Food and Chemical Toxicology: Bozena Smolkova, Naouale El Yamani, Andrew R. Collins, Arno C. Gutleb, Maria Dusinska

ARTICLE IN PRESS
Food and Chemical Toxicology (2015)
Contents lists available at ScienceDirect
Food and Chemical Toxicology

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f o o d c h e m t o x
Invited Review
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Nanoparticles in food. Epigenetic changes induced by nanomaterials

and possible impact on health
Bozena Smolkova a, Naouale El Yamani b,c, Andrew R. Collins c, Arno C. Gutleb d,
Q2 Maria Dusinska b,*
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Department of Genetics, Cancer Research Institute of Slovak Academy of Sciences, Bratislava, Slovakia
Health Effects Laboratory, Department of Environmental Chemistry (MILK), NILU- Norwegian Institute for Air Research, 2027 Kjeller, Norway
c
Department of Nutrition, University of Oslo, Oslo, Norway
d Centre de Recherche Public Gabriel Lippmann, Luxembourg, Luxembourg
b
A R T I C L E
I N F O
Article history:
Received 27 September 2014
Accepted 18 December 2014
Available online
Keywords:
Nanomaterials in food
Nanoparticles
Epigenetic effects
Impact on health
Risk assessment
A B S T R A C T
Disturbed epigenetic mechanisms, which developmentally regulate gene expression via modications
to DNA, histone proteins, and chromatin, have been hypothesized to play a key role in many human diseases. Recently it was shown that engineered nanoparticles (NPs), that already have a wide range of
applications in various elds including food production, could dramatically affect epigenetic processes,
while their ability to induce diseases remains poorly understood. Besides the obvious benets of the new
technologies, it is critical to assess their health effects before proceeding with industrial production. In
this article, after surveying the applications of NPs in food technology, we review recent advances in the
understanding of epigenetic pathological effects of NPs, and discuss their possible health impact with
the aim of avoiding potential health risks posed by the use of nanomaterials in foods and food-packaging.
2014 Published by Elsevier Ltd.
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1. Introduction
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Nanoparticles can be of natural origin or man-made and are ubiquitous in the environment (Buzea et al., 2007; Smita et al., 2012).
Nowadays engineered nanoparticles (NPs) are already included in
various consumer products including food, feed, biocides and veterinary drugs, as well as in applications such as agriculture, water
purication techniques and soil cleaning (Bradley et al., 2011; Li et al.,
2008; Peters et al., 2014; Sekhon, 2010; Wei et al., 2007). Within
the food sector they are used as supplements and additives that
prolong shelf-life for fresh and processed products. They may also
serve as nano-sensors to provide information about the food item
storage history. Dietary exposure to NPs is also happening through
food packaging where NPs can minimize carbon dioxide leakage from
bottles and inhibit bacterial growth (Neethirajan and Jayas, 2011;
Silvestre et al., 2011). Nanotechnology is furthermore applied to
improve food colouring and avouring and to encapsulate and later
specically release nutritional additives. Traces of NPs have been
found in vegetables, derived from the use of agrochemicals and fertilizers (Bouwmeester et al., 2009). The majority of the NPs in food
production reported a few years ago were non-biodegradable metals
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* Corresponding author. Health Effects Laboratory, Department of Environmental

Chemistry (MILK), NILU- Norwegian Institute for Air Research, 2027 Kjeller, Norway.
Tel.: +4763898157.
E-mail address: mdu@nilu.no (M. Dusinska).
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and metal oxides (EPA, 2007). However, the recent inventory of
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nanomaterials in food, feed and agriculture performed under the
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European Food Safety Authority (EFSA) shows a trend from inor68
ganic materials (metals, metal oxides, clay and full carbon materials)
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to organic nanomaterials such as nano-encapsulates and
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nano-composites. The most used nanomaterials at present are
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nano-encapsulates, silver and titanium dioxide (TiO2) (Peters et al.,
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2014).
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Exposure of NPs to biological molecules results in the forma74
tion of a bio-corona, and this is an important factor in subsequent
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interactions with organelles and macromolecules that nally may
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result in negative effects on cells (Ahluwalia et al., 2013). Apart from
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cytotoxicity, cell death, oxidative stress, immunotoxicity and
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genotoxicity (Dusinska et al., 2013), NPs can also induce more subtle
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epigenetic processes associated with aberrant gene expression (Yao
and Costa, 2013) or induce changes in the proteome (personal com- Q4 80
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munication). Epigenetics covers heritable changes in the functions
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of genes that occur without direct alteration in the DNA sequence
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itself (Egger et al., 2004). Epigenetic mechanisms include DNA meth84
ylation at specic sites in regulatory regions; a complex set of histone
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modications, including acetylation, methylation, phosphoryla86
tion, ubiquitination and ATP-ribosylation that lead to chromatin
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remodelling; and post-transcriptional changes of gene expression
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mediated by miRNAs. It was shown that epigenetic changes can be
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triggered by environmental and lifestyle factors (Alegra-Torres et al.,
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2011; Jaenisch and Bird, 2003). Epigenetic marks can in some cir91
cumstances be transferred into the subsequent generation by the
http://dx.doi.org/10.1016/j.fct.2014.12.015
0278-6915/ 2014 Published by Elsevier Ltd.
Please cite this article in press as: Bozena Smolkova, Naouale El Yamani, Andrew R. Collins, Arno C. Gutleb, Maria Dusinska, Nanoparticles in food. Epigenetic changes induced by
nanomaterials and possible impact on health, Food and Chemical Toxicology (2015), doi: 10.1016/j.fct.2014.12.015
ARTICLE IN PRESS
Nanomaterials from
agriculture use (Pesticides,
fertilizers such as
biosolids)
Nanomaterials as feed
additives, supplements and
feed enzymes
Veterinary drugs
Biocides
Food contaminants from
other sources (NMs in
water, soil, food processing,
air, etc.)
Nanoparticles to detect
chemicals of foodborne
pathogens
Biodegradable nanosensors
for temperature and
moisture monitoring
Nanoclays and nanolms
as barrier materials to
prevent spoilage and
oxygen absorption
Nanoparticles for
antimicrobial and
antifungal surface coatings
Nanoparticle suspensions
as antimicrobials
Nanomaterials immersed
in gels as edible lms to
coat food
Contact materials
Nanocapsules to improve
dispersion, bioavailability
and absorption of
nutrients
Nanomaterials as colour
enhancers
Nano-structures in stable
emulsions to improve
consistency, taste, avour
and texture attributes
Nanoparticles for selective
binding and removal of
chemicals and pathogens
from food
Nanomaterials as anticaking agents, or to
thicken pastes
Nanoparticles in packaging
materials
Food supplement
Food enzymes
Carriers for enzyme

