Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics

Mankind has been exposed to airborne nano-sized particles for eons, yet mechanization and industrialization of societies has increased the overall aerosol pollution load to which humans are exposed to. Nano-aerosols with a diameter below 1 μm, can be incorporated via any biological surface structure and in particular when the area available is large enough – as is the case with the skin (approx. 1.5-2 m2), the digestive tract (intestinal villi, approx. 200 m2) or the respiratory tract (alveolar surface area reaching approx. 140 m2).(Raab et al, 2010) Since aerosolised particles are readily inhaled rather than ingested, the lungs represent an ideal gateway with high penetration efficiency rates. From a toxicological rather than from a therapeutic point of view, a deposited xenobiotic particle first interacts with biological tissues on a cellular level. From there it is readily translocated into the cell to interfere with metabolic pathways, eventually inducing inflammatory cellular responses. At an organismic level along with long-term exposure these particles become redistributed via the lymphatic or the blood circulatory system to reach sensitive organs or tissues, such as the central nervous system, bone marrow, lymph nodes, spleen, heart, etc.(Oberdörster et al. 2005a) At this level, persistent particle exposure may trigger chronic diseases or when already present, modulate the severity of its course.


Introduction
Mankind has been exposed to airborne nano-sized particles for eons, yet mechanization and industrialization of societies has increased the overall aerosol pollution load to which humans are exposed to.Nano-aerosols with a diameter below 1 µm, can be incorporated via any biological surface structure and in particular when the area available is large enoughas is the case with the skin (approx.1.5-2 m 2 ), the digestive tract (intestinal villi, approx.200 m 2 ) or the respiratory tract (alveolar surface area reaching approx.Raab et al, 2010) Since aerosolised particles are readily inhaled rather than ingested, the lungs represent an ideal gateway with high penetration efficiency rates.From a toxicological rather than from a therapeutic point of view, a deposited xenobiotic particle first interacts with biological tissues on a cellular level.From there it is readily translocated into the cell to interfere with metabolic pathways, eventually inducing inflammatory cellular responses.At an organismic level -along with long-term exposure -these particles become redistributed via the lymphatic or the blood circulatory system to reach sensitive organs or tissues, such as the central nervous system, bone marrow, lymph nodes, spleen, heart, etc. (Oberdörster et al. 2005a) At this level, persistent particle exposure may trigger chronic diseases or when already present, modulate the severity of its course.

Classification of nano-aerosols
With every breath, with every bite, with every sip, we introduce countless nano-sized particles, viruses and bacteria into our organism.Since the onset of the industrial revolution, some 150 years ago, people are progressively exposed to elevated concentration of arbitrarily shaped nano-aerosols in combination with chemical by-products such as carbon monoxide (CO), nitric oxide (NO), semi-volatile (SVC) and volatile organic compounds (VOCs) of anthropogenic origin -mostly in the form of incompletely combusted byproducts that leave stacks or tailpipes as macromolecular clusters (Figure 1).Chang, 2010;Alessandrini et al., 2009) Depending on their origin, particles of this size have Fig. 1.Schematic representation revealing the formation process and the fractal nature of a nano-sized DEP/MEP cluster and its adsorbed vapour-phase compounds.Model of the carbon core of a DEP that is covered with a layer of inorganic components as well as (bio)organic compounds and pollutants.modified after Madl, 2003)

Particle deposition and clearance within the human respiratory tract
Deposition of inhaled particles in the human respiratory tract is determined by several biological factors, such as lung morphology and breathing patterns, as well as by physical factors, such as fluid dynamics, particle properties, and deposition mechanisms.Hofmann, 2011) In principle, particle deposition within the respiratory tract is bound to physical principles such as impaction, gravitational settling, diffusion, and electrical attraction (Figure 2).With the introduction of particle filters and catalytic converters in the exhaust stream, most coarse particles are efficiently removed.Filtering out the coarse fraction usually leaves the smaller without the coarser sibling where the former tend to agglomerate on.Due to their minute dimensions, nano-sized particles largely escape filtering devices and are emitted into the environment where they interact photochemically to form secondary by-products.Donaldson et al., 1998) Fig. 2. Total deposition function versus particle diameter for an adult individual with a tidal lung volume of 660 mL at 30 breaths per minute (left).modified after Yip., 2003) www.intechopen.comExposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 309

