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Environmental exposure to xenoestrogens and estrogen
related cancers: reproductive system, breast, lung, kidney,
pancreas and brain.
Aleksandra Fucic1§, Marija Gamuli2, Zeljko Ferencic3, Jelena Katic1, Martin Kreyer von Kraus4,
Alena Bartonova5, Domenico F Merlo6
1 Institute for Medical Research and Occupational Health, Zagreb, Ksaverska c 2, Croatia
2University Hospital “Zagreb”, Zagreb, Kispaticeva 12, Croatia
3Children’s Hospital “Srebrnjak”, Zagreb, Srebrnjak 100, Croatia
4WHO, Regional Office for Europe,Copenhgen, Scherfigsvej 8, Denmark
5NILU – Norwegian Institute for Air Research, Kjeller, Norway
6National Institute for Cancer Research, Genoa, Largo R. Benzi 10, Italy
§Corresponding author
Aleksandra Fucic, Institute for Medical Research and Occupational Health,
10 000 Zagreb, Ksaverska c 2, Croatia,
Tel +38514673188, Fax 38514673303,
E mail: afucic@imi.hr
E mail addresses:
AF: afucic@imi.hr
MG: marija.gamulin@zg.t-com.hr
ZF: zferencic@bolnica-srebrnjak.hr
JK: jkatic@imi.hr
MKK: mak@euro.who.int
AB: Alena.Bartonova@nilu.no
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DFM: franco.merlo@istge.it
- 3 -
Abstract
The role of steroids in carcinogenesis has become a major concern in environmental protection,
biomonitoring and clinical research. Although historically oestrogens have been related to sexual
development, research over the last decade has confirmed their crucial role in the development and
homeostasis of all other organic systems. As a number of anthropogenic agents are xenoestrogens,
investigation of oestrogen receptor and level disturbances and of aromatase polymorphisms has
entered the spotlights of environmental health. Oestrogens and xenoestrogens mediate critical
points in carcinogenesis and bind to estrogen receptors which distribution is age, gender and tissue
specific. This review brings data about cancer types whose cause may have been environmental
exposure to xenoestrogens. Cancer types that have been well documented in literature include the
reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show
(a) a significant correlation between exposure to xenoestrogens and increased, sex-related, cancer
risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key
molecules in carcinogenesis. This revision may be applied in future investigations of cancer
aetiology and to improve legislation. Investigation of the aetiology of cancers caused by
xenoestrogens may also be valuable for oncology and development of new treatment protocols, as it
may elucidate yet unknown mechanisms of disease development.
Background
Despite the considerable efforts to decrease environmental pollution we still witness uncontrolled
introduction of new compounds in living and working environment. There is a limited improvement
in pollution control in low income and developing countries. The balance between needs of a fast
growing human population and technology/science development is questionable, partially as a
consequence that the available knowledge is not always applied in an efficient way as it should be.
In the last century simple paradigm 'one agent - one disease' enabled the discovery of major causal
pathways and the identification of pollution related diseases, including cancer. Activities towards
reduction of pollution and preventive measures were taken, in most cases, after the findings
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reported by epidemiological studies. However, despite the large body of data accumulated during
the last decade with the recent significant contribution of molecular biology, interpretation of
biomonitoring data still follows historical approach where the causal chain of one agent/one disease
represents the most frequently applied approach for the investigation of possible environmental
threats to human health.
Cancer incidence fluctuations are monitored with relative accuracy in developed countries. A better
classification of cancer types, the networking of cancer registries and the increasing population
coverage for cancer registration are unfortunately still suffering from time gap of several years
delay of public available cancer registers reports due to unsolved technical and organizational
difficulties. This gap represents a serious problem in the ability of quickly recognizing
environmental health risk and setting effective measures by the relevant institutions in charge for
implementing protective or preventive measures.