immobilization and based
protein separationpurication. (e.g. allowing
enzymes to be easily
reused multiple times for
the same reaction with
longer half-lives and less
degradation)
Stable enzyme based
coating or sprays in food
supply infrastructure (e.g.
enzyme-based listericidal
nanocomposite creating a
special coating to
selectively kill harmful
bacteria)
Flavourings
Nano-encapsulated
avour enhancers
Novel food
Nano-sized
nutraceuticals to
improve health and
well-being
Micronized starch,
cellulose, wheat
and rice our, and
a range of spices
and herbs for
herbal medicine
and food
applications
Food additives/ingredients
Nanoparticle applications in food
Nanotechnology has been used in the food industry for many

years without considering it as nanotechnology an example being
low-fat products such as mayonnaise in which emulsied fat droplets are diluted by the inclusion in them of nano-sized water
droplets with no effect on taste, when compared with the highfat version of the product. NPs can give benets such as better
dispersibility of water-insoluble additives in food products without
the use of additional fat or surfactants. Nano-texturing of foodstuffs targets the development of nano-structures and stable
emulsions to improve consistency, taste, avour and texture attributes. Major applications of NPs can be found in the health-food
sector, where nano-sized supplements and nutraceuticals have been
developed to improve health and well-being. The focus in Asian
countries is on development of micronized starch, cellulose, wheat
and rice our, and a range of spices and herbs for herbal medicine
and food applications (Tsukamoto et al., 2010). Recent research found
that foods with caramelized sugar, including bread and corn akes,
contain carbon NPs (Sk et al., 2012).
Uses of nanomaterials in the food industry include food additives, food ingredients, food contact materials, novel food, avourings,
enzymes, and supplements (Table 1). An extensive literature search
and inventory of EFSA resulted in the selection of 779 relevant references to nanomaterials used in the food, agriculture and feed
sectors. Of these, 633 nanotechnology applications described physicochemical characteristics of nanomaterials, reporting product names
and related suppliers; and 55 types of nanomaterials in 12 different applications were identied with the most common application
as food additives and food contact materials (Peters et al., 2014).
Q5
The EU FP7 project ObservatoryNANO (http://www
.observatorynano.eu) collected information about existing nanopatents on food; 35 patents were found worldwide. Nanotechnology
has a wide range of potential applications in the food processing,
from delivery and formulation to nano-sensors and nano-tracers for
food safety (Prakash et al., 2013). Given the fact that the consumer is so intimately exposed to food, the food industry faces many
challenges in introducing this technology into their repertoire.
However, for some applications, such as protection of certain labile
compounds in food or the addition of compounds with generally
unacceptable taste into relative stable lipid materials, nanotechnology may be a way to proceed (Souto and Severino, 2013).
In the food industry, synthetic amorphous silica (E551) has been
used for many years to clear beers and wines, as an anti-caking agent
to maintain the ow properties of powder products, and to thicken
pastes. The conventional bulk form of TiO2 is approved as an additive for food use (Mura et al., 2013). However, EUFDA, US-FDA,
and FAO/WHO regulations do not require manufacturers to specify
the particle size on the label of consumer products (Dekkers et al.,
2010; Peters et al., 2012; Tran and Chaudhry, 2010) and it is likely
that in some cases such food grade additives may contain nanosized
particles whose properties differ from those of the conventional
chemical form.
TiO2, silicon dioxide (SiO2) and magnesium oxide NPs are used
in food to preserve colour or durability and to improve handling.
TiO2, aluminum silicate and SiO2 NPs, for example, are added as
anticaking agents to powdered products (in vending machine
Nano-encapsulation for
targeted delivery of
nutraceuticals
Nano-sensors for the food
item storage history or as
oxygen sensors
Nano-tracers for food
safety
Solid lipid NPs in
combination with
functional food to increase
stability and protection
from degradation in the
gastric system
Calcium and magnesium
salts NPs, iron based NPs,
as health supplements
2. Uses of NPs in the food industry
Nanoparticles unintentionally
present in food
process of transgeneration inheritance (Jablonka and Raz, 2009;

Skinner et al., 2013).
A growing body of evidence suggests that epigenetic modications have an important role in a subset of human diseases, including
cancer, neurological, autoimmune, cardiovascular and metabolic diseases (reviewed in Portela and Esteller, 2010; Nilsson and Skinner,
2014). The observation that epigenetic changes are reversible makes
them an attractive target for disease prevention and treatment.
Table 1
Overview of nanoparticles and nanomaterials present in food and food packaging intentionally and unintentionally.
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Nanoparticles applied in
food packaging
B. Smolkova et al./Food and Chemical Toxicology (2015)
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powders, milk and cream powder substitutes, cheese and sugar).

