mitochondrial-produced ROS.
79
These increased levels of ROS
can promote the oxidation of ω-6 PUFAs, generating HNE. CS
is also believed to promote the generation of HNE through
increasing ROS as our lab has shown that CS exposure in
keratinocytes increases NAPDH oxidase activity resulting in
increased H
2
O
2
levels.
31
HNE is an unusual compound containing three functional
groups that in many cases act in concert, explaining its high
reactivity (Figure 2). There is, first of all, a conjugated system
consisting of a C=C double bond and a C=O carbonyl group
in HNE. The hydroxyl group at carbon 4 contributes to reactiv-
ity both by polarizing the C=C bond and by facilitating internal
cyclization reactions, such as thioacetal formation.
80,81
HNE is
an amphiphilic molecule; in fact, it is water soluble and also
exhibits strong lipophilic properties. Consequently, HNE tends
to concentrate in biomembranes, where phospholipids, like
phosphatidylethanolamine, and proteins, such as transporters,
ion channels, and receptors, quickly react with HNE. In addi-
tion, since it is a highly electrophilic molecule, it easily reacts
with low molecular weight compounds, such as glutathione,
and at higher concentrations with DNA (Figure 2).
82
Because
of its electrophilic nature, HNE can form adducts with cellular
protein nucleophiles. Indeed, the reactivity of HNE explains its
potential involvement in the modulation of enzyme activity,
signal transduction, and gene expression.
80,81
Besides being a
product of oxidative stress, HNE is also an efficient cell signal-
ing molecule able to modulate the expression of several genes;
therefore, it may influence important cellular functions such as
cell growth, differentiation, and apoptosis. An increasing
amount of literature indicates that HNE, depending on the con-
centrations, can potently activate stress response mechanisms,
such as mitogen-activated protein kinases (MAPKs), detoxifi-
cation mechanisms, and inflammatory responses, contributing
to cell survival against cytotoxic stress. Furthermore, HNE
may modulate redox-sensitive transcription factors such as
nuclear factor-kappa B (NFκB), activator protein-1 (AP1), and
nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Moreover, its
proven interaction with a variety of enzymes and kinases vari-
ously involved in cell signaling strongly support its important
role in pathophysiology as a cell signaling messenger
80,81
(Figure 2).
6PECORELLI ET AL.
4|HNE: METABOLISM, TOXICITY,
AND PROTEIN ADDUCTS
Once formed, under physiological conditions, HNE is rapidly
degraded in mammalian cells by multiple enzymatic pathways.
The best characterized of these enzymes include the glutathione-
S-transferases (GSTs), aldehyde dehydrogenase, and alcohol
dehydrogenase. GSTs catalyze the conjugation of reduced gluta-
thione (GSH) to HNE via Michael addition at the C-3 carbon,
thereby preventing further nucleophilic addition to this toxic
compound. Aldehyde dehydrogenase catalyzes the oxidation of
HNE to the innocuous 4-hydroxy-2-nonenoic acid, while alco-
hol dehydrogenase catalyzes reduction of the terminal aldehyde
to its alcohol, yielding the unreactive metabolite 1,4-dihydroxy-
2-nonene (DHN). Another enzyme involved in the metabolism
of HNE is aldose reductase, a member of the aldo–keto reduc-
tase superfamily. This enzyme has been shown to catalyze the
reduction of the GSH conjugate of HNE, leading to DHN–
GSH.
80,81
The half-life of HNE has been studied in several cell types,
in subcellular organelles, and even in whole organisms. Liver
tissue generally has the highest capacity to metabolize HNE,
while in other cells, the metabolism of HNE is not so fast, but
still very efficient.
80,81
Usually, HNE, even at very high lipid
peroxidation rates, cannot accumulate in an unlimited manner.