Potential health effects of nano-aerosol exposure
To a certain degree, macrophages possess the ability to process and detoxify organic constituents adhered to DEP surfaces.Once DEPs are endocytosed (Figure 3a), their clearance can occur by the so-called "mucociliary escalator" whereby mucus along with DEPloaded alveolar macrophages are transferred to the oropharyngeal region by movements of cilia.Their clearing transport might be assisted by an increase in pneumocytes of type-II, which are responsible for the secretion of the alveolar surfactant (see Figure 3b).Vostal, 1980) However, cilia-mediated clearance does neither cover terminal bronchioles nor alveoli.Here, nano-particle loaded macrophages readily enter the lymphatic as well as the blood circulatory system.Geiser & Kreyling, 2010;Oberdörster et al. 2005a) Although macrophages represent the most important defense mechanism in the alveolar region against fine and coarse particles, this mechanism is impaired in the case nano-aerosols, which -when inhaled in high abundances -renders phagocytosis inefficient.Geiser & Kreyling, 2010;Oberdörster et al., 2005a) As demonstrated in Figure 3a, removal of these particles can only occur via redistribution into the lymphatic or blood stream.With regards to the coarser particle fraction, the larger number of ultrafine siblings leads to particle dispersion into other tissues and organs representing a further burden for the entire organism.Approx.Vostal, 1980) Due to their minute size, these particles are also routed through the interstitial compartment between cells or straight through the cells via caveolae; these are openings of around 40 nm in diameter that engulf these nano-sized particles, forming vesicles that are thought to function as transport vehicles for macromolecules across the cells.A similar observation has been described for nano-particle translocation across the olfactoric bulb into the brain, thereby short-cutting the blood-brain-barrier (Figure 4).Oberdörster et al., 2004) Fig. 4. Nano-particle translocation across the olfactoric bulb into the brain.While approx.modified after Oberdörster et al., 2004, Tortora & Grabowski, 1996) In the context of nano-sized particle exposure, health consequences become even more challenging when considering that most nano-particles originating from incomplete combustion are of hydrophobic nature.Thus, hygroscopicity and growth via condensation of water vapour is almost inexistent, thereby increasing penetration efficiencies even further -particularly into the alveolar regime of the lungs.Donaldson et al., 1998) In combination, both their low solubility and their role as a "Trojan horse" act threefold: (i) as known with asbestos, insoluble or low soluble matter exerts chronic irritation onto the target cells, (Donaldson et al., 1998) (ii) adsorbed substances on the nano-particle surface unfold their bioreactive properties once in contact with tissues, (Baron & Willeke, 2001) and finally, (iii) UFPs are known to be far more toxic than their coarser siblings (Geiser & Kreyling, 2010;Oberdörster et al. 2005b) -compare with Figure 5.Studies confirmed that nano-particles measuring 20 nm, which were administered directly into the lungs trigger stronger inflammatory reactions than 250 nm particles that are chemically identical.Oberdörster et al. 2005a) www.intechopen.com

Toxicity at the cellular level
Adverse effects of nano-aerosols at the cellular level regard (i) inflammation, (ii) oxidative stress, (iii) modulation, enhancement and induction of immune-as well as allergic reactions, e.g.Oberdörster et al., 2007) Due to their oxidative properties (step "a" in Figure 6), nano-particles are capable to induce lipid peroxidation.Upon endocytosis (step "b"), these particles exert intracellular oxidative stress and increase cytosolic calcium ion concentration, besides triggering the activation of NADPH oxidase and generation of reactive oxygen species (ROS).Chang, 2010) Fig. 6.modified after Oberdörster et al., 2007) Both the particles together with the adhered organic fraction and the consecutively induced oxidative stress can activate cell receptors (step "c") -thereby exploiting the energy reservoir of cells for the induction of appropriate compensatory pathways, which trigger several intracellular signalling cascades.These cascades, along with transcription factors activate the expression of pro-inflammatory genes (steps "d").Apart from interfering with intracellular communication pathways, nano-particles may also enter the cytosol from where they can access mitochondria (steps "e, f") and disrupt normal electron transport, leading to additional oxidative stress (step "f").Translocation of nano-aerosols into the nucleus may also occur where they interact with the genetic material (step "g").Eventually, lipid peroxide-derived products can form DNA adducts, which may lead to genotoxicity and mutagenesis (step "h").Elder et al., 2000) However, apoptosis leaves behind cellular debris together with a toxic particle load that requires clean-up by other cells.
