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MUTGEN-401548; No. of Pages 9 ARTICLE IN PRESS

Mutation Research xxx (2008) xxx–xxx

Contents lists available at ScienceDirect

Mutation Research/Genetic Toxicology and
Environmental Mutagenesis
journal homepage: www.elsevier.com/locate/gentox
Community address: www.elsevier.com/locate/mutres

Mini review

Oxidative stress in environmental-induced carcinogenesis

Salvador Mena, Angel Ortega, José M. Estrela ∗
Department of Physiology, University of Valencia, 17 Av. Blasco Ibañez, 46010 Valencia, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Reactive oxygen species (ROS) are the more abundant free radicals in nature and have been related with a
Received 19 September 2008 number of tissue/organ injuries induced by xenobiotics, ischemia, activation of leucocytes, UV exposition,
Accepted 23 September 2008 etc. Oxidative stress is caused by an imbalance between ROS production and a biological system’s ability to
Available online xxx
readily detoxify these reactive intermediates or easily repair the resulting damage. Thus, oxidative stress
is accepted as a critical pathophysiological mechanism in different frequent human pathologies, including
Keywords:
cancer. In fact ROS can cause protein, lipid, and DNA damage, and malignant tumors often show increased
Oxidative stress
levels of DNA base oxidation and mutations.
Cancer
Environment
Different lifestyle- and environmental-related factors (including, e.g., tobacco smoking, diet, alcohol,
Carcinogens ionizing radiations, biocides, pesticides, viral infections) and other health-related factors (e.g. obesity or
Obesity the aging process) may be procarcinogenic. In all these cases oxidative stress acts as a critical pathophys-
Aging iological mechanism. Nevertheless it is important to remark that, in agreement with present knowledge,
oxidative/nitrosative/metabolic stress, inflammation, senescence, and cancer are linked concepts that
must be discussed in a coordinated manner.
© 2008 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Role of ROS in oncogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Accumulation of mutations and oncogenesis is a multifactorial phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Lifestyle- and environmental-related factors, oxidative stress and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Tobacco smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Ionizing radiations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. UV radiations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.6. Biocides and pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.7. Viral infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.8. Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Obesity and the aging process: additional procarcinogenic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction

The increased incidence of cancer over the last 50–60 years may
∗ Corresponding author at: Department of Physiology, Faculty of Medicine and
be largely attributed to two factors: the ageing of the population
Odontology, University of Valencia, 17 Av. Blasco Ibañez, 46010 Valencia, Spain.
and the diffusion of carcinogenic agents, present not only in the
Tel.: +34 963864649; fax: +34 963864642. occupational, but also in the general environment [1]. There are
E-mail address: jose.m.estrela@uv.es (J.M. Estrela). studies supporting evidence that lifespan exposure to carcinogenic

1383-5718/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.mrgentox.2008.09.017

Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
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agents, beginning during developmental life, produces an overall
increase in carcinogenic processes [1].
Oxidative stress is caused by an imbalance between the produc-
tion of reactive oxygen and a biological system’s ability to readily
detoxify the reactive intermediates or easily repair the resulting
damage. Thus, oxidative stress is accepted as a critical pathophys-
iological mechanism in different frequent pathologies, including
cardiovascular diseases, cancer, diabetes, rheumatoid arthritis, or
neurological disorders such as Alzheimer or Parkinson disease
[2–6].
The increasing risk of suffering pathologies related with
oxidative stress confronts the scientific community about their
molecular origin and nature. There are scientific evidences linking
environmental changes over the time period preceding the growing
incidence of some types of cancer. These changes have not stopped
and the accumulation of carcinogens keeps growing [7].
Lifestyle-related factors are not considered as cancer causing
agents, but are risk factors directly associated with the develop-
ment of cancer. However we are frequently or constantly exposed
to known and unknown environmental carcinogenic factors. How
or when all these factors are critical for the genesis of cancer are
problems only partially understood.
The main goal of this review is to show the procarcinogenic
action of reactive oxygen species (ROS) produced by a group of
environmental agents.
2. Role of ROS in oncogenesis
It is generally accepted that ROS eventually cause DNA damage,
whereby insufficient cellular repair mechanisms may contribute to
premature aging and apoptosis. Conversely, ROS-induced imbal-
ances of the signalling pathways for metabolic protein turnover
may also result in opposite effects to recruit malfunctioning aber-
rant proteins and compounds that trigger tumorigenic processes
[8]. Consequently, DNA damage plays a role in the development of
carcinogenesis, but is also associated with an aging process in cells
and organisms [9]. Hence additional actions of ROS must be impor-
tant, possibly their effects on p53, cell proliferation, invasiveness
and metastasis. Chronic inflammation predisposes to malignancy,
but the role of ROS in this is likely to be complex because ROS can
sometimes act as anti-inflammatory agents [10].
The damaged nucleosides accumulate with age in both nuclear
and mitochondrial DNA. Mitochondrial DNA (mtDNA) mutations
appear involved in tumorigenesis, tumor growth promotion and/or
metastatic potential [11]. An example is the mutated complex I
(NADH dehydrogenase, a mtDNA gene), and its reduced activity,
which in certain tumors may lead to overproduction of ROS [12],
thus inducing up-regulation of different nuclear genes associated
with high metastatic potential: antiapoptotic MCL-1 (myeloid cell
leukemia-1), HIF-1␣ (hypoxia-inducible factor-1␣) and VEGF (vas-
cular endothelial growth factor) [13]. High metastatic potential
is regulated by ROS-mediated reversible up-regulation of nuclear
genes but not by ROS-mediated acceleration of genetic instabil-
ity, which suggests that ROS scavengers may be therapeutically
effective in suppressing metastasis [13].
3. Accumulation of mutations and oncogenesis is a
multifactorial phenomenon
Genetic alterations, immune suppression, and malignant trans-
formation are phenomena linked to the origin of cancer [14]. Cancer
is generally believed to arise from a single cell which has become
“initiated” by mutation of a few crucial genes, caused by random
errors in DNA replication or a reaction of the DNA with free radicals
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
or other chemical species of exogenous or endogenous origin. It is
not obvious how the epidemiological data on cancer incidence can
be interpreted within the framework of this paradigm. For example,
it cannot account quantitatively for the age dependence of cancer
incidence, or for the fact that the incidence of cancer in people with
hereditary mutations in tumor-suppressor genes is much lower
than expected, or for the observation that while in some types of
cancer, like colon and pancreas, certain highly oncogenic mutations,
such as that of p53, are prevalent, there is no significant increase
in the incidence of these cancers in people who carry the muta-
tions by heredity. The epidemiological data are consistent with the
hypothesis that the rate limiting processes involve large numbers
of cells. Conceivably, the mutations directly underlying neoplastic
transformation may be the result of a local collapse in the sys-
tem of intercellular processes on which the stability of the normal
genotype and phenotype depends, and thereby trigger a cascade
of mutations, among them the highly oncogenic ones. This local
collapse may be due to mutations of many different genes in many
cells as well as to other factors affecting the integrity of tissues [15].
This mutagenic origin of cancer may be due, in some cases, to expo-
sition to different carcinogens present in our environment [16]. For
instance, there are evidences, based on studies in murine models,
showing that air contaminants may cause mutations in germinal
cells [17].
In addition, accumulation of mutations appears necessary for
tumor development. In this sense it is known that mutations of ∼11
critical genes are required in mammary and colon cancers, whereas
once tumor growth starts gene mutations keep accumulating up to
∼90 [18]. Therefore it is not acceptable to think that all these muta-
tions are caused by a single mutagen, although it is reasonable to
expect a higher rate of mutations in toxic environment containing
one or more carcinogens.
These mutations can affect genes of relevant xenobiotic metab-
olizing enzymes, produce polymorphisms leading to altered ligand
affinity and activity, or influencing the expression of downstream
target genes [19], thus resulting in a differential susceptibil-
ity towards environmental toxicants [19]. N-acetyltransferase
isozymes (catalyzing the N-acetylation and O-acetylation of
aromatic amines), isoforms of glutathione S-transferase (GST)
(involved in the detoxification of PAH), cytochrome p450 and sulfo-
transferase isoforms, are all involved in the detoxification of active
metabolites from the environment [20]. Besides, although poly-
morphisms in oxidative stress-related genes (e.g. mangano-type
superoxide dismutase, catalase, or glutathione peroxidase) may not
be directly associated with cancer risk, it is possible that accu-
mulative defects in protection from oxidative stress may result in
increased risk of the disease [21].
4. Lifestyle- and environmental-related factors, oxidative
stress and carcinogenesis
4.1. Tobacco smoking
Despite widespread knowledge about high risks for health of
smoking tobacco, there are still over 1 billion smokers in the world.