Various materials such as nanoclays, cellulosic nanomaterials,
electrospun nanobres and nanocapsules, carbon-based
nanomaterials, NPs of metal and metal oxides, and NP-containing
carriers all nd application in food packaging (Ahmadi et al., 2009;
Monteiro-Riviere et al., 2011; Nemmar et al., 2008; Roblegg et al.,
2012).
TiO2 nanocomposites act as oxygen sensors and could be used
as packaging lms for a variety of oxygen-sensitive food products.
Their major drawback is the requirement of UVA light for their activation (Azeredo, 2009). Another example of the application of TiO2
is in polypropylene lms to inhibit the growth of microorganisms.
As an additive, TiO2 is labelled as E171 but it is not specied whether
or not it is nanosized. In fact, when E171 was analysed, a considerable fraction was found to have dimensions below 100 nm. As TiO2
is used as a white colourant, typical uses of TiO2 are in confectionery, white-coloured sauces and dressings, and non-dairy creamers
(Lomer et al., 2002).
Nanotechnology offers new possibilities to develop food-based
delivery systems for a range of labile or sensitive compounds ranging
from bioactive natural compounds to pharmaceuticals, thereby potentially improving health as such systems may result in increased
bioavailability of the active compounds (McClements, 2013). Such
functional compounds can be incorporated into solid lipid NPs resulting in increased stability and protection from degradation in the
gastrointestinal tract (GIT) (Weiss et al., 2008). Overall the high potential of such technologies has not yet been fully exploited.
It has been estimated that TiO2 NPs were produced at a level of
5000 t/year in 2010. Altogether 58 000 tons of NPs are expected to
be produced by 2020. Unfortunately, it is very dicult to estimate
the real production volumes of NPs. Apart from EFSA external report
(Peters et al., 2014) only scientic reports containing admittedly wild
guesses are available (Landsiedel et al., 2010).
US Patent (US5741505) describes the potential application of nanoscale inorganic coatings directly on food surfaces to provide a
barrier to moisture and oxygen, and thus to improve shelf life and/
or the avour impact of foods (Mura et al., 2013). The materials used
for the nanocoatings, intended to be applied in a continuous process
as a thin amorphous lm of 50 nm or less, include TiO2, silicon
dioxide and magnesium oxide (Ma et al., 2010).
Aluminium NPs are used to improve the functioning of aluminium foil. It acts as an ecient barrier for gases (CO2 and oxygen),
and has a UV screening effect. It is also used as an anti-adhesive
coating to prevent sticking and for black coating of baking foil so
that it does not reect heat in the oven. Also in nanopackaging, composite layers containing nanoplatelets of clay minerals, e.g.,
Q6 montmorillonite, have been used since 1986 when the process was
invented by Toyota Corporation. Different layers in nanopackaging
slow down the passage of gases. Such polymers have been applied
also to produce plastic bottles (Miller Brewing Company) that are
impermeable to O2 and CO2 (Duncan, 2011).
Another important application is related to the fact that bioactive
compounds with low resorption rates may be more bioavailable
when present in a nanosized form (Oehlke et al., 2014; Rao et al.,
2013). Selenium NPs are being marketed as an additive to a green
tea product, with a number of (proclaimed) health benets resulting from enhanced uptake of selenium (Mura et al., 2013). Calcium
salts NPs are the subject of patent applications (Sustech GMBH &
Co, Dsseldorf, Germany; http://www.nanomat.de) for intended use
in chewing gums. Calcium and magnesium salts NPs, as well as iron
based NPs, are also available as health supplements (Mura et al.,
2013).
While food grade nanomaterials have a high likelihood to enter
waste (water) streams following digestion and excretion (Yang et al.,
2014), at the same time TiO2 NPs are used as a photocatalysts in
water treatment applications, especially to oxidize heavy metals and
organic pollutants, and to kill microbial pathogens (Liu et al., 2014).