As outlined in Figure 6 (step "g"), genotoxic effects are known to occur also upon MEP exposure as this kind of aerosol induces structural aberrations of chromosomes, formation of micronuclei and DNA adducts.Cheng et al., 2004) Apart from ROS-mediated activity (step "b"), oxidative DNA damages, such as strand breaks, are associated with the cocktail of UFPs and organic pollutants, e.g.Avogbe et al., 2005;Dybdahl et al., 2003) The encountered genotoxity is apparently induced by intracellular ROS, since observed adverse effects were reduced by pre-treatment of cells with anti-oxidants.However, the extent of attenuation depends on the applied anti-oxidant and the protective effects were not complete.Organic fractions of DEPs and MEPs induced ROS are involved in the formation of DNA adducts, e.g.8-hydroxy-deoxy-guanosine (8-OHdG), at least in the mouse model.Nagashima et al., 1995) Nevertheless, PAHs have to be metabolized into their active forms via the P450-1A1 pathway.Cheng et al., 2004) Furthermore, a genetic pre-disposition has to be considered, since genetic polymorphism in protective protein systems, e.g.Avogbe et al., 2005) As mentioned before, organic chemicals adhered to DEPs are apparently directly involved in the formation of reactive nitrogen oxygen species (RNOS) and thus the induction of oxidative stress.Halogenated hydrocarbons and PAHs can induce phase-I drug metabolizing enzymes in alveolar macrophages and epithelial cells, such as cytochrome P450-1A1, which in turn degrade PAHs to redox active metabolites, e.g.Nel et al., 1998;Devouassoux et al., 2002) Benzo-[a]-pyrene (B[a]P) attached to black carbon enhanced the tumor necrosis factor- (TNF-) release of macrophages.Kocbach et al., 2008) The increase in transcription induced by PAHs has been postulated to be promoted by a cytoplasmatic aryl hydrocarbon receptor (AhR), acting as a nuclear transporter/DNA binding protein PAH complex.Once released from DEPs, PAHs enter adjacent cells due to their hydrophobicity and adhere to the PAH ligand binding part of AhR which is then translocated to the nucleus.There, a heterodimer is created between the AhR and a nuclear translocator.This heterodimer binds to response sequences situated upstream of the target genes promoting e.g. the expression of plasminogen activator inhibitor and interleukin-1 (IL-1), which would explain the modulating effects of PAHs upon expression.Kakizawa et al., 2011) As mentioned before, the expression of several enzymatic systems, e.g. the P450-1A1 cytochrome system, are induced.The latter metabolizes PAHs to electrophilic epoxides, which are mutagenic and can interact with DNA.Takenaka et al., 1995)

Short term exposure to airborne pollutants
Studies have shown a decrease in pulmonary function associated with short-term exposure to UFPs.These decrements in lung function appear to persist for several weeks after exposure even when the distressing particle load is no longer present.Stobbs, 1952)   1. Confirmed deaths of the short-term London smog event (5 th -9 th Dec. 1952) with analysis of autopsy, demographics and cause of death.Hunt et al., 2003) London insert: Reduced visibility due to smogrelated light scattering and absorption at Nelson's Column in that period.