A cigarette smoke contains thousands of chemicals, of which more
than 60 are known carcinogens, i.e. polycyclic aromatic hydrocar-
bons, nitrosamines, aromatic amines, aldehydes, volatile organic
compounds, metals, and others [22,23]. Furthermore, cigarette
smoke contains high levels of free radicals which can produce
lesions in DNA and generate different oxidized bases, i.e. 8-oxo-
dG, which is a classical biomarker of oxidative DNA damage [24].
Indeed, in chronic smoking an internal oxidative environment is
favored. In fact, markers of oxidative stress can be analyzed and
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Fig. 1. Tobacco smoking promotes oxidative/nitrosative stress leading to cell damage and procarcinogenic mutations. This figure schematically illustrates the complex
molecular network activated in lungs by different carcinogens. Abbreviations used are: iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase;
MPT, mitochondrial permeability transition; CytC, cytochrome C; AIF, apoptosis-inducing factor; GSH, glutathione; GSSG, glutathione disulphide; SODMn, mangano-type
superoxide dismutase; SODCu/Zn, copper/zinc-type superoxide dismutase; GPx, glutathione peroxidase; GR, glutathione reductase; CAT, catalase.

detected in bronchoalveolar lavage fluid, peripheral blood, breath
condensate, exhaled air and lung tissue [25].
The inflammatory effects of cigarette smoke generate a group
of conditions that potentiate the carcinogenic process: oxidation
of glutathione (GSH), with the consequent increase in glutathione
disulphide (GSSG) levels, in lung tissue and extra- and intracellular
bronchoalveolar lavage fluid; increase of 8-OH-dG levels, inducible
nitric oxide synthase (iNOS) and endothelial nitric oxide synthase
(eNOS) mRNA, in lung tissue; decrease of blood antioxidants such as
methylumbelliferone glucuronide or ferroxidase; increase of differ-
ent markers of lipid peroxidation (e.g. 8-epi-PGF2a); and increase
O2 •− release from bronchoalveolar lavage fluid leucocytes [25] are
some examples of the reaction of the organism to tobacco products
inhalation (Fig. 1).
Cigarette smoking is the most established risk factor for lung car-
cinogenesis, and lung cancer is the leading cause of cancer mortality
worldwide. Genotoxic carcinogens, as those mentioned above, are
capable of inducing mutations and potentiate the development of
lung cancer. The failure in repairing this damage typically results in
gain of function of some oncogenes, i.e. K-ras, or/and loss of function
of protein suppressor genes, e.g. p53 and p16 [26–29]. Major classes
of carcinogens present in tobacco and tobacco smoke are converted
into DNA-reactive metabolites by cytochrome P450 (CYP), some
CYP variants have been associated with increased risk for cancers
of the lung, esophagus, and head and neck [30]. The glutathione
S-transferase (GST) enzyme family is known to catalyze detoxifica-
tion of electrophilic compounds, including carcinogens, therapeutic
drugs, environmental toxins, and products of oxidative stress. Inter-
action between multiple variants of CYP and GST result in further
increases in lung cancer risk [31].
Besides mutations, ROS stimulate other alterations characteris-
tic of lung cancer: chromosomal abnormalities, DNA and protein
adduct formation, epigenetic alterations such as methylation and
acetylation, etc. (Fig. 1). In addition to these facts, the identifica-
tion of host differences in susceptibility to lung carcinogens, in
particular to cigarette smoke, is essential in predicting who is at
highest risk. Interestingly, susceptibility differences in the form of
rare, high-penetrance genes are suggested from studies of famil-
ial aggregation of lung cancer and a linkage study [32]. Whereas,
low-penetrance genes in the tobacco smoke metabolism path-
ways (phase I and phase II enzymes) and DNA repair pathways,
as are inflammation and cell cycle-related genes and DNA adducts
as intermediate biomarkers, also play relevant roles [32]. In the
future, studies that focus on complex interactions between multi-
ple genes and environmental exposures within pertinent pathways
are needed.
4.2. Diet
The food intake imbalance is a lifestyle factor to be considered
as a risk factor but not as a carcinogen, i.e. 0.5–2% of infections
by Helicobacter pilori result in gastric adenocarcinoma depending
on factors such as virulence of the H. pilori strain; the host immune
response; and environmental factors such as diet and smoking [33].
The excessive consumption of calories derived of animal protein
and fat combined with a poor diet in fruit, cruciferous vegeta-
bles, vegetables high in carotenoids, and green leaf vegetables,
fosters the occurrence of some cancers including, e.g., non-Hodgkin
lymphoma [34], colon, prostate, endometrium, and breast [7,35].
Fruits and vegetables are rich in antioxidants such as vitamin C,

Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
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vitamin E, carotenoids, natural flavonoids and other compounds
able to remove oxidant species, thus providing a diet-dependent
protection system for our organism [36–38]. The World Health
Organization attributed insufficient consumption of fruits and veg-
etables to 19% of the stomach, 20% of the esophagus, 12% of the lung,
and 2% of colorectal cancer cases worldwide [39].
At this step it is important to remark that the incidence of sev-
eral cancers in the Mediterranean area is lower than in other areas
of the world (e.g. in northern Europe and the USA). As nutrition and
dietary factors comprise one of the three major factors for human
carcinogenesis, the hypothesis was formulated that the dietary pro-
file of the Mediterranean area, rich in antioxidants, might exert
preventive actions. Yet, even though the exact role of antioxidants
in the Mediterranean diet is yet to be fully established, data from
observational studies are strong enough to reinforce the notion that
a diet low in saturated fat and alcohol and rich in plant food and
whole grain, such as the traditional Mediterranean diet, is associ-
ated with lower risk of cancer [40].
Furthermore, the genomic era of human nutrition is upon
us: the human genome and several plant genomes have been
characterized, and genetically modified foods are in the mar-
ketplace. New genomic technologies have made possible the
investigation of nutritional modulation of the carcinogenesis path-
way with nutrients, micronutrients, and phytochemicals. Current
study of nutrient-modulated carcinogenesis involves exploring the
effect of nutrients on DNA damage and repair mechanisms; DNA
methylation and other epigenetic changes, which influences gene
expression and cellular phenotypes; antioxidant redox state and
oxidative stress; target receptors and signal transduction path-
ways; cell cycle controls and check points; cell death mechanisms;
and antiangiogenic processes. Nutritional genomics, proteomics,
and metabolomics, will facilitate to simultaneously elucidate the
biological effects of dietary constituents on cell function and
global gene expression. This generation of new knowledge on
nutrient-gene interactions must provide background for a research
framework for diet and cancer prevention focused on identi-
fying and developing new biomarkers for dietary intervention
[41].
4.3. Alcohol
On the basis of epidemiological data, alcohol has been classi-
fied as a human carcinogen [7]. However, although alcohol is not a
mutagenic molecule, it has the ability to act as a cocarcinogen by
potentiating the effects of different carcinogens (e.g. those present
in tobacco) [42]. In fact, after tobacco, alcohol is the second risk
factor for oral, neck and head cancer [43,44].
Alcohol facilitates ROS production, cytokine release and, in
general, the formation of an in vivo oxidative microenvironment
[45,46], thus creating suitable conditions for the development of
pathologies directly related with oxidative stress such as cancer, or
the alcoholic liver disease [46,47].
Different mechanisms have been postulated to explain the asso-
ciation among oxidative stress, alcohol and cancer. One hypothesis
is that oxidation of ethanol to acetaldehyde, via alcohol dehy-
drogenase, is associated with reduction of NAD to NADH. NADH
inhibits xanthine dehydrogenase activity, promoting purine oxida-
tion, and also favors microsomal oxidations and ROS production
[48]. ROS can cause lipid peroxidation and generate DNA and pro-
tein adducts with aldehydic end products of lipid peroxidation
(MDA and 4-hydroxynonenal), which may have pathological con-
sequences as those described above [45,49–53]. On the other hand,
alcohol depletes levels of antioxidant defences such as GSH, and
induces the CYP2E1 form of cytochrome P450 which activates dif-
ferent procarcinogens into carcinogens [45,54–57].
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
4.4. Ionizing radiations
It is now accepted that ionizing radiation can cause cancer in any
organ in which cancer occurs naturally. Organs vary significantly in
their susceptibility to cancer and in their latent period before the
onset of malignant transformation. Age and sex are also significant
variables [58].
Radiation can, by itself, induce a type of genomic instability
in cells, which enhances the rate at which mutations and other
genetic changes arise in the descendants of the irradiated cell after
many generations of replication. Preliminary evidence has been
presented that irradiation targeted to the cytoplasm yields a signif-
icant increase in the frequency of mutations. Finally, genetic events
including the induction of mutations and changes in gene expres-
sion may occur in neighbour cells that receive no direct radiation
exposure at all. This ‘bystander effect’ involves, e.g. gap junction
mediated cell–cell communication, and activation of the p53 dam-
age response pathway [59].