Iron-based NPs are also used in the treatment of contaminated water,
where they are claimed to decontaminate water by breaking down
organic pollutants and killing microbial pathogens (Scherer et al.,
2000).
Silver NPs (Ag NPs) are used as an antibacterial agent, or as enoses to detect food degradation while not being in direct contact
with the foodstuffs (Tung et al., 2014). Ag NPs release toxic ions,
which could contaminate food. It is even likely that we regularly
ingest Ag NPs that are shed from our forks, spoons and knives (Glover
et al., 2011).
Ag NPs immersed in gels (e.g., alginate) so called edible lms
have been used to coat food products such as carrots, asparagus,
etc. Such treated food has less water loss and higher consumer acceptability. Ag NPs immersed in cellulose pads placed in contact with
beef were shown to reduce the microbial loads in meat extracts.
Copper and zinc oxides are still mostly used in scientic studies,
but are currently being targeted also at food applications.
Another aspect of engineered NPs in food that needs to be mentioned is the fact that the detection of NPs is still not straightforward.
No validated methods or suitable reference standards are available for detecting, identifying and quantifying nanomaterials in
complex matrixes such as food. Food structure is highly complex
and variable and many types of NPs exist. No single, universally applicable method is expected to be developed. The methods to choose
from include but are not limited to Inductively Coupled Plasma Mass
Spectrometry (ICP-MS), High Performance Liquid Chromatography (HPLC), Field Flow Fractionation (FFF), Atomic Force Microscopy
(AFM), Transmission Electron Microscopy (TEM) etc. The fact that
physical, chemical and biological transformations may alter surface
and other properties of the nanomaterials, only further increases
the challenge for analytical determinations of nanomaterials in food
(Szakal et al., 2014).
There are also NPs that are not intended to enter the food supply,
but because of their minuscule size they can slip through wastewater treatment and take up residence in the biosolids created at
the end of the wastewater treatment process. These biosolids are
later applied to elds as fertilizer for their nitrogen and phosphorus content, and so food may also contain traces of NPs (Buzea et al.,
2007).
There is concern about possible release of NPs from packaging
material. A study by Avella et al. (2005) analysed vegetables that
were in contact with nanopolymer packaging: no increase in mineral
content of the vegetables was observed. On the contrary,
nanopolymer packaging lm was effective in decreasing the migration of optical whitener 2,5-thiophenediylbis(5-tert-butyl-1,3benzoxazole) into food products. In another study, Simon et al. (2008)
reported that only NPs of 1 nm are able to diffuse from packaging
material to food, while bigger particles do not migrate. Ag or ZnO
antimicrobials were found to enter orange juice from antimicrobial packaging material (Emamifar, 2011). Ag NPs in packaging
material may release Ag ions into the exudates of meat contained
in it (Fernndez et al., 2010).
3. Food as vehicle for NPs
The main physiological routes of NP uptake are inhalation, dermal
absorption or ingestion; NPs can be distributed to the same organ
by several routes of exposure. The extent of NP exposure is affected by their characteristics, inuencing absorption, metabolism,
distribution and excretion (reviewed in Hagens et al., 2007). NPs
entering the GIT are separated from blood by epithelial barriers. They
can reach the capillaries in the connective tissue under the epithelial layer covering the intestines, which can lead to translocation
into secondary organs. Uptake of NPs by healthy orogastrointestinal
mucosa appears to be low but absorption differs between various
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types of GIT cells; for instance it is higher in the small intestine than
in the oral cavity (Roblegg et al., 2012).
Previous investigations have found that TiO2 accumulates in the
intestine in rats (Jani et al., 1994) and sh (Zhang et al., 2007) and
migrates to other organs. Accumulation of TiO2 inside the intestinal cells, especially in lymphoid-rich areas (Peyers patches), might
lead to damaging outcomes such as inammation and could be involved in the pathogenesis of inammatory bowel disease (Evans
et al., 2002; Lomer et al., 2002).
Lesions and inammation may lead to increased uptake of NPs
from the GIT. Also without penetration into the body, NPs in
intraepithelial compartments can trigger inammatory responses
and competition between food NPs with normal uptake (reviewed by Frhlich and Roblegg, 2012).
For the estimation of a health risk of ingested NPs we have to
take into account that they are suspended in biological uids such
as the mucus of saliva and they are affected by pH, ionic strength,
protein, sugar and lipid content that can change their surface properties and size (Frhlich and Roblegg, 2012). When NPs reach the
systemic circulation they can interact with plasmaproteins, coagulation factors, platelets and red and white blood cells as well as
with organelles and DNA of the cells.
Although penetration of NPs into the human body appears to
be low, long-term exposure can cause accumulation of NPs due to
their limited excretion rate. Commonly used toxicity screening is
based on testing rather high-dose short exposures. In the human
body more often long-term low-dose exposures occur, and so accumulation of minor changes rather than acute toxicity is probable.
Currently we lack knowledge about the biological effects of combined, long-term NP exposure.
4. Epigenetic processes affected by NP exposure
Epigenetic regulation involves complex interacting structures that
along with genetic information in DNA allow sophisticated, timeand tissue-specic control of gene expression, with major consequences for cell fate decision, in both normal and pathological
development (Jenuwein and Allis, 2001). Although it is widely accepted that epigenetic mechanisms are key regulators of gene
transcription, with ability to respond to environmental signals
(Jaenisch and Bird, 2003), there are still many gaps in our understanding of the role of individual epigenetic processes and their
interactions in health and disease.
4.1. DNA methylation
DNA methylation is a postreplication modication that predominantly involves the covalent addition of a methyl (CH3) group, in
mammals almost exclusively found on the 5 positions of cytosines in the dinucleotide sequence CpG. CpG dinucleotides in the
genome are generally methylated except for CpG clusters located
in the promoter region and rst exon of many genes. CpG islands
have been found in all known housekeeping genes and some tissuespecic genes (Larsen et al., 1992). Methylation/demethylation of
CpG islands is important for maintenance of cell- or tissue-specic
gene expression; as a general rule, methylation in promoters suppresses transcription. Methylation patterns are cell- or tissuespecic and are reversible. DNA methylation plays a role in
embryogenesis, imprinting, X chromosome inactivation and maintaining genome integrity (Holliday and Pugh, 1975; Reik, 2007; Riggs,
1975). Global hypomethylation has been associated with increased chromosome instabilities and oncogenesis and is commonly
accompanied by gene-specic hypermethylation of CpG islands. Epigenetic inactivation of tumour suppressors or activation of oncogenes
leads to unregulated cell growth and carcinogenesis. Recently reported gene body methylation or so-called intragenic DNA
methylation that is not located in the promoter region of a gene (reviewed in Shenker and Flanagan, 2012) might stimulate transcription
elongation and might have an impact on splicing. The role of DNA
methylation in altering the activities of enhancers, insulators and
other regulatory elements is only just beginning to be understood. Patterns of DNA methylation are generated during
development involving de novo methylation and demethylation activities. DNA methyltransferases (DNMTs) are responsible for
maintaining methylation status in the genome, and catalyse the
transfer of a methyl group from S-adenosyl-l-methionine (SAM) to
the cytosine of a CpG dinucleotide. A family of DNMTs is involved
in de novo DNA methylation and its maintenance. Recently
5-hydroxymethyl-2-deoxycytidine (hmdC) has been discovered as
a marker of methylation in the brain (Kriaucionis and Heintz, 2009)
and is suggested to play a role in the epigenetic regulation of neuronal function. 5-hydroxymethylcytosine (5hmC) is the most
abundant of 5-methylcytosine (5mC) oxidation products. The biological role of 5hmC is still unclear. Current models propose that
5hmC is an intermediate base in an active or passive DNA
demethylation process that operates during important reprogramming phases of mammalian development. Tumour tissues have been
shown to have strongly depleted levels of 5hmC (Pfeifer et al., 2013).
Even though the role of aberrant DNA methylation in rare and
complex disorders is well documented, still many key questions
remain unanswered. One of the most intriguing is the interaction
between the various epigenetic mechanisms (Portela and Esteller,
2010).
4.2. Histone modications
In the nucleus, DNA is associated with histone proteins in the
complex that constitutes chromatin. The nucleosome is 147 bp of
DNA wrapped around an octameric core of histone proteins consisting of two H3-H4 histone dimers surrounded by two H2A-H2B
dimers. The N-terminal histone tail protrudes from nucleosomes into
the nuclear lumen. Nucleosome spacing determines chromatin structure, broadly described as hetero- and eu-chromatin. Histones can
be post-transcriptionally modied to restructure chromatin in many
ways, including acetylation, methylation, phosphorylation,
ubiquitination, sumoylation and ATP-ribosylation (Bannister and
Kouzarides, 2011; Suganuma and Workman, 2008). The histone code
hypothesis suggests that different combinations of histone modications may regulate chromatin structure and transcriptional status
(Jenuwein and Allis, 2001). Post-translational modications of histones lead to changes in chromatin structure that can inuence
transcription. The most common modications are acetylation and
methylation on histone lysine residues. Increased acetylation results
in open chromatin conguration and transcription activation, while
methylation of histones can result either in repression or activation of transcription (Rice and Allis, 2001). Histone modications
are extremely dynamic and highly regulated by a complex of histonemodifying enzymes including histone acetyltransferases (HATs),
deacetylases (HDACs), histone methyltransferases (HMTs) and histone
demethylases (HDMs). Their aberrant functions cause misregulation
of chromatin structure and activity with impact on access of transcription factors to DNA and gene transcription.
4.3. RNA interference
RNA interference is a process of posttranscriptional control of
protein expression. One type of molecule involved in this process
is microRNA (miRNA) whose role is to regulate gene expression by
interfering with mRNA processes, affecting mRNA stability, targeting mRNA for degradation or both; or in rare cases it can also increase
gene transcription (Mathers et al., 2010). miRNAs can also be involved in establishing DNA methylation and may inuence chromatin
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structure by regulating histone modiers. Eukaryotic cells use RNA