However, compared with other oxidants, such as most types
of ROS, HNE is chemically better suited for its role as a sig-
naling molecule because of its longer half-life and thus greater
range of diffusion and a higher selectivity for reaction with
specific targets. Therefore, despite the fact that humans have
developed several enzymatic systems to rapidly detoxify
HNE molecules, HNE can escape detoxifying processes and
migrate from the site of origin to other intracellular sites,
reacting rapidly with biological macromolecules, especially
proteins to form HNE protein adducts (PAs).
83
HNE PAs are physiological constituents of mammalian
organisms. They are easily detectable in peripheral blood,
where they primarily involve albumin, transferrin, and immu-
noglobulins, and also proteins related to blood coagulation,
lipid transport, blood pressure regulation, and protease inhibi-
tion.
80,81
Nevertheless, as proteins play an important role in
the normal structure and function of cells, oxidative modifica-
tions promoted by increased HNE levels may greatly alter their
structure. These protein alterations may subsequently lead to
loss of normal physiological cell functions and/or may lead to
abnormal function of the cell and eventually to cell death. For
instance, HNE can modify mitochondrial proteins such as
cytochrome c, impairing mitochondrial metabolism.
84
HNE
PAs also contribute to the pool of damaged enzymes, which
increases during aging and in several pathological states.
85
As previously mentioned, HNE can regulate a variety of
normal cell processes including cell growth, differentiation,
FIGURE 2 Schematic
representation of adduct formation by
HNE. (a) 4-Hydroxynonenal (HNE)
contains three functional groups: a C=C
double bond, a C=O carbonyl group, and
a hydroxyl group at carbon 4. All of these
functional groups contribute to its
reactivity. (b,c) HNE can form HNE
protein adducts through Schiff base
addition to lysines and Michael addition to
lysines, histidines, and cysteines.
Specifically, HNE can form adducts with
glutathione through cysteines present in
this protein. (d) HNE can also damage
DNA by forming adducts with
nitrogenous bases (i.e., deoxyguanosine).
In red, we have indicated where bonds
form between HNE and its partner
PECORELLI ET AL.7
and apoptosis. This is likely because HNE can activate a
variety of signal transduction pathways including the Erk
pathway, p38MAPK, c-Jun N-terminal kinases (JNK) path-
way, and epidermal growth factor receptor (EGFR) path-
way.
86
In addition, it can upregulate the extrinsic and
intrinsic apoptotic pathways. Moreover, it can regulate the
activity of critical transcription factors involved in OS
responses such as Nrf2 and peroxisome-proliferator-
activated receptors (PPARs). For instance, HNE can induce
Nrf2 activation by modifying its inhibitor Keap1, releasing
Nrf2 for nuclear export.
87
Moreover, it can enhance the
DNA-binding activity of AP1 and both negatively and posi-
tively regulate NFκB.
86,88
Because of these findings, it is
believed that HNE can be causally involved in many of the
pathophysiological effects associated with oxidative stress in
cells and tissues,
89
especially for the skin due to its rich con-
centration of omega-6 fatty acids. Most studies assessing
HNE production in the skin have primarily focused on
assessing the levels of HNE as a marker of oxidative stress;
therefore, the role of HNE in skin biology remains largely
unexplored.
5|PATHOLOGICAL EFFECTS OF
POLLUTION-INDUCED HNE IN
THE SKIN
Indeed, the presence of HNE adducts in the skin after pollu-
tion exposure has been well documented and in several cases
linked to skin aging, making this marker a possible common
mediator of skin oxidative damage. For instance, HNE levels
were increased after O
3
exposure in both 2D and 3D
models
90,91
and in human skin biopsies after 5 days of O
3
exposure.
41
These results are in line with previous animal
work, wherein hairless mice exposed to O
3
exhibited a clear
increase of HNE PAs in the epidermis.
37
Interestingly, cutane-
ous HNE levels were also significantly higher after O
3
expo-
sure in old animals, compared to young animals, in a wound
healing study, suggesting their role in delaying cutaneous
wound closure in aged mice,
63
possibly via the aberrant acti-
vation of metalloproteinases (MMPs).