Following the events of the great London smog, several investigations tried to highlight the adverse health effects of airborne pollutants.Dockery et al. 1993) Stimulated by the outcome of this study, and due to the occurrence of several severe air pollution events following thereafter, it was attempted to relate cardiopulmonary mortality as well as lung cancer with long-term exposure to particle-related air pollution.Indeed, exposure to fine particle in combination with sulfur oxide (SO 2 ) could be associated with the formation of lung cancer and cardiopulmonary mortality.Perez et al., 2008) .This correlation is most obviously related to the cubic relationship between particle mass [µg/cm 3 ] and number concentration [cm -3 ] on one side as well as the higher penetrability of the smaller, fine and ultrafine particle fractions for the deeper lung on the other side.Hussain et al., 2011) Despite their low overall mass concentration, the fractions of nano-particles can reach high concentrations in terms of particle numbers -a tribute that is related to the improved combustion efficiencies and the applied filtering technologies.Hoek et al., 2002) .When exposed to long-term elevated doses of nano-sized particles, such as diesel fumes and the corresponding by-products of nitrogen dioxide (NO 2 ), the authors documented organismic-wide effects, such as cardio-pulmonary mortality, which was significantly increased by at least a factor of two.This disturbing observation is not correlated to intense short-term air pollution events that last for a few days, but more related to chronic and long-term exposure of significantly lower dosages that cover several weeks or even months.
The combination of UFPs, which are wrapped with a soluble organic fraction (e.g.Ring et al., 2001) This prompted allergists to coin the so-called hygiene hypothesis, which assumed that frequent contact to pathogenic agents, particularly in early infancy, reduces the likelihood of the immune-system for a polarization towards immunoglobulin (IgE)-based responses (i.e.allergies).Such triggers include bacteria, molds, microbial agents (such as LPS), viruses, and potential antigens.Galli et al., 2008;Ring et al., 2001;Yazdanbakhsh et al., 2001) To shed some light on this intrinsically interwoven network, synergism between two types of aerosols shall be demonstrated -the combined effect of carbonaceous nano-particles, such as UFPs, and pollen allergens.Solomon, 2002) The release of allergens, amyloplasts and cytoplasmic debris occur by a rupture of pollen grains triggered by a cycle of wetting -e.g.Chang, 2010;Ormstad et al., 1995) Similar carrier functions for Fel-d1 might also be assigned for DEPs.Ormstad et al., 1995) Furthermore, mite allergens, e.g.Warner, 2000) Although these data are not referring to UFPs, (Warner, 2000) release as airborne particulate matter cannot be ruled out.Alessandrini et al., 2006) Hence, allergen-sensitized individuals are more susceptible to the detrimental health effects of nano-particle exposure.Similar studies investigating the conditioning effects of DEPs with adsorbed volatile organics on the immune system confirmed the pro-allergenic potential.Alessandrini et al., 2006) Furthermore, there is evidence that UFPs induce autoimmune diseases.Mice exposed to ambient PM on a weekly basis showed an accelerated onset of diabetes type-1.Adequately, similar risks were shown for lupus and collagen induced arthritis in murine models.Crohn´s disease was found to be related to micro-particle contamination of food.However, one has to be aware that the apparent UFP-related autoimmune effects are multi-factorial.Chang, 2010) Beside PAHs, bioavailable, ionizable metals might induce inflammation.Fly ash from domestic oil-burning furnaces was found to contain up to 166 g total metal content per mg particulate matter.Metals increase recruitment of macrophages and neutrophils but also eosinophils -the latter are also involved in parasitic and allergic inflammation.An induced cell influx of UFPs was found to be correlated with an elevated intracellular metal content.Chang, 2010;Costa & Dreher, 1997) www.intechopen.com Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 317 Cantone et al., 2011) Thus, the information due to conditioning of the immune system leads to memorization of long-term exposure events at cellular level and is somatically passed on to progeny cells via epigenetic means.As will be exemplified, this also enables cells to leave marks on reproductive cells so that these events can be passed on the filial generation.Bird, 2007) Passing from milder to more severe, chronic disease pattern, it can easily be deduced that (epi-)genotoxic properties of long-term nano-aerosol exposure replaces acute symptoms by unfolding the full spectrum that obviously includes even cancer cases.Calderón-Garcidueñas et al., 2004) Although the list is not extensive, the high occurrence of various types of cancers is striking.Marley, 2006)  Table 2. Clinical data for subjects experiencing long-term UFP-pollution exposure.modified after Calderón-Garcidueñas et al., 2004) Insert: Aerial view of Mexico City revealing reduced visibility due to nano-particles from combustion sources.