interference to silence transposable elements after transcription, protecting the cell against genomic damage. More than 1050 miRNA
have been identied up to now in human cells with impact on almost
all genetic pathways, through their effects on transcription factors,
receptors and transporters (Esquela-Kerscher and Slack, 2006;
Griths-Jones et al., 2008). The aberrant expression of miRNAs has
been linked to various human diseases, including cancer, Alzheimers disease and heart disease (Montgomery and van Rooij, 2010;
Olive et al., 2010; Provost, 2010).
5. Epigenetic effects of NPs in vitro and in vivo
Although emerging evidence indicates that environmental factors
affect epigenetic patterns and disease risk (reviewed by Ho et al.,
2012), epigenetic effects of NPs have been examined only rarely (reviewed by Stoccoro et al., 2013; Mytych and Wnuk, 2013). Initially
the focus of research was on the abilities of studied NPs to change
gene expression, without analysing the relationship with epigenetic modications. Gene expression studies were performed with
a wide range of NPs showing that certain NPs can impair the expression of genes involved in DNA methylation reactions leading
to changes in global as well as gene specic DNA methylation. Upand down-regulation of DNA damage response genes, cell cycle progression, DNA repair, metal metabolism, protein folding genes,
inammatory markers and many other effects were shown (Asharani
et al., 2012; Cui et al., 2012; Dawson and Kouzarides, 2012; Gao et al.,
2012; Gojova et al., 2009; Gui et al., 2013; Moos et al., 2011; Park
et al., 2008). Elevated oxidative stress, lipid peroxidation, membrane damage and reduced antioxidant levels were also associated
with exposure to NPs (Li et al., 2011a; Lin et al., 2006).
Generally, there are two main mechanisms through which environmental factors including NPs can affect DNA methylation. First
is a decreased availability of methyl donors and second is an altered
activity of the DNMT enzymes. Histone marks can be affected by
altered abundance and/or ecacy of the enzymes responsible for
their modication and changed availability of the enzyme substrate (McKay and Mathers, 2011).
Stoccoro and colleagues summarized the epigenetic effects of NPs.
They showed the potential of NPs to induce global DNA methylation changes, as well as changes of gene-specic methylation
patterns, including tumour suppressor genes (APC, p16, RASSF1A, p53),
inammatory genes (iNOS, IFNG, IL4), DNA repair genes (PARP-1),
and impaired expression of genes involved in DNA methylation reactions (DNMT1, DNMT3A, DNMT3B, MBD2), all potentially relevant
to cancer development. These authors also showed that exposure
to nanomaterials induced changes in the acetylation and methylation of the histone tails and global or gene-specic alteration of
miRNA expression (Stoccoro et al., 2013).
An altered global DNA methylation pattern was associated with
pro-oxidative properties of NPs. Oxidative damage to DNA may affect
the ability of DNMTs to interact with DNA (Simk et al., 2011). Moreover, reactive oxygen species (ROS) can alter the expression of genes
that are regulated by DNA methylation (Fratelli et al., 2005).
SiO2 NPs are used as anticaking agents in food or packaging materials where their direct contact with food allows penetration into
the human body. SiO2 NPs were reported to show size- and dosedependent cytotoxicity, cellular uptake, to increase ROS levels and
to be pro-inammatory (Napierska et al., 2010). In vivo studies demonstrate largely reversible lung inammation, granuloma formation
and focal emphysema. SiO 2 NPs were found to induce global
hypomethylation in the immortalized epithelial HaCaT cell line in
association with a dose-dependent decrease in DNMT1, DNMT3a and
methyl-CpG binding protein 2 (MBD2) gene and protein expressions (Gong et al., 2010). The DNA-binding domain protein family
that includes also MBD2, binds to methylated DNA and sup-
presses transcription from a methylated target gene, promoting