According to recent data [1] childhood cancer incidence for Europe increases 1% annually in all
geographical regions. In adult population the rising trend is reported for soft tissue sarcoma, brain
tumours, germ-cell tumours, lymphomas, renal cancers, leukemias, breast cancer and lung cancer in
women. Only limited part of the detected increase may be related to screening programmes, and the
origin of the upward trend remain to be explained. Breast cancer, colorectal, prostate and lung
cancer are the most commonly diagnosed cancers in the European population [2].
During the last decade estrogen as an evolutionary conserved molecule raised great interest in the
field of environmental health and oncology. Estrogen's biological activity, with its endocrine,
paracrine and neurotransmitter activity [3,4,5] is not clearly limited to a role in reproductive tract
development and regulation: new evidence confirms a strong impact of this molecule in the process
of cancerogenesis [6]. Indeed the distribution of estrogens’ receptors in mammalian tissues suggests
that estrogens could have a significant role in orchestrating a number of pathways in living
organisms during development and adulthood [7,8,9].Very little is known about changes of estrogen
levels and ratio of estrogen receptors during development [10]. During the second trimester of
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human foetal development the highest concentrations of estrogen receptor mRNA are detected in
the genital tract with higher levels of estrogen receptor β mRNA in testis and ovary and estrogen
receptor ά mRNA in uterus. Relatively high concentrations are also present in spleen while low
levels are detected in kidney, thymus, skin and lung [11]. Prepubertal ratio of estrogen receptors in
human tissues in males and females is not known. Additionally, estrogen alpha and estrogen beta
receptors are polymorphically distributed playing different roles in carcinogenesis [12,13,14].
An increased level of estrogen is carcinogen [15] and may produce reactive oxygen species,
hypomethylation and microsatellite instability similar to ionizing radiation [9,16,17,18]. Its
metabolites, quinones, cause formation of DNA adducts, depurination, lipid-derived aldehyde-DNA
adducts and aneuploidy [15,19]. By decreasing glutathione-S-transferases, estrogens may increase
cellular oxidative DNA damage in estrogen-responsive tissues when the organism is simultaneously
exposed to other genotoxicants an early step of the process of carcinogenesis [20].
Gender difference in cancer incidence such as lung adenocarcinoma, cancer of the kidney or
pancreas suggests the possibility of an hormonal impact on their etiology [21]. According to recent
knowledge it seems that all neoplastic mammalian tissues are characterised by disturbances of the
estrogen receptor levels [6]. By different gender related levels in foetal, prepubertal and adult tissue,
the tissue specific estrogen receptors distribution and bimodal activity [22] modulates the biological
pathways and organogenesis [23].
The general population is on every day basis exposed to a number of hormonally active compounds
that were introduced in the living environment during the last few decades the majority of which are
xenoestrogens. Groups of chemicals like polycyclic aromatic hydrocarbons (PAH), pesticides,
polychlorinated biphenyl (PCB), dichlorodiphenyl-trichlorethane (DDT), some drugs (e.g.,
antiepileptic drugs), fungicides, cotinine, phytoestrogens, mycotoxins, bisphenol A (a plastics
additive), phthalates, alkylphenols, metalloestrogens are some known major groups of agents which
mimic estrogen, impact on estrogen levels or bind to estrogen receptors [24, 25, 26, 27, 28, 29].
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Xenoestrogens are present in a number of different substrates such as cigarette smoke, automobile
exhaust, chemical industry pollution, grilled meat, volcano dust and smoke from forest fires, milk,
water and cosmetic products. This means that all human population may be exposed.
The aim of this paper is to give an insight on the impact of environmental exposure to
xenoestrogens on etiology of breast, lung, kidney, brain, pancreas and reproductive system cancers
which are all characterised by disturbances of estrogen receptors.
Breast cancer
The increased reports in breast cancer incidence in women 50-69 years old is related to
improvement of preventive measurements such as mammography screening. In the United States,
Australia and western Europe the decrease of breast cancer incidence seems to follow the reduction
of hormonal therapy[30] as estrogen plays important role in pathogenesis of breast cancer [31,32].