Epigenetics
Yauk et al., 2007;Vineis & Husgafvel-Pursiainen, 2005;Mahadevan et al., 2005) These findings support the already pursued hypothesis that mutagenic volatile chemicals adsorbed onto airborne particle pollutants induce somatic and germ-line mutations.Mathers et al., 2010) The epigenome, in its literal sense, can be regarded as a molecular sleeve sitting on top (epi-) of the genome.Nadeau et al., 2010;Blum et al., 2010) In fact, many disorders, related either to epi-or genetic mutations can lead to similar or even congruent phenotypes, with the only difference that mutations of the genome are irreversible, whereas epigenomic changes in theory are plastic, thus of non-permanent nature.So far, the relationships between the genome and the epigenome have broadened the spectrum of molecular events, which are related to human diseases.These can be induced de novo or inherited, genetic or epigenetic, and most interestingly, some events are influenced by environmental factors.
The findings that environmental factors, such as exposure to environmental stimuli (diet, toxins, and even stress) alter the epigenome provide insight to a broad spectrum of disorders.In a bee-hive for example, worker-bees and queens share the same genetic material, yet the differences among them does not consist in altered genetic information, but in the phenotype, fertility, size and life expectancy.Haydak, 1970) This nutritional difference induces epigenetic modifications that determine the accessibility of genes for their expression (see schematic Figure 7).Similarly, it was possible to show that nutrition during embryonic development affects adult metabolism in humans and other mammals, via persistent alterations in DNA methylation.Waterland & Jirtle, 2003) Even pure physico-environmental stimuli unveiled their epigenetic effects on stem cells that have been exposed to THz radiation.Zoghbi & Beaudet, 2007) The basics of epigenetics are rooted in bio-physico-chemical processes, which can be considered as bookmarks placed into the book of life.Indeed, faulty epigenetic regulations are regularly behind chronic diseases.Rodríguez-Paredes & Esteller, 2011) Fig. 7.The epigenome plays an essential role together with the genotype and environmental factors in determining phenotypes.Biochemical reactions affecting gene expression and genome stability include DNA methylation (Me), chromatin-remodelling complexes, covalent histone modifications (mod), the presence of histone variants, or non-coding regulatory RNAs (ncRNAs).The greyish arrows indicate the line and strength of progression.

Modulating the epigenome
As shown in Figure 8, enabling or inhibiting ribosomal activity to access genetic information is regulated by three major pathways.Zoghbi et al, 2007) A central epigenetic regulatory mechanism comprises methylation of cytosine -whereby DNA-methyl-transferases attaches a methyl-group from the cofactor Sadenosyl-methionin (SAM) onto the cytosine atom C5.DNA methylation mostly takes place at cytosine-guanine-nucleotide.Numerous copies of these dinucleotide sequences are Small nuclear RNA (snRNA). (modified after Walker & Gore, 2011& Qiu, 2006).