interactions with other proteins (Bogdanovic and Veenstra, 2009).
SiO2 NP treatment induced also global hypoacetylation implying a
global epigenomic response (Gong et al., 2010). A decrease in the
mRNA expression of poly(ADP-ribose) polymerase-1(PARP-1), a
pivotal repair enzyme, was associated with PARP-1 gene
hypermethylation (Gong et al., 2012) following SiO2 NP exposure.
PARP-1 modies various nuclear proteins including histones by
poly(ADP-ribosyl)ation, thus inducing local relaxation of the chromatin and facilitating the access of repair proteins to damaged DNA.
PARP1 detects and relocates to single strand breaks or nicks in chromosomal DNA playing an important role in the initiation of the DNA
repair pathway. PARP-1, was found in a complex with DNMT1, the
histone H3K9 methyltransferase G9a and the histone ubiquitin ligase
Np95, indicative of a link between poly(ADP-ribosylation) and the
epigenome (Shall and de Murcia, 2000). Low expression of PARP-1
is thought to be involved in carcinogenesis. High levels of activation are associated with increased apoptosis in response to genotoxic
stress (Kauppinen and Swanson, 2007).
Gold NPs (Au NPs), frequently used in food packaging, beverages, toothpaste and Au NPs based biomedical products, are being
developed for drug delivery, cancer therapy, diagnostic devices, and
biosensing. Au NPs were found to penetrate the nucleus and modulate heterochromatin connections with lamin proteins and core
histones (Mazumder and Shivashankar, 2007). Chromatin condensation and reorganization was also observed in the nucleus of human
foetal lung broblasts exposed to Au NPs (Ng et al., 2011). In the
same study Au NPs exposure signicantly altered the expression of
19 genes; among them up-regulation of miR-155 was observed concomitant with down-regulation of the PROS1 gene with no changes
in methylation. PROS1 codes for S protein that acts as a cofactor in
processes controlling blood clotting. Au NPs were also found to decrease HDAC activity by binding to sulfhydryl groups on the surface
of HDAC8 (Sule et al., 2008). Balansky and colleagues showed that
Au NPs produced signicant changes in microRNA expression and
transplacental size-dependent clastogenic and epigenetic effects in
the mouse foetus. The authors reported dys-regulated expression
of 28 out of 1281 miRNAs in prenatally exposed mouse foetal lung
and 5 up-regulated miRNAs in foetal liver. Let-7a and miR-183 were
signicantly up-regulated in both organs (Balansky et al., 2013). Upregulation of miR-183 expression was recently correlated with lung
cancer incidence (Vsa et al., 2013).
TiO2 NPs are one of the most commonly used NPs in food industry as anticaking agents or for antimicrobial plastic packaging.
The majority of in vitro studies with TiO2 NPs show increased levels
of DNA breaks and in some studies oxidized DNA lesions
(Magdolenova et al., 2014). However, the induction of DNA damage
depends on the conditions in which NPs are dispersed and the secondary physical-chemical properties of TiO2 NPs. Magdolenova et al.
(2012) tested the same TiO2 NPs in two different agglomeration states
on TK6 human lymphoblastoid cells, EUE human embryonic epithelial cells and Cos-1 monkey kidney broblasts, using the comet
assay. Depending on the state of agglomeration different genotoxic
responses were obtained. The TiO2 NPs, in dispersion with large agglomerates, induced DNA damage in all three cell lines, while the
TiO2 NPs dispersed with agglomerates less than 200 nm had no effect
on genotoxicity (Magdolenova et al., 2012).
Treatment of HaCaT cells with TiO2 NPs caused dysfunction of
the methylation cycle and methionine deciency (Tucci et al., 2013).
As the methionine cycle has a crucial role in the availability of methyl
groups for methylation processes in living cells, deregulation of the
cycle can have a dramatic impact on global as well as genespecic DNA methylation particularly during embryogenesis. Global
DNA hypomethylation and hypermethylation of tumour suppressor promoters have been consistently associated with cancer
initiation and progression. Several miRNA were signicantly altered
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Table 2
Main ndings of in vitro studies analysing epigenetic effects of nanoparticle (NP) exposure on various cell types.
NP
Cells
Effect of NPs exposure
Reference
SiO2
Immortalized epithelial HaCaT cell line
Gong et al., 2010
CdTe QDs
HaCaT cell line

THP1 human monocytic cell line
MCF-7 human breast adenocarcinoma cells
Global hypomethylation; dose-dependent decrease in DNMT1,

DNMT3a and methyl-CpG binding protein 2 (MBD2) gene and
protein expressions
PARP-1 hypermethylation and repression of gene expression
Binding to core histones and stimulation of aggregate formation
Histone 3 hypoacetylation and chromatin decondensation leading
to reduction in global gene transcription especially for antiapoptotic genes; increase in p53 protein level by its activation via
phosphorylation, nuclear and mitochondrial translocation
Global alteration of miRNAs expression patterns resulting in the
apoptosis-like cell death
Modulation of heterochromatin connections with lamin proteins
and core histones
Decrease of histone deacetylase activity by NPs binding to
sulfhydryl groups on the surface of HDAC8
Upregulation of miR-155 with downregulation of PROS1 gene,
chromatin condensation
Dysfunction of methylation cycle and methionine deciency
Changes of various miRNAs expression
K-182 HDACI-coated cationic NPs resulted in an increase in gene
expression and core histone hyperacetylation
Cholesterylbutyrate solid lipid NPs releasing butyric acid have
been shown to act as histone deacetylase inhibitors
NIH/3T3 mouse embryonic broblast line