Social, medical, environmental and genetic factors which have an impact on breast cancer incidence
are: the socioeconomic status, some food additives, pesticides, estrogen and progesterone
replacement therapy, some antibiotics, radiation, mutations at genes BRCA1, BRCA2, CYP
polymorphism, epidermal growth factor and its receptor (HER)), androgen levels and insulin-like
growth factor [33, 34, 35]. The impact of age (including transplacental, prepubertal) on breast
cancer risk by estrogen exposure is significant and probably involve epigenetic mechanisms
[36,37,38,39].
Currently there are some 160 chemicals which act as xenoestrogens that may be involved in
mammary gland cancer development [40,41,42]. Women are the largest consumers of cosmetic
products which may be a significant source of xenoestrogens. Metalloestrogens (e.g., aluminium
salts) and other estrogen like compounds (parabens, cyclosiloxanes, triclosan, UV screeners,
phthalates, Aloe Vera extracts, musk fragrance) are present in numerous cosmetics products.
Human are exposed to these chemicals transcutaneously and measurable levels have been detected
in human breast tissue [23].
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It is known that alcohol causes increase in estradiol levels in dams, elevated levels of ERalfa in
offspring’s mammary gland and tumorigenesis [37]. Even a low alcohol consumption, increases
serum estradiol (especially for carriers of a certain alcohol dehydrogenase allele) and stimulates
estrogen alfa receptors [43,44].
The role of diet on breast cancer incidence was observed in Japanese women after the Second
World War when dramatic changes in diet happened. The increase consumption of meat, eggs and
milk containing estrogens or estrogen like compounds affected the development breast (and
ovarian) cancer [45]. Milk represents a source of estrogen in diet due to the practice of milking
pregnant cows [46].
Heterocyclic amine and their metabolites, especially 2-amino-1-methyl6-phenylimidazo(4,5-b)
pyridine (PhIP) as the one present in the highest concentration in well-done cooked muscle meat
binds to breast cells' estrogen alpha receptor and activates it [47,48]. In animal model it causes
mammary tumours [49]. The suggested mechanism is the production of PhIP-DNA adducts and
increase of proliferation in mammary gland terminals and buds [50]. Similarly polyaromatic
hydrocarbons, also present in food, in case of early life exposure to concentration higher than 140
μg/m3 causes a 2 fold increase of breast cancer risk in postmenopausal women [51].
Styrene, a widely used plastic, has been associated with breast cancer risk both in men and women
[52]. Direct intake of styrene is via food packed or even cooked in styrene boxes with a direct
migration of styrene to food. Styrene and metabolites of styrene oligomers binds as xenoestrogen to
ER-alpha receptors [53], crosses the placental barrier and has also an impact on development of
reproductive organs [54,55].
The carcinogenic potency of xenoestrogens depends in some cases on the polymorphic distribution
of metabolic enzymes. It is shown that subpopulation carrying metabolic polymorphism of
CYP1A1 m2 is more susceptible to develop breast cancer after exposure to polychlorinated
biphenyls (PCB) which may explain contradictory epidemiological reports on association between
breast cancer incidence and PCB exposure [35,56,57].
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Lung cancer
Lung cancer is the predominant cause of cancer mortality [58]).There is a gender difference in the
incidence of lung cancer types. The predominant subtype in men is squamous cell carcinoma, while
in women is adenocarcinoma. The estrogen could be the main cause of this difference as normal
and non-small cell lung cancer both express estrogen receptors [59,60]. Despite the fact that lung
cancer incidence is increasing in women [61,62,63,64] studies reporting lung cancer incidence
basically rarely give significance to possibly gender related susceptibility [65, 66,67]. Lung cancer
is about 70% ERbeta positive. The ratio between ERalfa and ERbeta in lung tissue seems to be
relevant for lung cancer development and may be the explanation for the higher incidence of lung
adenocarcinoma reported in women than in men [68]. However, caution must be taken in some
cases when studies show increase risk of lung cancer in women which is related with specific social
status and high level of indoor pollution during cooking as a consequence of coal usage [69,70].