located within CpG-islands that constitute the promoter region of genes.Yang et al., 2005) Another crucial epigenetic mechanism concerns histone-modification and addresses the dense packing of the DNA-filament.If stretched out, the DNA of a cell would cover at least two meters in total length.Supercoiling of the filament enables its packing into a cell nucleus of 10 to 100 μm in diameter.Such packing is achieved via small basic proteins, termed histone cores.Luger et al., 1997) This protein-DNA-unit is known as a nucleosome.Upon DNA-attachment of the linking histone H1, supercoiling occurs in a cascading manner until chromatin is present in its most condensed form: the chromosome (Figure 8).Epigenetics on the histone-level affects the N-terminal tails that protrude from the histone-octamer (see Figure 8).In particular, this regards the basic amino acids lysine and arginine but also serine and threonine.Histone-modifying enzymes append or dislodge specific amino acids.Strahl & Allis, 2004) Modification of the Nterminal tails loosen the chromatin's density that enables genes to be readily accessible and transcribed.The opposite effect regards densification of the chromatin and concomitant inhibition of gene readability.In addition to the aforementioned modifications, there are also numerous non-histone proteins that can be biochemically modified, likewise yielding de-or activation of corresponding genes.Luo et al., 2000) Furthermore, a surprisingly large number of RNAs neither functions as messenger, transfer or ribosomal RNAs, and are thus called non-coding RNAs (ncRNAs).Such RNAs regulate gene expression on various levels, including chromatin modification, transcription, RNA modification, RNA splicing, RNA stability and translation.Among them, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are most prominent.Both regulate gene expression through the RNA interference (RNAi) pathway.More than 1% of predicted genes in higher eukaryotic genomes and up to 30% of protein-encoding genes are assumed to be subjected to miRNA regulation.Yu, 2007) Although all cell types within an organism share identical genetic material, they perform different tasks.Task sharing requires a cell-specific readout of genes, which is realized by biochemical markers.Here, epigenetics controls the fate of progeny cells after mitotic division.i.e. lung specific stem cells yield differentiated lung cells although their genome would potentially enable differentiation into any kind of cell.This kind of cellular memory requires to be passed on to the progeny cells.Hollick et al., 1997, Sarge & Park- Sarge, 2005) While the former regards cellular regeneration during the fetal stage all the way through the adulthood, the latter is a characteristic feature for the embryonic phase.

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Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 321

Adult epigenome
Bookmarking transmits cellular memory (i.e.patterns of cellular gene expression) via mitosis to somatic progeny cells of the same type.Throughout one's lifespan, tissue-specific stem cells are responsible for the development and regeneration of entire organs, such as skin, lung, gut, blood system, etc.In order to meet this task, these stem cells, besides revealing an extensive self-renewal potential, encompass also pluripotency.These properties give rise to all cell types of an organ that differentiate to multipotent progenitors with gradually restricted developmental potential.Fisher, 2002) In other words, stem cells and resulting progenitors as well as specialized tissue cells share the same genome.Yet, the lower the ranking within cellular ontogenesis, the more genes have to be silenced in order to fulfil the requirements that match organ function.Practically, a healthy somatic epithelial lung stem-cell divides to yield a progeny cell that becomes epigenetically tagged in such a way as to provide a specialized cell.This differentiated cell becomes part of the cellular consortium that constitutes an ensemble yielding the lung with all its physiological functions.Under normal physiological conditions, it would be senseless to differentiate into a cell linage other than e.g.specialized epithelial lung cells.This kind of epigenetic tagging (e.g.Tost, 2008) Studies based on monozygotic twins with similar epigenomes during early