Exposure of cells to ionizing radiation results in complex cel-
lular responses eventually resulting in DNA damage, cell death
and/or altered proliferation states. The underlying cytotoxic, cyto-
protective and cellular stress responses to radiation are mediated by
existing signalling pathways, activation of which may be amplified
by intrinsic cellular radical production systems. These signalling
responses include the activation of plasma membrane receptors,
the stimulation of cytoplasmic protein kinases, transcriptional
activation, and/or altered cell cycle regulation [60]. In case of
radiation-induced cytotoxicity, the ultimate consequence of these
signalling events after multiple exposures may be to reprogram the
irradiated and affected bystander cells in terms of their expression
levels of growth-regulatory and cell survival proteins, resulting in
altered mitogenic rates and thresholds at which genotoxic stresses
cause cell death [61]. Tumor cells, in particular, are dynamic with
respect to their reliance on specific cell signalling pathways to exist
and rapidly adapt to repeated toxic challenges in an attempt to
maintain tumor cell survival [61].
Exposure of cells to ionizing radiation and a variety of other toxic
stresses induces, simultaneously, multiple signalling pathways:
PI3K, MAPK, JNK, and p38 pathways, signalling to pro-caspases and
NF-␬B. Reactive oxygen and nitrogen species may play an impor-
tant role in this process by inhibiting protein tyrosine phosphatase
activity [62]. The ability of radiation to activate these signalling
pathways may depend on the expression of multiple growth factor
receptors, autocrine factors and on Ras mutations. Following irra-
diation, these signals play critical roles in controlling cell survival
and repopulation in a cell-type-dependent manner [63].
DNA is a target of ionizing radiation, and facilitates activation of
cascades of growth factors and chemokines, and of molecules ini-
tiating multiple signalling pathways that modulate different cell
functions. Nevertheless, under some circumstances, it may pro-
mote metastasis. At certain doses and within certain time frames,
ionizing radiations enhance the activities of tumor-associated host
cells that support invasion and metastasis [64]. After irradiation
of prostate carcinomas and cervix cancer, the risk for rectal and
bladder tumors increases, respectively [65].
4.5. UV radiations
Solar radiation is divided into three major wavelengths
bands: ultraviolet (UV) radiation ( = 290–400 nm), visible light
( = 400–760 nm) and infrared (IR) radiation ( = 760–1 mm).
Ultraviolet A radiation (UVA), which corresponds to 90% of the
sunlight, can penetrate the skin in a dose accumulation fashion,
associates with the effect of UVB, and facilitates dermal colla-
gen degeneration, thus causing skin inflammation and premature
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aging. UVA has genotoxic effects, linked to the appearance of chro-
mosome aberrations caused by breaks in the DNA strands [66].
Unlike shorter wavelength UVB, which damages DNA directly,
UVA is absorbed poorly by DNA. Nevertheless, UVA damages, e.g.
proliferating cell nuclear antigen (PCNA), the homotrimeric DNA
polymerase sliding clamp. Crosslinking between the PCNA subunits
through a histidine residue in the intersubunit domain occurs after
treatment with higher (although still moderate) doses of UVA alone
or with chemical oxidants. By this and other similar mechanisms
UVA can affect diverse biological functions including DNA repli-
cation, repair, cell cycle control, and chromatin remodeling [67].
All these facts may contribute to the increased risk of skin cancer
associated with UVA exposure.
UVB increases ROS in epidermal cells, and activates signalling
pathways involved in regulating cell growth, differentiation, and
proliferation, thus facilitating the clonal expansion of tumor cells
[68]. UVB-induced H2 O2 production promotes the phosphoryla-
tion of MAPKs [69], such as ERK1/2, JNK, and p38 [70]. Activation
of ERK, JNK and p38 occurs through inhibition of their inhibitors,
MKP-1 (a family of dual-specificity protein phosphatases), and
not by direct activation of MAPKs [71]. ERK1/2 activates growth
factors and starts the tumor process [72]; phosphorylated JNK
actives activator protein-1, involved in processes such as stimula-
tion of tumor inflammation, invasion, metastasis and angiogenesis;
whereas p38-ERK is involved in the regulation of NF-␬B [73].
Indeed, in vivo studies have found that exposure to UVB activates
NF-␬B/p65 and its translocation to the nucleus, thereby activating
genes involved in different mechanisms, e.g. inflammation (COX-2
and iNOS), or the cell cycle (PCNA, cyclin D1) [73].
UVB, by inducing lipid and protein oxidation at the plasma mem-
brane, may also cause a loss of membrane fluidity, inactivation of
enzymes, and alteration of the permeability to ions. These changes
may cause rupture of the cells by an osmotic process [74].
4.6. Biocides and pesticides
There are traces of herbicides and insecticides which can be
measured in tap water, insects, bees (including their honey), or veg-
etables. Most of these products are lethal to insects and plants with
high specificity, but many also show different degrees of toxicity in
humans [75].
Synthetic pesticides (i.e. polyhalogenated cyclic hydrocarbons,
chlorinated acetamide herbicides, and organophosphate pesti-
cides) and organochlorines are environmental contaminants with
known neurological toxicity, and related with different neurologi-
cal pathologies (e.g. Parkinson’s disease) and others diseases [76].
Besides, there are evidences of cancer in farm-workers or people in
contact with these products [77].
DNA damage and oxidative stress have been proposed as mech-
anisms that could explain these effects. Pesticides can induce
oxidative stress via a multi-step pathway, resulting in an imbal-
ance between pro-oxidant and antioxidant defense mechanisms
in different tissues, including alterations in antioxidant enzymes
[78]. Studies in experimental animals [79] and tissue culture stud-
ies show that pesticides, especially organophosphate pesticides,
induce oxidative stress [78,80–82]. Moreover, it has been shown
that herbicides can affect catalase and superoxide dismutase activ-
ities [83].
Piperonyl butoxide (PBO), is a pesticide widely used along with
pyrethroids as grain protector and domestic insecticide [84]. PBO is
capable of increasing the gene expression of CYP1A1, a cytochrome
P-450 isoform and the most active enzyme catalyzing procar-
cinogens [85]. PBO has a liver-tumor-promoting effect increasing
production of ROS as a byproduct of hepatic microsomal oxidation
in mice [84]. The increase of ROS is due to PBO-induced regulation
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
5
of glutathione reductase (GRx), NAD(P)H: quinone oxidoreductase
1 (NQO1), and other antioxidant enzymes. This regulation is under
the transcriptional factor Nrf2 [86]. NQO1, detoxifies quinones and
thus decreases ROS formation [87], has been found within solid
tumors of the breast, ovary, lung, colon, thyroid, and adrenal gland
in an elevated concentration [88].
Organochlorines are persistent organic pollutants that may
accumulate in the environment and food. They are lipophilic and
can be detected, after ingestion, in human breast milk and adi-
pose tissue [89]. They are particularly harmful during pregnancy
(these compounds cross the placenta and reach the fetus blood)
and after birth (neonates are exposed through the breast milk)
[90].
Polychlorinated biphenyls (PCBs) are organochlorines, which
have been used for a variety of applications, such as flame retar-
dants, paints, plasticizers, or in the electricity industry. PCBs include
chlorinated dioxins and furans, and pesticides such as dichloro-
diphenyl-trichloroethane (DDT), aldrin and dieldrin [91]. They may
cause mutations in p53 and K-ras oncogenes and, consequently, rep-
resent risk factors for, e.g. colorectal and pancreatic cancers [92].
People are exposed to PCBs primarily through the diet and, in par-
ticular, by ingestion of fish from polluted waters, although possible
inhalation and/or dermal contact must be also taken into account.
This is not to say that all people exposed to high levels of PCBs
develop cancer, however people clearly appear at greater risk if they
have genetic predisposition. Moreover, exposure to organochlo-
rines is a risk factor for, e.g. breast cancer because of their potential
estrogenic activity [93], immunosuppressive and tumor-promoting
properties [91].
Aldrin and dieldrin are active against a wide range of insects, and
show high effectiveness by combined contact and ingestion. Dield-
rin was also used as a residual spray for several public health and
domestic purposes, including the control of termites and garden
insects. Based largely on evidence of aldrin- and dieldrin-induced
hepatocarcinogenesis in mice, and the persistence of dieldrin in the
environment, these insecticides were prohibited by their cancer
risk [94].
4.7. Viral infections
Among microorganisms, oncogenic viruses are the most well
established procarcinogenic agents. A decade ago studies on the
relationship between cancer and infections estimated that viruses
were involved in about 16% of all neoplasias [95]. Recent epi-
demiological data point out that one-fifth of all neoplasias in
low-income countries are promoted or influenced by viruses,
whereas only one out of ten occurs in high-income countries
[96,97].
Different groups of viruses have been related with human
cancer, meaning that they are able to initiate the carcinogenesis
process by mutagenesis induction. The most frequent oncogenic
DNA viruses are the human papilloma DNA virus type 16 or 18
(HPV-16, HPV-18), the DNA hepatitis B virus (HBV), and the RNA
hepatitis C virus (HCV) [98,99]. The direct mutagenic action of HPV
[100] causes more than 90% of cervical cancers, which is spread
by skin-to-skin contact during sexual intercourse [101]. HBV and
HCV constitute about 80% of the major risk factors for liver cancer
[98] and induce chronic inflammation, which is thought to pro-
mote carcinogenesis in a mechanism mediated by ROS [102–104].