ERbeta levels in lung cancer are gender related and have impact on survival rate [71]. While
ERbeta positive and negative lung cancers has no impact on survival in women, in man ERbeta
positive lung cancer have significant reduction of mortality [72]. ERalpha modulates directs lung
differentiation and maturation while ERbeta when stimulated causes proliferation of lung cancer
cells [73,74]. Gender specific distribution of CYP19 (aromatase) in lung cells put in correlation
estrogen levels and lung cancer etiology [75]. Additionally women taking hormonal (estrogen)
therapy experience an increased lung cancer incidence [76]. As for breast cancer epidermal growth
factor and its receptor HER plays a significant role in non-small cell carcinoma and is associated
with endogenous estrogen exposure [77].
Smoking remains the major cause of lung cancer in humans [78]. Methylnitrosamino-pyridyl-
butanone, a powerful carcinogenic agent contained in cigarette smoke is ERbeta receptor related
[69]. It is interesting to observe that the gender specific activity of nicotine [79] is probably
originating from fact that cotinine, a nicotine metabolite, is an aromatase inhibitor [80] which
decreases estrogen end increase testosterone levels. Polonium 210 as metalloid present in cigarettes
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[81] may have similar estrogen like activity as other metalloestrogens [24,82]. Other carcinogens
present in cigarette smoke should be re-evaluated for their xenoestrogen or aromatase inhibitor
potency.
Traffic air pollution is related to lung cancer [83,84]. A number of compounds from traffic
emissions are estrogen ligand active compounds [85]. PAHs represent one of the major mixtures of
agents that are present in polluted air with a known impact on estrogen homeostasis [86,87,88].
Emissions of industrial areas contain also pollutants with estrogen like activity, such as heavy
metals, dioxins, etc. [89]. A significant association between industrial air pollutants and lung cancer
risk has been reported in females [90].
Arsenic is a known lung cancerogen [6] which biological effects also include increase in ERalfa
transcript. Transplacental exposure to arsenic in animal model causes lung cancer in female
offspring. This finding shows that arsenic as an estrogen like agent can cause genetic modelling in
lung tissue during development which may cause lung cancer later in life, during adulthood [91].
Figure 1 shows schematic presentation of complex lung cancer etiology
Non-small cell lung cancerSmall cell lung cancer
Adenocarcinoma
↑
women
Large cell carcinoma
↑
women
Squamous cell cancer ↓man
LUNG CANCER
DNA adducts, methylation, aneuploidy
chromosome rearrangments
Heavy metals
Cd Pb Ni Cr
As+aneugen
Dioxin
Heavy metals cause methylation
if estrogen receptors in lung cancer
Air polutio n: SO2 NO2,
NO, O3
Asbestos
Radon above100 Bq/m3
Cadmium
synergism
PAH
Estrogene like mechanisms
:
PM
2,5 and
PM
10
particles
Estrogen related genes
associated with breast
and lung cancer,
matenal breast cancer
↑
in children lung
cancer risk in non-
smoker
Sterols, estrogens PAH
Aerosols wastewater treatment plant
Cancer risk depends on glutathione S
transferase- genotypes vary ethnicaly
molds
Arsenic on animal model
transplacental exposure
estrogen alfa activation
related with lung
adenocarcinoma in
adulthood
pesticides
smoking
Petroleum
?estrogen
Cooking oil fumes
Heterocyclic
amines welldone
meat increase risk
in non-smokers
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Kidney cancer
Data on the environmental etiology of kidney cancer are not available and much more research is
needed. The fact that renal cell carcinoma, the most common type of kidney cancer, can be induced
by exposure to estrogens [92] in animal model suggests the involvement of estrogen receptors in the
aetiology of renal cancer and of a possible role of xenoestrogens. Indeed, renal cancer incidence is
gender related with an incidence that is two times higher in men than in women [93]. Genetic
polymorphisms of ERalpha receptor in kidney seems to play significant role in development of
kidney cancer [92]. Our knowledge of the etiology of kidney cancer includes the evidence of the
role played by xenoestrogens on cadmium and arsenic induced cancers [94,95]
Pancreatic cancer
The incidence of pancreatic cancer has been relatively stable worldwide during the last decades
[96,97,98]. Pancreatic cancer is gender related [99,100]. The importance of understanding its
etiology is crucial since it is for example the fourth leading cause of cancer deaths in USA [64] and
among the most aggressive form of malignancy. Cell proliferation is estrogen sensitive and
pancreatic cancer cells are ER alfa and beta receptor positive. The ratio of ERalfa/ERbeta
modulates the impact of estrogen on these cells [101]. Cancer of the pancreas is more frequent in
men than in women, a gender related difference that is consistent with gender differences observed
for xenoestrogen related cancers [102].