years of life revealed remarkable differences in methylated DNA and acetylated histones during later stages of life.Fraga et al., 2005) Now, how is epigenetics related to nano-aerosol exposure?Anway et al., 2005) Metastability affects responsiveness to oxidative stress (Figure 6) and as such Fig. 9. Potential mechanism linking environmental exposures to epigenetic effects.These effects include DNA methylation, histone codes and miRNA expression.modified after Baccarelli & Bollati, 2009) renders the organism more susceptible to cardio-vascular as well as respiratory effects of air pollution.Tarantini et al., 2009) The same authors also reported demethylation effects induced by longterm exposure to particle mass (PM 10 ) exposure in younger individuals individuals.These effects resemble demethylation patterns that are typically observed in old age.Histone modifications have been observed in workers who experienced long-term exposure to nanosized aerosols at smelters.Cantone et al., 2011) Another key concept for the developmental origin of diseases comprises a transfer of the acquired predisposition onto subsequent generations without further environmental impacts (see Figure 10).Such trans-generational epigenetic inheritance is responsible for wider effects, such as a fast-track pathway of adaptation to environmental stress.Finnegan, 2002) Fig. 10.Epigenotype model of developmental origins of disease.Environmental factors acting in early life (from conception to early infancy) have consequences, which become as an altered risk for diseases in later life.The mother conveys a forecast of the post-natal environment to the genome of the unborn.This includes modifications to its metabolism, whole body physiology and growth trajectory to maximize its chances of postnatal survival.These adaptations become detrimental if the environmental conditions after birth differ from those of the fetal stage.modified after Sandovici et al., 2008) www.intechopen.comExposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 323

Embryonic epigenome
Paramutation in comparison to bookmarking, regards the quasi "inheritance" of genecharacteristics (allelic interactions) that are "remembered" and expressed in later generations (e.g. via the germ cell linage).Paramutation occurs when certain control alleles impose an epigenetic imprint on susceptible (paramutable) inferior alleles.The epigenetic imprint is inherited through meiosis and persists even after the interacting alleles have segregated.Chanlder & Stam, 2004) Paramutation fulfils the criteria for a parental identity mark or "imprint" because it can be established either in the sperm or the oocyte by de novo methyl-transferases that act only in one gamete.Barlow & Bartolomei, 2008) .
The newly fertilized egg or zygote is unique since no other cell has the potential to develop into an entire organism.Morgan et al., 2005) Hence, gene expression depends on the origin of inheritance.This implies that at an imprinted diploid locus, there is unequal expression of the maternal and paternal alleles.So much so, that in each generation, the parent-specific imprinting marks have to be erased, reset, and maintained.It is obvious that imprinted loci are somewhat prone to errors that may occur during these processes.Surani & Reik, 2007).Tissue-specific stem cells are responsible for the development and regeneration of entire organs, such as skin, gut, and blood system throughout life.To comply with this task, stem cells encompass two unique properties: (i) an extensive selfrenewal potential that enables them to propagate in their uncommitted state; (ii) pluripotency that gives rise to all cell types of an organ by differentiation to multipotent progenitors with gradually restricted developmental potential.Fisher, 2002) Transcription factors reprogram the expression of large sets of genes.They act indirectly by (i) affecting gene expression programs (antagonizing other transcription factors through protein-protein interaction) and directly by (ii) the control of gene transcription (recruiting coactivators or corepressors with histone-modifying or chromatin-remodeling activities to regulatory DNA elements).Jaenisch & Gurdon, 2007) With reference to Table 2, it becomes evident that chronic disease processes can be readily attributed to a long-term exposure to environmental nano-aerosols.