The long time period between primary infection and hepatocel-
lular carcinoma development (10–20 years in humans), implies
that hepatitis virus is not directly oncogenic [98]. The increasing
ROS production has been associated with the action of HBVx pro-
tein and core protein NS5A encoded by HBV and HCV, respectively
[105,106].
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4.8. Metals
Several metals and metalloids have been rated as certain or
probable carcinogens by the International Agency for Research
on Cancer (IARC). For instance, exposure to chromium or nickel
has been found to be associated with nasopharyngeal carcinoma,
exposure to lead or mercury to brain tumors, exposure to lead or
cadmium to kidney cancer, and exposure to cadmium to prostate
cancer [107–109].
The mechanisms of the action of metals and metalloids are
not clear yet. They could act as cocarcinogens by activating pro-
carcinogens in the liver, or by increasing the promoting effect of
sexual hormones. They could also act by replacing natural enzyme-
associated metals and thereby inactivate their activity [7].
Metals such as iron, copper, cadmium, chromium, lead, mercury,
nickel, and vanadium exhibit the ability to produce ROS via the
Fenton-like production of superoxide anion and hydroxyl radical,
thus resulting in molecular damages and alteration of cell home-
ostasis [110]. Carcinogenic metals and metalloids, such as arsenic,
cadmium, nickel, and cobalt can inhibit zinc finger containing DNA
repair proteins [111]. Moreover, some metals and metalloids may
also be mutagenic through other mechanisms, e.g. by interacting
with DNA.
Ni(II), Fe(III), and Co(II) can react with H2 O2 to produce a
hydroxyl free radical, 1 O2 , and metal–oxygen complexes that cause
site-specific DNA damage [112], at thymine and cytosine residues
[113]. On the other hand indirect oxidative DNA damage may also
occur due to the action phagocytic cells such as neutrophils and
macrophages [114] [115].
Iron catalyzes the formation of ROS, but only free iron is active.
Most iron is complexed, and little free iron exists in nature. A vari-
ety of xenobiotics (paraquat, diquat, nitrofurantoin, adriamycin,
daunomycin, and diaziquone) has been shown to facilitate the
release of iron from ferritin [110]. Similar to iron, copper acts as
a catalyst in the formation of ROS and catalyzes peroxidation of
membrane lipids [116].
Inhalation of arsenic oxides has been reported to be associated
with a very large spectrum of common cancer types, including can-
cers of the lung, kidney, or liver [117].
Human exposure to nickel occurs primarily via inhalation and
ingestion. The accumulation of nickel in the body can lead to
lung fibrosis, cardiovascular and kidney diseases, and cancer [118].
Nickel induces oxidative stress and interferes in the activation of
some transcription factors, including AP-1, NF-␬B, and HIF-1 [118].
Nickel promotes oxidative DNA damage and inhibition of DNA
repair activity. Moreover, nickel increases the extent of DNA methy-
lation (histone H4 acetylation) leading to the inactivation of gene
expression [119], causes the formation of nickel-bound abnormal
proteins [118], and can bind to histones and specifically cleave C-
terminal of histone H2A [120].
5. Obesity and the aging process: additional
procarcinogenic factors
5.1. Obesity
Different studies suggest that high energy intake, obesity, and/or
nutritional imbalance (diabetes) may favor development of col-
orectal cancer [121]. This could be explained, at least in part,
by alterations in genes encoding elements of insulin signalling,
adipocyte metabolism and differentiation, and regulation of energy
expenditure [122]. In fact several reports indicate an association
between plasma insulin balance and colorectal cancer, thus con-
firming a 10–40% increase in colorectal cancer in subjects with
diabetes mellitus [123].
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
The propensity to become obese is inheritable but it only
becomes a health problem under conditions of excessive energy
intake, and is dependent on environmental factors [124]. Abdomi-
nal obesity has been linked to cardiovascular risks, type 2 diabetes
mellitus and others diseases [124]. Obesity is associated with a state
of chronic inflammation, and produces a proinflammatory oxida-
tive environment [125,126]. In these conditions, adipocytes express
highs levels of proinflammatory cytokines [127]. Inflammation in
the colon leads to DNA damage and the promotion of carcinogen-
esis [128]. Obesity is also associated with breast [129], colon [130],
and prostate neoplasias [131].
Glucose plays a role in oxidative stress. Low antioxidant capacity
is observed in diabetes mellitus type 2 patients [132], a com-
mon observation in different susceptibility variants [133]. Exposure
of colonocytes to high concentrations of insulin may induce an
increase in cell proliferation; whereas metabolic alterations, due
to the presence of high levels of glucose and fatty acids, may cause
changes in cell signalling pathways and oxidative stress [134].
5.2. Aging
As a result of time and cumulative divisions, normal cells with
proliferation capacity enter an irreversible nonproliferative state
termed cellular senescence, which is thought to contribute to
organism aging [135]. Both telomere shortening and cumulative
oxidative damage have been shown to contribute to senescence,
probably acting to different degrees according to proliferation
index, cell type, or environment [136]. Because of its associated
molecular/structural damages and irreversible cell-cycle arrest
induced by shortened telomeres, senescence is basically consid-
ered a tumor-suppressor mechanism that stops the proliferation of
genetically altered cells (i.e., preneoplastic or cancerous cells) [137].
ROS generation increases in aging cells, and oxidative stress is a
critical modulator of telomere loss [138]. The telomere shortening
causes different diseases, aging and senescence [139]. However, the
incidence of frequent cancers in humans exponentially increases
with age; whereas, on the other hand, when aging is delayed by
caloric restriction, the cancer incidence decreases [136]. Can this
positive link between aging and tumorigenesis be explained if
senescence is a tumor-suppressor mechanism? Reasonably, oxida-
tive damage could affect oncogenes and/or tumor-suppressor
genes in some senescent cells, hence promoting their evolution
toward initiated cancer cells. This mechanism could be particu-
larly relevant for age-associated carcinomas because senescence
in epithelial cells is driven more by oxidative stress than by telom-
ere shortening [140]. Nevertheless, it is important to remark that
pro-oxidant factors can influence telomere-length variation [141].
6. Concluding remarks
As discussed in this review environment-related factors, oxida-
tive stress as a pathophysiological mechanism, and carcinogenesis
are closely linked. Nevertheless, although not the strict focus of this
review, today it is well recognized that oxidative and nitrosative
stresses are coexisting mechanisms [142]. In fact inflammatory pro-
cesses may induce DNA mutations in cells via oxidative/nitrosative
stress [143]. Reactive intermediates of oxygen and nitrogen may
directly oxidize DNA, or may interfere with mechanisms of DNA
repair. These reactive substances may also rapidly react with pro-
teins, carbohydrates and lipids, and the derivative products may
induce a high perturbation in the intracellular and intercellular
homeostasis, until DNA mutation (Fig. 1). The main substances
that link inflammation to cancer via oxidative/nitrosative stress
are prostaglandins and cytokines [144]. Thus, in agreement with
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present knowledge oxidative/nitrosative/metabolic stress, inflam-
mation, and cancer are linked concepts that should be discussed in
a coordinated manner.
ROS, reactive nitrogen species (RNS, e.g. nitric oxide), and
mixed intermediates (e.g. peroxynitrite, –ONOO), are well recog-
nized for playing a dual role as both deleterious and beneficial
species [6]. ROS and RNS are normally generated by tightly reg-
ulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase
isoforms, respectively [6]. Overproduction of ROS/RNS results in
oxidative/nitrosative stress (Fig. 1). In contrast, beneficial effects
of ROS/RNS occur at low concentrations and involve physiologi-
cal roles in cellular responses to noxia, as for example in defense
against infectious agents, in the function of a number of cellular
signalling pathways, and the induction of a mitogenic response [6].
Ironically, various ROS-mediated actions in fact protect cells against
ROS-induced oxidative stress and re-establish or maintain “redox
balance” or “redox homeostasis”. Indeed ROS within cells act as
secondary messengers in intracellular signalling cascades which
induce and maintain the oncogenic phenotype of cancer cells, how-
ever, ROS can also induce cellular senescence and apoptosis and can
therefore function as anti-tumorigenic species [145].
This review also illustrates the importance of properly control-
ling all environment-related factors that can be deleterious, and
carcinogenic in particular, for human health. In this sense to go
“green” must be seriously considered as the best option not only
for us but for nature in general.
References
[1] M. Soffritti, F. Belpoggi, D.D. Esposti, L. Falcioni, L. Bua, Consequences of
exposure to carcinogens beginning during developmental life, Basic Clin. Phar-
macol. Toxicol. 102 (2008) 118–124.
[2] I. Dalle-Donne, R. Rossi, R. Colombo, D. Giustarini, A. Milzani, Biomarkers of
oxidative damage in human disease, Clin. Chem. 52 (2006) 601–623.