Au
HeLa cervical cancer cell line

Enzymatic method
MRC5 lung broblast line
TiO2
MWCNTs
Super paramagnetic Fe
HaCaT cells
NIH/3T3 cell line
Human prostate cancer cells PC-3 and human
breast cancer cells Sk-Br-3
Different cancer cell lines
(U87, U373, Lipari, DF)
Gong et al., 2012

Conroy et al., 2008
Choi et al., 2008
Li et al., 2011b
Mazumder and
Shivashankar, 2007
Sule et al., 2008
Ng et al., 2011
Tucci et al., 2013
Li et al., 2011a
Ishii et al., 2009
Brioschi et al., 2008
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by TiO2 NP exposure (miR-449, miR-1 and miR-135b) (Halappanavar

et al., 2011).
The main ndings of in vitro studies analysing epigenetic effect
of NP exposure on various cell types are summarized in Table 2.
An increasing number of studies reporting NP-induced epigenetic alterations call for implementation of new testing methods to
allow their safety assessment. To achieve this, there is a need for
better understanding of their adverse epigenetic effects and to
improve currently available technologies to study DNA methylation, histone modications and non-coding RNAs. There are several
large-scale initiatives to study epigenomic organization (Greally and
Jacobs, 2013). We hope these studies will provide insights into how
epigenomes are organized and regulated, and how the three major
mechanisms of epigenetic regulation interact to inuence gene expression. Among them, DNA methylation has been the most widely
studied to date and there are a number of techniques for
5-methylcytosine quantication. Methods based on sodium
bisulphite sequencing, pyrosequencing or quantitative real time PCR
(qPCR) are commonly used but major limitations of these approaches when used for screening purposes are that they are labourintensive and low-throughput. Large-scale studies of the epigenome,
based on microarray technology or massive parallel sequencing
(MPS), on the other hand, allow acquisition of a huge amount of
data; but there are still unsolved technical and nancial problems. The analysis challenge is also substantial and new
bioinformatics tools for data analysis and integration, using highperformance computing resources with cloud computing will be
crucial. However, the trend of MPS is towards rapidly growing capacity with decreasing costs which makes it a promising new tool
for future epigenomic studies. Regulation of chromatin organization is part of the mechanism for rapid activation or silencing of
gene expression. Several methods have been developed to analyse
the state of histone modications, including chromatin immunoprecipitation (ChIP), ChIP coupled with microarray hybridization
(ChIP-chip) and ChIP coupled with next generation sequencing (ChIPseq). ChIP-based assays are largely qualitative with more complex
sample preparation which is the major reason for limited use of this
method compared with DNA methylation analyses. miRNA research techniques include three major methods; miRNA microarray
platforms, qPCR and MPS. Use of these tools has strengths and limitations (infrastructure, processing time, costs). Although there are
certain methods available to measure toxicant-induced changes in

miRNA, our current understanding of these processes is limited. A
goal of many ongoing studies is to be able to dene optimal methods
for integrating different types of genome-wide data in order to be
able to understand epigenomic and transcriptional regulation and
to consider these endpoints in hazard identication and product
safety management (Rasoulpour et al., 2011).
6. Implications for human health
The recent ndings that common genetic variants alone tend not
to identify causal loci of complex diseases or predict individual susceptibility opens the possibility that epigenetic factors as functional
modiers of the genome are key determinant of disease risk (Gibson,
2012; Heyn and Esteller, 2012; Petronis, 2010). During early development epigenetics plays a key role in embryogenesis controlling
cell differentiation while later in development it regulates tissuespecic protein expression. Epigenetic patterns not only vary from
tissue to tissue but alter with advancing age and are sensitive to
environmental exposures. They are mitotically inheritable and therefore can be long-lasting or passed to the next generation. The concept
of continued editing of early-life epigenetic markings or memories has been proposed by Tang et al. (2008). According to this
hypothesis epigenetic marks gained during the prenatal period are
edited over the life course and may modify disease susceptibility.
The reversible character of epigenetic patterns and their responsiveness to nutritional and environmental factors thus give us
opportunities for prevention, delay or treatment of complex diseases (Hou et al., 2012).
The role of aberrant epigenetic processes has been well established in several developmental and neurobehavioural disorders. The
rst group comprises diseases whose aetiologies include deregulation of one or more imprinted genes; they include Albrights
hereditary osteodystrophy, Angelman, BeckwithWiedemann, and
PraderWilli syndromes (Nicholls, 2000). The second group of diseases are those whose aetiologies include aberrant methylation of
repeated sequences or gene-specic sequences such as ATR-X, Fragile
X and ICF syndromes. Syndromes whose aetiology involves mutations in the genes related to epigenetic regulation, such as DNA
methyltransferase 3b (DNMT3b) mutations in ICF syndrome, mutations of CpG binding protein 2 (MeCP2) gene in Rett syndrome,
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mutations in CREBBP gene (histone acetylation) in Rubinstein