64
O
3
is not the only
pollutant that induces the formation of cutaneous HNE in the
skin; indeed, similar effects have been observed after both CS
and PM exposure. Our group was able to demonstrate the for-
mation of HNE PAs in both keratinocytes and reconstituted
human epidermis tissues (RHEs) after CS and PM expo-
sure.
75,92
The formation of HNE PAs, as mentioned before,
leads to the covalent modification of proteins, which can be
subsequently ubiquitinated and degraded. Therefore, a conse-
quence of HNE adduct formation is the loss of important cel-
lular proteins, such as SRB1,
31
which we observed in both
keratinocytes and sebocytes.
30,31
In a very recent work by
Verdin et al. (2019), the ability of UFPs to increase HNE
levels in RHEs was also observed, suggesting a role of HNE
in regulating skin differentiation and cornification.
93
In the skin, we believe that the physiological effects of high
levels of HNE in response to pollutant-induced oxidative stress
results in the development/exacerbation of premature aging,
psoriasis, and AD. Several studies have demonstrated a role for
HNE in skin aging
94,95
and in skin color.
96
In addition, HNE
PAs have been detected in photodamaged skin elastosis.
97
The
FIGURE 3 4-Hydroxynonenal (HNE) as a pollutant-induced signaling mediator. Exposure of the skin to ozone, cigarette smoke, and
particulate matter induces lipid peroxidation and subsequent production of HNE, resulting in the Michael addition of HNE to protein products such
as cytochrome c, which results in ROS production via mitochondria, and Keap1, which releases NrF2 from sequestration. In addition, HNE activates
NAPDH oxidase, again resulting in the generation of ROS and oxidative stress, which can activate NFκB and AhR. HNE can also activate MAPK
pathways, ultimately resulting in the activation of HSPs and transcription factors NFB and AP1. Moreover, modification of cytochrome cby this
signaling mediator can induce caspase activation and PARP1 cleavage. ROS, reactive oxygen species
8PECORELLI ET AL.
effects of HNE in skin aging, associated with pollutant expo-
sure, could be due to its ability to degrade collagen due to alter-
ing MMP levels, which are transcriptionally regulated by
NFκB.
98
A general review of the role of HNE in aging can be
found here.
99
Increased HNE levels have been also detected in
skin samples from psoriatic patients as well as in the cases of
AD.
100,101
Since inflammation is the primary cause of both of
these skin conditions, it is likely that the ability of HNE to reg-
ulate the activity of the key proinflammatory mediator NFκB
contributes to these conditions.
6|CONCLUSION
Cutaneous exposure to pollutants is associated with the dev-
elopment/exacerbation of premature aging, psoriasis, and
AD conditions, and these effects are believed to be mediated
by pollutant-induced oxidative stress. Since oxidative stress
results in the production of HNE, it is no surprise that pollut-
ant exposure results in increased levels of HNE in the epithe-
lium. However, HNE is not just a marker of oxidative stress
but also an important signaling mediator that plays its roles
in a variety of cellular pathways including apoptosis, differ-
entiation, cell growth, and migration through the formation
of HNE adducts as well as modulation of signal transduction
pathways. Thus, being able to prevent cutaneous HNE for-
mation could be a possible innovative cosmeceutical
approach for future topical applications targeting the afore-
mentioned skin conditions (Figure 3).
ACKNOWLEDGMENTS
GV and RP thank the CITYCARE project, funding from the
European Union‘s Horizon 2020 research and the innovation
program under the Marie Sklodowska-Curie grant agreement
No 765602.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
ORCID
Giuseppe Valacchi https://orcid.org/0000-0002-8792-
0947
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How to cite this article: Pecorelli A, Woodby B,
Prieux R, Valacchi G. Involvement of 4-hydroxy-2-
nonenal in pollution-induced skin damage.
BioFactors. 2019;1–12. https://doi.org/10.1002/
biof.1513
12 PECORELLI ET AL.