[3] N.S. Dhalla, R.M. Temsah, T. Netticadan, Role of oxidative stress in cardiovas-
cular diseases, J. Hypertens. 18 (2000) 655–673.
[4] P. Jenner, Oxidative stress in Parkinson’s disease, Ann. Neurol. 53 (Suppl. 3)
(2003) S26–S36 (discussion S36–28).
[5] L.M. Sayre, M.A. Smith, G. Perry, Chemistry and biochemistry of oxidative
stress in neurodegenerative disease, Curr. Med. Chem. 8 (2001) 721–738.
[6] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals
and antioxidants in normal physiological functions and human disease, Int. J.
Biochem. Cell. Biol. 39 (2007) 44–84.
[7] P. Irigaray, J.A. Newby, R. Clapp, L. Hardell, V. Howard, L. Montagnier, S. Epstein,
D. Belpomme, Lifestyle-related factors and environmental agents causing can-
cer: an overview, Biomed. Pharmacother. 61 (2007) 640–658.
[8] Y. Wang, Bulky DNA lesions induced by reactive oxygen species, Chem. Res.
Toxicol. 21 (2008) 276–281.
[9] C. Bertram, R. Hass, Cellular responses to reactive oxygen species-induced
DNA damage and aging, Biol. Chem. 389 (2008) 211–220.
[10] B. Halliwell, Oxidative stress and cancer: have we moved forward? Biochem.
J. 401 (2007) 1–11.
[11] Y. Shidara, K. Yamagata, T. Kanamori, K. Nakano, J.Q. Kwong, G. Manfredi, H.
Oda, S. Ohta, Positive contribution of pathogenic mutations in the mitochon-
drial genome to the promotion of cancer by prevention from apoptosis, Cancer
Res. 65 (2005) 1655–1663.
[12] D.C. Wallace, Mitochondrial diseases in man and mouse, Science 283 (1999)
1482–1488.
[13] K. Ishikawa, K. Takenaga, M. Akimoto, N. Koshikawa, A. Yamaguchi, H. Iman-
ishi, K. Nakada, Y. Honma, J. Hayashi, ROS-generating mitochondrial DNA
mutations can regulate tumor cell metastasis, Science 320 (2008) 661–664.
[14] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (2000) 57–70.
[15] H.B. Steen, The origin of oncogenic mutations: where is the primary damage?
Carcinogenesis 21 (2000) 1773–1776.
[16] L.D. Claxton, G.M. Woodall Jr., A review of the mutagenicity and rodent car-
cinogenicity of ambient air, Mutat. Res. 636 (2007) 36–94.
[17] C.M. Somers, B.E. McCarry, F. Malek, J.S. Quinn, Reduction of particulate air
pollution lowers the risk of heritable mutations in mice, Science 304 (2004)
1008–1010.
[18] T. Sjoblom, S. Jones, L.D. Wood, D.W. Parsons, J. Lin, T.D. Barber, D. Mandelker,
R.J. Leary, J. Ptak, N. Silliman, S. Szabo, P. Buckhaults, C. Farrell, P. Meeh, S.D.
Markowitz, J. Willis, D. Dawson, J.K. Willson, A.F. Gazdar, J. Hartigan, L. Wu,
C. Liu, G. Parmigiani, B.H. Park, K.E. Bachman, N. Papadopoulos, B. Vogel-
stein, K.W. Kinzler, V.E. Velculescu, The consensus coding sequences of human
breast and colorectal cancers, Science 314 (2006) 268–274.
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
7
[19] L.M. Dong, J.D. Potter, E. White, C.M. Ulrich, L.R. Cardon, U. Peters, Genetic
susceptibility to cancer: the role of polymorphisms in candidate genes, JAMA
299 (2008) 2423–2436.
[20] R.J. Hung, P. Boffetta, P. Brennan, C. Malaveille, A. Hautefeuille, F. Donato, U.
Gelatti, M. Spaliviero, D. Placidi, A. Carta, A. Scotto di Carlo, S. Porru, GST, NAT,
SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental
exposures and bladder cancer risk in a high-risk population, Int. J. Cancer 110
(2004) 598–604.
[21] S.W. Ryter, H.P. Kim, A. Hoetzel, J.W. Park, K. Nakahira, X. Wang, A.M. Choi,
Mechanisms of cell death in oxidative stress, Antioxid. Redox Signal 9 (2007)
49–89.
[22] S.S. Hecht, Tobacco carcinogens, their biomarkers and tobacco-induced can-
cer, Nat. Rev. Cancer 3 (2003) 733–744.
[23] S.S. Hecht, Progress and challenges in selected areas of tobacco carcinogenesis,
Chem. Res. Toxicol. 21 (2008) 160–171.
[24] J.T. Thaiparambil, M.V. Vadhanam, C. Srinivasan, C.G. Gairola, R.C. Gupta, Time-
dependent formation of 8-oxo-deoxyguanosine in the lungs of mice exposed
to cigarette smoke, Chem. Res. Toxicol. 20 (2007) 1737–1740.
[25] H. van der Vaart, D.S. Postma, W. Timens, N.H. ten Hacken, Acute effects of
cigarette smoke on inflammation and oxidative stress: a review, Thorax 59
(2004) 713–721.
[26] J.C. Lacal, S.K. Srivastava, P.S. Anderson, S.A. Aaronson, Ras p21 proteins with
high or low GTPase activity can efficiently transform NIH/3T3 cells, Cell 44
(1986) 609–617.
[27] W.H. Westra, R.J. Slebos, G.J. Offerhaus, S.N. Goodman, S.G. Evers, T.W. Kensler,
F.B. Askin, S. Rodenhuis, R.H. Hruban, K-ras oncogene activation in lung ade-
nocarcinomas from former smokers. Evidence that K-ras mutations are an
early and irreversible event in the development of adenocarcinoma of the
lung, Cancer 72 (1993) 432–438.
[28] S.A. Belinsky, K.J. Nikula, W.A. Palmisano, R. Michels, G. Saccomanno, E.
Gabrielson, S.B. Baylin, J.G. Herman, Aberrant methylation of p16(INK4a) is
an early event in lung cancer and a potential biomarker for early diagnosis,
Proc. Natl. Acad. Sci. U.S.A. 95 (1998) 11891–11896.
[29] E. Baryshnikova, A. Destro, M.V. Infante, S. Cavuto, U. Cariboni, M. Alloisio, G.L.
Ceresoli, R. Lutman, G. Brambilla, G. Chiesa, G. Ravasi, M. Roncalli, Molecular
alterations in spontaneous sputum of cancer-free heavy smokers: results from
a large screening program, Clin. Cancer Res. 14 (2008) 1913–1919.
[30] H. Bartsch, U. Nair, A. Risch, M. Rojas, H. Wikman, K. Alexandrov, Genetic
polymorphism of CYP genes, alone or in combination, as a risk modifier of
tobacco-related cancers, Cancer Epidemiol. Biomarkers Prev. 9 (2000) 3–28.
[31] C. Carlsten, G.S. Sagoo, A.J. Frodsham, W. Burke, J.P. Higgins, Glutathione S-
transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based
systematic HuGE review and meta-analysis, Am. J. Epidemiol. 167 (2008)
759–774.
[32] A.G. Schwartz, G.M. Prysak, C.H. Bock, M.L. Cote, The molecular epidemiology
of lung cancer, Carcinogenesis 28 (2007) 507–518.
[33] J.C. Atherton, The pathogenesis of Helicobacter pylori-induced gastro-
duodenal diseases, Annu. Rev. Pathol. 1 (2006) 63–96.
[34] V. Blinder, S.G. Fisher, The role of environmental factors in the etiology of
lymphoma, Cancer Invest. 26 (2008) 306–316.
[35] A.P. Simopoulos, Energy imbalance and cancer of the breast, colon and
prostate, Med. Oncol. Tumor Pharmacother. 7 (1990) 109–120.
[36] M. Valko, C.J. Rhodes, J. Moncol, M. Izakovic, M. Mazur, Free radicals, metals
and antioxidants in oxidative stress-induced cancer, Chem. Biol. Interact. 160
(2006) 1–40.
[37] A. Damianaki, E. Bakogeorgou, M. Kampa, G. Notas, A. Hatzoglou, S. Pana-
giotou, C. Gemetzi, E. Kouroumalis, P.M. Martin, E. Castanas, Potent inhibitory
action of red wine polyphenols on human breast cancer cells, J. Cell Biochem.
78 (2000) 429–441.
[38] L.E. Kelemen, J.R. Cerhan, U. Lim, S. Davis, W. Cozen, M. Schenk, J. Colt, P. Hartge,
M.H. Ward, Vegetables, fruit, and antioxidant-related nutrients and risk of
non-Hodgkin lymphoma: a National Cancer Institute-Surveillance, Epidemi-
ology, and End Results population-based case-control study, Am. J. Clin. Nutr.