Taybi syndrome and mutations in RSK-2 gene (histone
phosphorylation) in ConLowry syndrome, constitute the last
group of inherited disorders with epigenetic aetiology. Most of
these disorders are associated with mental retardation.
Despite the large body of evidence for an association between
environmental exposure and epigenetic alterations, data supporting the link between epigenetic variation and common complex
disease phenotypes, with the exception of cancer, are still missing.
Cancer was the rst human disease linked to epigenetics (Feinberg
and Vogelstein, 1983). Since then several recent discoveries point
to a genome-scale disruption of the epigenome that involves large
blocks of DNA hypomethylation, mutations of epigenetic modier
genes and alterations of heterochromatin. Epigenome-modifying
gene mutations include histone variants; DNMTs; HATs; HDACs;
HMTs; HDMs; and chromatin remodelling factors, which can induce
changes in euchromatin and heterochromatin. Surprisingly, the mutation frequencies of epigenome modiers in cancer are quite high
in haematopoietic malignancies and rare solid tumours and epigenetic mutations also frequently occur in cancers that relapse or
that are otherwise resistant to therapy (Timp and Feinberg, 2013).
Teschendorff and colleagues recently showed that the variability of
DNA methylation was more predictive of cancer progression than
were mean changes in DNA methylation, suggesting a fundamental disruption in the mechanism for maintaining epigenetic integrity
in cancer cells (Teschendorff et al., 2012). This has important implications for cancer diagnosis and therapy.
The role of DNA methylation in the function of the CNS (Guo et al.,
2011) and ageing-related cognitive decline (Chouliaras et al., 2013;
Oliveira et al., 2012; Sanchez-Mut et al., 2013) has recently been
highlighted. Aberrant DNA methylation was also associated with osteoarthritis (Fernndez-Tajes et al., 2014) and cardiovascular disease
(Kim et al., 2013), pre-eclampsia (Anderson et al., 2013), rheumatoid arthritis (Liu et al., 2013) and metabolic disorders (Bruce and
Cagampang, 2011; Kirchner et al., 2013). Epigenomic alteration in
immune function is associated with systemic lupus erythematosus, with T lymphocyte DNA demethylation contributing to lupus
are severity (Sawalha et al, 2012).
Studying the role of deregulated epigenetic mechanisms caused
by NP exposure in disease pathogenesis, we have to challenge many
obstacles. First of all epigenetic alterations are cell type- and tissuespecic. DNA methylation patterns were shown to reect cell lineages
rather than inter-individual differences (Reinius et al., 2012). We have
to consider the impact of long-term exposures and their consequences for patterns of gene expression, cell function and death.
Induction of oxidative stress, inammation and inhibition of antioxidant defence mechanisms could be induced by NP exposure. The
term exposome refers to the summation of all exposures experienced by an individual over a lifetime. Another issue is instability
and changes in behaviour of NPs in the heterogeneous environment of biological systems including food. Nevertheless, nding
epigenetic biomarkers may allow for estimation of past exposure
and may have application in identifying high-risk individuals or
diagnostics.
7. Risk assessment of nanomaterial in food
Legislation and regulation of nanomaterials in food in European Union (EU) and non-EU countries was reviewed on the basis of
a literature research and a questionnaire by Peters et al. (2014). A
legal basis for regulating nanomaterials and the application of nanotechnology in the food industry has been set up. In 2011 the
European Commission published a Recommendation on the denition of a nanomaterial (2011/696/EU (European Commission,
Q7 2011)) and recently also a draft law on novel food (COM/2013/
Q8 0435 (European Commission, 2013)) was released. Additionally the
EFSA Scientic Committee published guidance on the risk assessment of the application of nanoscience and nanotechnologies in the
food and feed chain (EFSA Scientic Committee, 2011). These documents provide a framework for regulation of nanomaterials in the
food sector. In a similar way as for chemical safety, the strategy for
hazard assessment of nanomaterials is based on using standard tests
recommended by Organisation of Economic Co-operation and Development (OECD) guidelines.
The current absence of standardized assays and analytical approaches to test epigenetic effects of NPs is a reason for concern.
There are many obstacles in the implementation and validation of
the tests and there remains a need for further fundamental research to allow a more robust basis for OECD Test Guideline
(OECD TG) recommendations. At the beginning there is a need to
improve our knowledge on the links between modulation of the
epigenome by chemical compounds, including nanomaterials, and
the phenotype.
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8. Conclusion
Notwithstanding the potential advantages of new technologies
utilizing nano-sized materials, NPs may cause undesirable hazardous interactions with biological systems. The consequences of
epigenetic changes induced by exposure to NPs and their causal relationship with complex diseases are still poorly understood. In
particular, the possible epigenetic effects of NPs present in food have
as yet hardly been investigated. Development of new test guideline recommendations for hazard identication and product safety
management, including epigenetic endpoints, will be possible only
after a further increase in our understanding of the normal variability of the epigenetic landscape and causality between NP
exposure-induced epigenetic alterations and their consequences for
the phenotype.
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Conict of interest
The authors declare that there are no conicts of interest.
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Transparency document
The Transparency document associated with this article can be
found in the online version.
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Acknowledgements
This work was supported by the European Commission FP7 projects NANoREG, [NMP.2012.1.3-3], Contract no. 310584 and
QualityNano [INFRA-2010-1.131], Contract no: 214547-2.
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Food and Chemical Toxicology: Bozena Smolkova, Naouale El Yamani, Andrew R. Collins, Arno C. Gutleb, Maria Dusinska

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Food and Chemical Toxicology (2015)

Contents lists available at ScienceDirect

Food and Chemical Toxicology

Nanoparticles in food. Epigenetic changes induced by nanomaterials

* Corresponding author. Health Effects Laboratory, Department of Environmental

Carriers for enzyme

Nanoparticle applications in food

Nanotechnology has been used in the food industry for many

2. Uses of NPs in the food industry

process of transgeneration inheritance (Jablonka and Raz, 2009;

B. Smolkova et al./Food and Chemical Toxicology (2015)

powders, milk and cream powder substitutes, cheese and sugar).

organic pollutants, and to kill microbial pathogens (Liu et al., 2014).

structure by regulating histone modiers. Eukaryotic cells use RNA

presses transcription from a methylated target gene, promoting

Effect of NPs exposure

Immortalized epithelial HaCaT cell line

Gong et al., 2010

HaCaT cell line

Global hypomethylation; dose-dependent decrease in DNMT1,

NIH/3T3 mouse embryonic broblast line

HeLa cervical cancer cell line

Gong et al., 2012

by TiO2 NP exposure (miR-449, miR-1 and miR-135b) (Halappanavar

certain methods available to measure toxicant-induced changes in

mutations in CREBBP gene (histone acetylation) in Rubinstein

B. Smolkova et al./Food and Chemical Toxicology (2015)

B. Smolkova et al./Food and Chemical Toxicology (2015)

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