As for kidney cancer there are very few data on the impact of xenoestrogens on pancreatic cancer
incidence. Methylnitrosamino-pyridyl-butanone is the only known compound which causes
pancreatic cancer in animal models [104], a finding that has been reported also for adenocarcinoma
of the lung and has been related to ERbeta receptor activation [68].
It is also shown that consumers of well done meat have higher risk of pancreatic cancer
development probably due to exposure to benzo(a)pyrene and other food contaminants which are
products of pan-fried meat and which have xenoestrogenic properties [45,105].
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Brain tumour
Brain tumours are characterized by disturbances of estrogen receptors [106,107,108].
Transplacental exposure to xenoestrogens may play a role on the increased risk of brain tumour
development as the modulation of brain development detected in experimental model [79,80].
Xenobiotics which have aromatase inhibitor characteristics inhibit conversion of estrogen to
testosterone and may have a significant impact on brain pathology given the evidence that increased
levels of testosterone cause disturbances of apoptosis and intracellular signalling [109].
Increased brain cancer incidence has been reported in human populations living in residential areas
near by petrochemical industries [110]. Despite the fact that the exact chemical composition of the
mixture of air pollutants remains unknown, polycyclic aromatic hydrocarbons (PAH) are present in
polluted air in such areas [67]. PAHs as xenoestrogen like agents (Van de Wiele, 2005) may have
played a causal role on the excess of brain cancer incidence detected.
Reproductive system
Testicular cancer has significantly increased during the last few decades with yet no clear
hypothesis on impact of environment on its etiology [111]. As this trend cannot be explained by
cryptorshidisem, smoking habits, genetical variations or physiological stress, the potential role of
environmental exposures is being investigated to elucidate their etiology and adentify preventive
measures [112].
Both ER isoforms alpha and beta are expressed in human testis and involved in control of testicular
function [113]. The role played by xenoestrogens on testis development is still only partially
described in animal model, with results showing very dynamic changes in tissue sensitivity
xenoestrogens wit unknown consequences during puberty and adulthood [114].
There are a limited number of studies reporting possible etiology of testicular cancer due to
disturbances of estrogen levels. Testicular cancer is reported in sons of smoking mothers [115] but
also in mothers who took antiepileptic therapy during pregnancy [116]. Both antiepileptic drugs and
cotinine from cigarette smoke are aromatase inhibitors. Transplacental exposure to aromatase
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inhibitors and consequently increased levels of testosterone may have long term effects in humans
as shown in animal model [117].
However, epidemiological studies suggest increased risk of testicular cancer also following prenatal
exposure to estrogens [118].
Styrene storage containers may contaminate food which become a source of styrene exposure.
Styrene express estrogen like activity in vivo and in vitro. Transplacental exposure to styrene causes
the destruction of male genital organ at very low levels [54] and the impact on cancer development
remains unknown.