83 (2006) 1401–1410.
[39] K. Lock, J. Pomerleau, L. Causer, D.R. Altmann, M. McKee, The global burden of
disease attributable to low consumption of fruit and vegetables: implications
for the global strategy on diet, Bull. World Health Organ. 83 (2005) 100–108.
[40] F. Visioli, S. Grande, P. Bogani, C. Galli, The role of antioxidants in the mediter-
ranean diets: focus on cancer, Eur. J. Cancer Prev. 13 (2004) 337–343.
[41] V.L. Go, R.R. Butrum, D.A. Wong, Diet, nutrition, and cancer prevention: the
postgenomic era, J. Nutr. 133 (2003) 3830S–3836S.
[42] G. Poschl, H.K. Seitz, Alcohol, cancer, Alcohol Alcohol. 39 (2004) 155–165.
[43] A. Altieri, W. Garavello, C. Bosetti, S. Gallus, C. La Vecchia, Alcohol consumption
and risk of laryngeal cancer, Oral Oncol. 41 (2005) 956–965.
[44] G. Corrao, V. Bagnardi, A. Zambon, S. Arico, Exploring the dose–response rela-
tionship between alcohol consumption and the risk of several alcohol-related
conditions: a meta-analysis, Addiction 94 (1999) 1551–1573.
[45] S.K. Das, D.M. Vasudevan, Alcohol-induced oxidative stress, Life Sci. 81 (2007)
177–187.
[46] O. Sergent, B. Griffon, P. Cillard, J. Cillard, Alcohol and oxidative stress, Pathol.
Biol. (Paris) 49 (2001) 689–695.
[47] D. Wu, A.I. Cederbaum, Alcohol, oxidative stress, and free radical damage,
Alcohol Res. Health 27 (2003) 277–284.
[48] L. Conde de la Rosa, H. Moshage, N. Nieto, Hepatocyte oxidant stress and
alcoholic liver disease, Rev. Esp. Enferm. Dig. 100 (2008) 156–163.
G Model
MUTGEN-401548; No. of Pages 9 ARTICLE IN PRESS
8 S. Mena et al. / Mutation Research xxx (2008) xxx–xxx
[49] T.L. Freeman, D.J. Tuma, G.M. Thiele, L.W. Klassen, S. Worrall, O. Niemela, S.
Parkkila, P.W. Emery, V.R. Preedy, Recent advances in alcohol-induced adduct
formation, Alcohol Clin. Exp. Res. 29 (2005) 1310–1316.
[50] E. Albano, Alcohol, oxidative stress and free radical damage, Proc. Nutr. Soc.
65 (2006) 278–290.
[51] O. Niemela, Distribution of ethanol-induced protein adducts in vivo: relation-
ship to tissue injury, Free Radic. Biol. Med. 31 (2001) 1533–1538.
[52] S. Warnakulasuriya, S. Parkkila, T. Nagao, V.R. Preedy, M. Pasanen, H. Koivisto,
O. Niemela, Demonstration of ethanol-induced protein adducts in oral leuko-
plakia (pre-cancer) and cancer, J. Oral Pathol. Med. 37 (2008) 157–165.
[53] H.K. Seitz, N. Homann, The role of acetaldehyde in alcohol-associated can-
cer of the gastrointestinal tract, Novartis Found Symp. 285 (2007) 110–119
(discussion 119–114, 198–119).
[54] I.H. McKillop, L.W. Schrum, Alcohol and liver cancer, Alcohol 35 (2005)
195–203.
[55] M.A. Robin, I. Sauvage, T. Grandperret, V. Descatoire, D. Pessayre, B. Fromenty,
Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat
hepatocytes, FEBS Lett. 579 (2005) 6895–6902.
[56] V. Salaspuro, M. Salaspuro, Synergistic effect of alcohol drinking and smok-
ing on in vivo acetaldehyde concentration in saliva, Int. J. Cancer 111 (2004)
480–483.
[57] H.K. Seitz, B. Maurer, F. Stickel, Alcohol consumption and cancer of the gas-
trointestinal tract, Dig. Dis. 23 (2005) 297–303.
[58] M. Sowa, B.J. Arthurs, B.J. Estes, W.F. Morgan, Effects of ionizing radiation
on cellular structures, induced instability and carcinogenesis, EXS (2006)
293–301.
[59] J.B. Little, Radiation carcinogenesis, Carcinogenesis 21 (2000) 397–404.
[60] R.K. Schmidt-Ullrich, P. Dent, S. Grant, R.B. Mikkelsen, K. Valerie, Signal
transduction and cellular radiation responses, Radiat. Res. 153 (2000) 245–
257.
[61] K. Valerie, A. Yacoub, M.P. Hagan, D.T. Curiel, P.B. Fisher, S. Grant, P. Dent,
Radiation-induced cell signaling: inside–out and outside–in, Mol. Cancer
Ther. 6 (2007) 789–801.
[62] P. Dent, A. Yacoub, J. Contessa, R. Caron, G. Amorino, K. Valerie, M.P. Hagan, S.
Grant, R. Schmidt-Ullrich, Stress and radiation-induced activation of multiple
intracellular signaling pathways, Radiat. Res. 159 (2003) 283–300.
[63] P. Dent, A. Yacoub, P.B. Fisher, M.P. Hagan, S. Grant, MAPK pathways in radiation
responses, Oncogene 22 (2003) 5885–5896.
[64] I. Madani, W. De Neve, M. Mareel, Does ionizing radiation stimulate cancer
invasion and metastasis? Bull. Cancer 95 (2008) 292–300.
[65] W. Dorr, T. Herrmann, Second tumors after oncologic treatment, Strahlenther.
Onkol. 184 (2008) 67–72.
[66] K. Wischermann, S. Popp, S. Moshir, K. Scharfetter-Kochanek, M. Wlaschek, F.
de Gruijl, W. Hartschuh, R. Greinert, B. Volkmer, A. Faust, A. Rapp, P. Schmezer,
P. Boukamp, UVA radiation causes DNA strand breaks, chromosomal aberra-
tions and tumorigenic transformation in HaCaT skin keratinocytes, Oncogene
27 (2008) 4269–4280.
[67] B. Montaner, P. O’Donovan, O. Reelfs, C.M. Perrett, X. Zhang, Y.Z. Xu, X. Ren,
P. Macpherson, D. Frith, P. Karran, Reactive oxygen-mediated damage to a
human DNA replication and repair protein, EMBO Rep. 8 (2007) 1074–1079.
[68] W. Zhang, A.N. Hanks, K. Boucher, S.R. Florell, S.M. Allen, A. Alexander, D.E.
Brash, D. Grossman, UVB-induced apoptosis drives clonal expansion during
skin tumor development, Carcinogenesis 26 (2005) 249–257.
[69] D.N. Syed, A. Malik, N. Hadi, S. Sarfaraz, F. Afaq, H. Mukhtar, Photochemo-
preventive effect of pomegranate fruit extract on UVA-mediated activation
of cellular pathways in normal human epidermal keratinocytes, Photochem.
Photobiol. 82 (2006) 398–405.
[70] J.G. Einspahr, G.T. Bowden, D.S. Alberts, N. McKenzie, K. Saboda, J. Warneke, S.
Salasche, J. Ranger-Moore, C. Curiel-Lewandrowski, R.B. Nagle, B.J. Nickoloff,
C. Brooks, Z. Dong, S.P. Stratton, Cross-validation of murine UV signal trans-
duction pathways in human skin, Photochem. Photobiol. 84 (2008) 463–476.
[71] M. Christmann, M.T. Tomicic, D. Aasland, B. Kaina, A role for UV-light-induced
c-Fos: stimulation of nucleotide excision repair and protection against sus-
tained JNK activation and apoptosis, Carcinogenesis 28 (2007) 183–190.
[72] R.P. Singh, S. Dhanalakshmi, S. Mohan, C. Agarwal, R. Agarwal, Silibinin inhibits
UVB- and epidermal growth factor-induced mitogenic and cell survival sig-
naling involving activator protein-1 and nuclear factor-kappaB in mouse
epidermal JB6 cells, Mol. Cancer Ther. 5 (2006) 1145–1153.
[73] D.A. Lewis, D.F. Spandau, UVB-induced activation of NF-kappaB is regulated
by the IGF-1R and dependent on p38 MAPK, J. Invest. Dermatol. 128 (2008)
1022–1029.
[74] A. Bommareddy, J. Hora, B. Cornish, C. Dwivedi, Chemoprevention by
alpha-santalol on UVB radiation-induced skin tumor development in mice,
Anticancer Res. 27 (2007) 2185–2188.
[75] S. Oberoi, R.S. Ahmed, S.G. Suke, S.N. Bhattacharya, A. Chakraborti, B.D. Baner-
jee, Comparative effect of topical application of lindane and permethrin on
oxidative stress parameters in adult scabies patients, Clin. Biochem. 40 (2007)
1321–1324.