Endocrine disrupting chemicals which have impact on ER receptor disturbance can cause female
reproductive dysfunction [119,120] Ovarian cancer therapy development is still not marked with
significant success and mortality is very high [121].
Cadmium, one of most investigated heavy metals, has a significant role on ovarian and reproductive
functions acting as an endocrine disrupting agent which lower progesterone levels and mimic
estrogen in various tissues by binding to ERalfa receptor. Exposure to cadmium is not only
confined to occupational exposures. It is found in cigarette smoke, food, nickel/cadmium batteries,
pigments and plastics [122].
Ovarian cancer is associated with milk and cheese consumption due to estrogen and insulin growth
factor present in milk of pregnant cows [46, 123].
According to recent experimental evidences uranium in water should be further considered in
research as an additional risk for reproductive cancers [82].
Conclusions
As an evolutionary conserved molecule, estrogen is present in both plants and animals. Estrogen is
recognized today as a critical modulator of development, homeostasis in adulthood and
orchestration of response to environment.
Although the distribution of polymorphic genes can change cancer incidence [124,125].it is clear
that environment has predominance over genes in cancer risk. Responses to environmental stressors
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are age and gender related and transplacental exposure to testosterone and xenoestrogens have been
shown to have long term effects in experimental model, modulating hormonal response in puberty.
This means that such exposure to endocrine active agents not only may pose a health risk during
exposure but also determining a higher susceptibility during the entire life [114,126,127]. The age
difference in susceptibility to xenoestrogens may be related to steroid and xenobiotic receptor, the
level of which is high in young adults (15-38y old) and decreases with age [128].
Current estimates of cancer risk in humans do not account properly for exposure to xenoestrogens
occurring during fetal life (transplacental exposure) and in occupational settings and in the living
environment. Xenoestrogens and their role on cancer etiology should be evaluated using new
approach based on the complexity of the carcinogenic process. Reductionism as a main scientific
philosophy of 20th century gave a significant input to environmental health. However, the quantity
of data available in noosphere, systems biology as a tool and new software for data sharing enable
the investigation of interactions of xenoestrogens with other environmental stressors like radiations
giving two new dimensions in research of cancer etiology. Contemporary mathematical models and
systems biology allows the incorporation of all available data and modelling cancer risk allowing
free interaction and clustering of data.
The collaboration of environmental health with oncology would be of crucial significance in the
study of xenoestrogens as estrogen has today significant position in oncological diagnostics and
therapy what includes measurements of estrogen receptor levels in different tissues. Oncology today
closely collaborate with science in order to achieve optimal treatments at the individual level (e.g.,
tailored therapy) and produces large amounts of data which reflects tight gene-environment
interaction and point at susceptible age periods and gender specific susceptibility. Collaboration of
pharamcokineticians, oncologists, histopathologists, molecular epidemiologists and
genotoxicologists may improve our knowledge on cancer etiology, and propose gender specific
therapies.
- 14 -
Complex interactions of xenoestrogens on genomic and non genomic levels with described dynamic
differences related with age and gender demands new data interaction software and maybe new
generation of biomathematician who will launch new graphical language as a common interface
between scientific fields in order to elucidate complex interactions of xenoestrogens with biological
pathways.
Using the available information systems and building integrated exposure-disease pathways will
give policymakers much more useful input than large number of agent- and disease-specific studies.
Competing interests
There is no competing interest in interpretation of data or presentation of information in this article
which may be influenced by personal or financial relationship with other people or organizations.
Authors' contributions
AF gave the basic idea/hypothesis and drafted the manuscript. MG, ZF and JK participated in its
design and helped to draft the manuscript. MAK and AB gave significant contribution in modeling
of approach of data interpreation.DFM drafted the manuscript and gave significant contribution in
interpretation of collected data. All authors read and approved the final manuscript.
Acknowledgments
This work was supported by the EU project HENVINET 6th Framework Programme, Coordination
Action (Contract no.037019), http://www.henvinet.org
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