[76] A. Nunomura, P.I. Moreira, H.G. Lee, X. Zhu, R.J. Castellani, M.A. Smith, G.
Perry, Neuronal death and survival under oxidative stress in Alzheimer and
Parkinson diseases, CNS Neurol. Disord. Drug Targets 6 (2007) 411–423.
[77] J.F. Muniz, L. McCauley, J. Scherer, M. Lasarev, M. Koshy, Y.W. Kow, V. Nazar-
Stewart, G.E. Kisby, Biomarkers of oxidative stress and DNA damage in
agricultural workers: a pilot study, Toxicol. Appl. Pharmacol. 227 (2008)
97–107.
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
[78] B.D. Banerjee, V. Seth, R.S. Ahmed, Pesticide-induced oxidative stress: per-
spectives and trends, Rev. Environ. Health 16 (2001) 1–40.
[79] S.G. Suke, A. Kumar, R.S. Ahmed, A. Chakraborti, A.K. Tripathi, P.K. Mediratta,
B.D. Banerjee, Protective effect of melatonin against propoxur-induced oxida-
tive stress and suppression of humoral immune response in rats, Indian J. Exp.
Biol. 44 (2006) 312–315.
[80] D. Bagchi, M. Bagchi, E.A. Hassoun, S.J. Stohs, In vitro and in vivo generation
of reactive oxygen species, DNA damage and lactate dehydrogenase leakage
by selected pesticides, Toxicology 104 (1995) 129–140.
[81] A. Srivastava, T. Shivanandappa, Hexachlorocyclohexane differentially alters
the antioxidant status of the brain regions in rat, Toxicology 214 (2005)
123–130.
[82] C. Nasuti, R. Gabbianelli, M.L. Falcioni, A. Di Stefano, P. Sozio, F. Cantalamessa,
Dopaminergic system modulation, behavioral changes, and oxidative stress
after neonatal administration of pyrethroids, Toxicology 229 (2007) 194–205.
[83] D. Braconi, S. Possenti, M. Laschi, M. Geminiani, P. Lusini, G. Bernardini, A.
Santucci, Oxidative damage mediated by herbicides on yeast cells, J. Agric.
Food Chem. 56 (2008) 3836–3845.
[84] M. Muguruma, A. Unami, M. Kanki, Y. Kuroiwa, J. Nishimura, Y. Dewa, T.
Umemura, Y. Oishi, K. Mitsumori, Possible involvement of oxidative stress
in piperonyl butoxide induced hepatocarcinogenesis in rats, Toxicology 236
(2007) 61–75.
[85] D. Canistro, G. Cantelli-Forti, G.L. Biagi, M. Paolini, Re: dioxin increases reactive
oxygen production in mouse liver mitochondria, Toxicol. Appl. Pharmacol. 178
(2002) 15–21 (To the editor, Toxicol. Appl. Pharmacol. 185 (2002) 74–75).
[86] H. Ellinger-Ziegelbauer, B. Stuart, B. Wahle, W. Bomann, H.J. Ahr, Comparison
of the expression profiles induced by genotoxic and nongenotoxic carcinogens
in rat liver, Mutat. Res. 575 (2005) 61–84.
[87] L.Y. Yang, W.L. Chen, J.W. Lin, S.F. Lee, C.C. Lee, T.I. Hung, Y.H. Wei, C.M. Shih,
Differential expression of antioxidant enzymes in various hepatocellular car-
cinoma cell lines, J. Cell Biochem. 96 (2005) 622–631.
[88] D. Siegel, D. Ross, Immunodetection of NAD(P)H:quinone oxidoreductase 1
(NQO1) in human tissues, Free Radic. Biol. Med. 29 (2000) 246–253.
[89] I. Cok, A. Bilgili, M. Ozdemir, H. Ozbek, N. Bilgili, S. Burgaz, Organochlorine
pesticide residues in human breast milk from agricultural regions of Turkey,
1995–1996, Bull. Environ. Contam. Toxicol. 59 (1997) 577–582.
[90] F.P. Perera, V. Rauh, R.M. Whyatt, D. Tang, W.Y. Tsai, J.T. Bernert, Y.H. Tu, H.
Andrews, D.B. Barr, D.E. Camann, D. Diaz, J. Dietrich, A. Reyes, P.L. Kinney, A
summary of recent findings on birth outcomes and developmental effects
of prenatal ETS, PAH, and pesticide exposures, Neurotoxicology 26 (2005)
573–587.
[91] M. Iscan, T. Coban, I. Cok, D. Bulbul, B.C. Eke, S. Burgaz, The organochlorine
pesticide residues and antioxidant enzyme activities in human breast tumors:
is there any association? Breast Cancer Res. Treat. 72 (2002) 173–182.
[92] M. Howsam, J.O. Grimalt, E. Guino, M. Navarro, J. Marti-Rague, M.A. Peinado,
G. Capella, V. Moreno, Organochlorine exposure and colorectal cancer risk,
Environ. Health Perspect. 112 (2004) 1460–1466.
[93] D.L. Davis, N.T. Telang, M.P. Osborne, H.L. Bradlow, Medical hypothesis: bifunc-
tional genetic-hormonal pathways to breast cancer, Environ. Health Perspect.
105 (Suppl. 3) (1997) 571–576.
[94] D.E. Stevenson, E.F. Walborg Jr., D.W. North, R.L. Sielken Jr., C.E. Ross, A.S.
Wright, Y. Xu, L.M. Kamendulis, J.E. Klaunig, Monograph: reassessment of
human cancer risk of aldrin/dieldrin, Toxicol. Lett. 109 (1999) 123–186.
[95] P. Pisani, D.M. Parkin, N. Munoz, J. Ferlay, Cancer and infection: estimates of
the attributable fraction in 1990, Cancer Epidemiol. Biomarkers Prev. 6 (1997)
387–400.
[96] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Estimating the world cancer burden:
Globocan 2000, Int. J. Cancer 94 (2001) 153–156.
[97] S.J. Talbot, D.H. Crawford, Viruses and tumours—an update, Eur. J. Cancer 40
(2004) 1998–2005.
[98] M. Tien Kuo, N. Savaraj, Roles of reactive oxygen species in hepatocarcinogen-
esis and drug resistance gene expression in liver cancers, Mol. Carcinog. 45
(2006) 701–709.
[99] A.V. Ramanakumar, Need for epidemiological evidence from the developing
world to know the cancer-related risk factors, J. Cancer Res. Ther. 3 (2007)
29–33.
[100] S. Song, H.C. Pitot, P.F. Lambert, The human papillomavirus type 16 E6 gene
alone is sufficient to induce carcinomas in transgenic animals, J. Virol. 73
(1999) 5887–5893.
[101] J. Herbert, J. Coffin, Reducing patient risk for human papillomavirus infection
and cervical cancer, J. Am. Osteopath. Assoc. 108 (2008) 65–70.
[102] J.H. Wang, C. Yun, S. Kim, J.H. Lee, G. Yoon, M.O. Lee, H. Cho, Reactive oxygen
species modulates the intracellular level of HBx viral oncoprotein, Biochem.
Biophys. Res. Commun. 310 (2003) 32–39.
[103] H. Bartsch, J. Nair, Accumulation of lipid peroxidation-derived DNA lesions:
potential lead markers for chemoprevention of inflammation-driven malig-
nancies, Mutat. Res. 591 (2005) 34–44.
[104] A.L. Jackson, L.A. Loeb, The contribution of endogenous sources of DNA dam-
age to the multiple mutations in cancer, Mutat. Res. 477 (2001) 7–21.
[105] G. Waris, K.W. Huh, A. Siddiqui, Mitochondrially associated hepatitis B virus
X protein constitutively activates transcription factors STAT-3 and NF-kappa
B via oxidative stress, Mol. Cell. Biol. 21 (2001) 7721–7730.
[106] G. Gong, G. Waris, R. Tanveer, A. Siddiqui, Human hepatitis C virus NS5A pro-
tein alters intracellular calcium levels, induces oxidative stress, and activates
STAT-3 and NF-kappa B, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 9599–9604.
G Model
MUTGEN-401548; No. of Pages 9 ARTICLE IN PRESS
S. Mena et al. / Mutation Research xxx (2008) xxx–xxx
[107] A. Navas-Acien, M. Pollan, P. Gustavsson, N. Plato, Occupation, exposure to
chemicals and risk of gliomas and meningiomas in Sweden, Am. J. Ind. Med.
42 (2002) 214–227.
[108] C. Wesseling, E. Pukkala, K. Neuvonen, T. Kauppinen, P. Boffetta, T. Partanen,
Cancer of the brain and nervous system and occupational exposures in Finnish
women, J. Occup. Environ. Med. 44 (2002) 663–668.
[109] M.P. Waalkes, Cadmium carcinogenesis, Mutat. Res. 533 (2003) 107–120.
[110] S.J. Stohs, D. Bagchi, Oxidative mechanisms in the toxicity of metal ions, Free
Radic. Biol. Med. 18 (1995) 321–336.
[111] A. Witkiewicz-Kucharczyk, W. Bal, Damage of zinc fingers in DNA repair
proteins, a novel molecular mechanism in carcinogenesis, Toxicol. Lett. 162
(2006) 29–42.
[112] S. Kawanishi, S. Oikawa, S. Inoue, K. Nishino, Distinct mechanisms of oxidative
DNA damage induced by carcinogenic nickel subsulfide and nickel oxides,
Environ. Health Perspect. 110 (Suppl. 5) (2002) 789–791.
[113] E. Rincon, M. Yanez, A. Toro-Labbe, O. Mo, Effect of Ni(ii), Cu(ii) and Zn(ii)
association on the keto-enol tautomerism of thymine in the gas phase, Phys.
Chem. Chem. Phys. 9 (2007) 2531–2537.
[114] M.B. Grisham, D. Jourd’heuil, D.A. Wink, Review article: chronic inflammation
and reactive oxygen and nitrogen metabolism—implications in DNA damage
and mutagenesis, Aliment Pharmacol. Ther. 14 (Suppl. 1) (2000) 3–9.
[115] S.K. Chakrabarti, C. Bai, K.S. Subramanian, DNA-protein crosslinks induced by
nickel compounds in isolated rat lymphocytes: role of reactive oxygen species
and specific amino acids, Toxicol. Appl. Pharmacol. 170 (2001) 153–165.
[116] S.K. Bopp, H.K. Abicht, K. Knauer, Copper-induced oxidative stress in rainbow
trout gill cells, Aquat. Toxicol. 86 (2008) 197–204.
[117] A. Szymanska-Chabowska, J. Antonowicz-Juchniewicz, R. Andrzejak, Some
aspects of arsenic toxicity and carcinogenicity in living organism with spe-
cial regard to its influence on cardiovascular system, blood and bone marrow,
Int. J. Occup. Med. Environ. Health 15 (2002) 101–116.
[118] E. Denkhaus, K. Salnikow, Nickel essentiality, toxicity, and carcinogenicity,
Crit. Rev. Oncol. Hematol. 42 (2002) 35–56.
[119] L. Broday, W. Peng, M.H. Kuo, K. Salnikow, M. Zoroddu, M. Costa, Nickel com-
pounds are novel inhibitors of histone H4 acetylation, Cancer Res. 60 (2000)
238–241.
[120] W. Bal, R. Liang, J. Lukszo, S.H. Lee, M. Dizdaroglu, K.S. Kasprzak, Ni(II) specifi-
cally cleaves the C-terminal tail of the major variant of histone H2A and forms
an oxidative damage-mediating complex with the cleaved-off octapeptide,
Chem. Res. Toxicol. 13 (2000) 616–624.
[121] E. Giovannucci, D. Michaud, The role of obesity and related metabolic distur-
bances in cancers of the colon, prostate, and pancreas, Gastroenterology 132
(2007) 2208–2225.
[122] G. Dionigi, V. Bianchi, F. Rovera, L. Boni, M. Annoni, P. Castano, F. Villa, R.
Dionigi, Genetic alteration in hereditary colorectal cancer, Surg. Oncol. 16
(Suppl. 1) (2007) S11–S15.
[123] E. Weiderpass, G. Gridley, O. Nyren, A. Ekbom, I. Persson, H.O. Adami, Diabetes
mellitus and risk of large bowel cancer, J. Natl. Cancer Inst. 89 (1997) 660–661.
[124] L.A. Barness, J.M. Opitz, E. Gilbert-Barness, Obesity: genetic, molecular, and
environmental aspects, Am. J. Med. Genet. A 143 (2007) 3016–3034.
[125] K. Esposito, F. Nappo, R. Marfella, G. Giugliano, F. Giugliano, M. Ciotola, L.
Quagliaro, A. Ceriello, D. Giugliano, Inflammatory cytokine concentrations
are acutely increased by hyperglycemia in humans: role of oxidative stress,
Circulation 106 (2002) 2067–2072.
[126] P. Mohanty, W. Hamouda, R. Garg, A. Aljada, H. Ghanim, P. Dandona, Glucose
challenge stimulates reactive oxygen species (ROS) generation by leucocytes,
J. Clin. Endocrinol. Metab. 85 (2000) 2970–2973.
Please cite this article in press as: S. Mena, et al., Oxidative stress in environmental-induced carcinogenesis, Mutat. Res.: Genet. Toxicol. Environ.
Mutagen. (2008), doi:10.1016/j.mrgentox.2008.09.017
9
[127] G.S. Hotamisligil, N.S. Shargill, B.M. Spiegelman, Adipose expression of tumor
necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science
259 (1993) 87–91.
[128] M. Jaiswal, N.F. LaRusso, L.J. Burgart, G.J. Gores, Inflammatory cytokines induce
DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric
oxide-dependent mechanism, Cancer Res. 60 (2000) 184–190.
[129] T.A. Sellers, L.H. Kushi, J.D. Potter, S.A. Kaye, C.L. Nelson, P.G. McGovern, A.R.
Folsom, Effect of family history, body-fat distribution, and reproductive fac-
tors on the risk of postmenopausal breast cancer, N. Engl. J. Med. 326 (1992)
1323–1329.
[130] E. Giovannucci, A. Ascherio, E.B. Rimm, G.A. Colditz, M.J. Stampfer, W.C. Willett,
Physical activity, obesity, and risk for colon cancer and adenoma in men, Ann.
Intern. Med. 122 (1995) 327–334.
[131] P.H. Gann, M.L. Daviglus, A.R. Dyer, J. Stamler, Heart rate and prostate can-
cer mortality: results of a prospective analysis, Cancer Epidemiol. Biomarkers
Prev. 4 (1995) 611–616.
[132] C.A. Veloso, C.A. Isoni, E.A. Borges, R.T. Mattos, M.R. Calsolari, J.S. Reis, A.A.
Bosco, M.M. Chaves, J.A. Nogueira-Machado, Inhibition of ROS production in
peripheral blood mononuclear cells from type 2 diabetic patients by autolo-
gous plasma depends on Akt/PKB signalling pathway, Clin. Chim. Acta (2008).
[133] E. Zeggini, M.I. McCarthy, Identifying susceptibility variants for type 2 dia-
betes, Methods Mol. Biol. 376 (2007) 235–250.
[134] M.J. Gunter, M.F. Leitzmann, Obesity and colorectal cancer: epidemiology,
mechanisms and candidate genes, J. Nutr. Biochem. 17 (2006) 145–156.
[135] M.A. Blasco, Telomere length, stem cells and aging, Nat. Chem. Biol. 3 (2007)
640–649.
[136] S. Martien, C. Abbadie, Acquisition of oxidative DNA damage during senes-
cence: the first step toward carcinogenesis? Ann. N. Y. Acad. Sci. 1119 (2007)
51–63.
[137] J.W. Shay, W.E. Wright, Hallmarks of telomeres in ageing research, J. Pathol.
211 (2007) 114–123.
[138] J.F. Passos, G. Saretzki, T. von Zglinicki, DNA damage in telomeres and mito-
chondria during cellular senescence: is there a connection? Nucl. Acids Res.
35 (2007) 7505–7513.
[139] J.G. Scandalios, Oxidative stress: molecular perception and transduction of
signals triggering antioxidant gene defenses, Braz. J. Med. Biol. Res. 38 (2005)
995–1014.
[140] J. Campisi, From cells to organisms: can we learn about aging from cells in
culture? Exp. Gerontol. 36 (2001) 607–618.
[141] T. Andrew, A. Aviv, M. Falchi, G.L. Surdulescu, J.P. Gardner, X. Lu, M. Kimura, B.S.
Kato, A.M. Valdes, T.D. Spector, Mapping genetic loci that determine leukocyte
telomere length in a large sample of unselected female sibling pairs, Am. J.
Hum. Genet. 78 (2006) 480–486.
[142] H. Bartsch, J. Nair, Chronic inflammation and oxidative stress in the genesis and
perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair,
Langenbecks Arch. Surg. 391 (2006) 499–510.
[143] A. Federico, F. Morgillo, C. Tuccillo, F. Ciardiello, C. Loguercio, Chronic inflam-
mation and oxidative stress in human carcinogenesis, Int. J. Cancer 121 (2007)
2381–2386.
[144] K.A. Peebles, J.M. Lee, J.T. Mao, S. Hazra, K.L. Reckamp, K. Krysan, M. Dohad-
wala, E.L. Heinrich, T.C. Walser, X. Cui, F.E. Baratelli, E. Garon, S. Sharma, S.M.
Dubinett, Inflammation and lung carcinogenesis: applying findings in preven-
tion and treatment, Expert Rev. Anticancer Ther. 7 (2007) 1405–1421.
[145] J.M. Mates, J.A. Segura, F.J. Alonso, J. Marquez, Intracellular redox status and
oxidative stress: implications for cell proliferation, apoptosis, and carcinogen-
esis, Arch. Toxicol. (2008).