Chronic diseases and cancer
It is well established that complex diseases, such as heart diseases, diabetes, obesity, Alzheimer's disease, schizophrenia, and bipolar disorder etc. result from the interplay between (epi-)genetic and environmental factors.The interaction with nano-aerosol exposure not only conditions the immune system, thereby inducing to allergic reactions, but also affects the epigenome, which leads to neuro-degenerative disorders or even towards malignancy.Petronis, 2001;Bjornsson et al, 2004) Examples include increased methylation levels at the estrogen receptor-alpha and the estrogen receptor-beta gene promotors in proliferating human aortic smooth muscle cells and in atherosclerotic cardiovascular tissues, respectively (Ying et al, 2000;Kim et al, 2007) It has also been demonstrated that Fig. 11.Interacting pathways to cancer -a mechanism-based model of the pathogenesis of human cancer.Sporadic cancers, which comprise 90-95% of all cancers, almost uniformly exhibit both genetic and epigenetic defects.As suggested by the vertical arrows, these mechanisms show substantial interaction.That is, epigenetic events can cause genetic events, and vice versa.Depending on the cancer type, each mechanism can be operative early, late or continuously during the development of the tumor (horizontal arrows).modified after Costello & Brena, 2008) workplace exposure to nano-particles and their associated volatile chemicals induce global demethylation especially of retro-transposons in LINE and SINE sequences.Baccarelli et al., 2010a, Baccarelli et al., 2010b) Blood samples screened for LINE-demethylation in exposed individuals (e.g.Bollati et al., 2007) This induces not only premature aging, increased risk of IHD and stroke, but also paves the way to chronic pathology, such as cancer.Ingrosso et al., 2003;Waterland & Jirtle, 2003) Thereby epigenetic changes take place despite the pre-systemic metabolic effect of the liver.Since this first-pass effect of the liver is almost inexistent during inhalation, it is apparent that modifications to the epigenome in response to airborne stimuli are even more pronounced and thus directly linked to chronic exposure to airborne pollution.Zhu et al., 2011) Although aging is the major risk factor associated with cancer development, epigenetic modifications occurring earlier in life underline the important role of the environment in various cancer types.Epigenetic changes induced by environmental factors in the pool of progenitor stem cells of each tissue might be the earliest events during carcinogenesis.Feinberg et al., 2006) .Ozanne & Constincia, 2007) Once environmentally induced epigenetic changes are established, they will be maintained throughout many cell divisions by the epigenetic signalling procedure.The maintenance of such altered epigenetic states leads to stable alterations in gene expression with physiological adapted consequences.Costello & Brena, 2007) Nano-aerosols in combination with benzene exposure for instance are known to induce a significant reduction in LINE-1 and Alu methylation.Bollati et al., 2007) Since the involvement of proteins in epigenetic pathways is tightly regulated, perturbations at a given level -e.g.through loss-of-function -inevitably will cause human disorders.Zoghbi et al., 2007) Evidence is given by studies employing both animals (Liu et al., 1997;Waterland & Jirtle, 2003;Weaver et al., 2004;Wolff et al. 1998) as well as humans (Albert el al., 2005;Bottiglieri et al. 1994;Reynolds et al. 1984;) , emphasize the crucial role of epigenetic modulation and the onset of a chronic disease pattern.
From all stated facts, it is obvious that the organism is capable to adapt to a vast range of environmental exposures.Thaler, 1994) Figure 12 presents a dynamic map that highlights the feedback-cycles of involuntarily as well as deliberate environmental exposure.Thus, epigenetics makes it possible to associate a given exposure related lifestyle to the corresponding phenotype.Hence, long-term environmental exposure must be epigenetically manifest also within the germ cell linage.In this case environmentally related stressinformation is passed on to progeny.However, inherited epigenetic imprints are not entirely permanent, as paramutating effects have been documented to persist for up to three generations before they are lost again without altering the sequence of the DNA itself.(Jablonka, 2001)   Fig. 12. Environmental influences, exposure to constituents in drinking water, consumed food, inhaled air along with stress and emotions, epigenetically modify genes, without altering the nucleotide sequence.The numbers above outline hierarchical interdependences of eco-systemic relationship in which the organism is embedded in: (1) The environment is the proximate agent of selection.(2) Organism perceives environment.(3) Organismic perception acts on physiology.(4) Organisms modifies genetic metabolism.( 5) Environmental impact on DNA.(6) Environmental interaction with genes.modified after Thaler, 1994)

Conclusion
Exposure to anthropogenically released nano-aerosols originating mainly from incomplete combustion processes fully unfold their toxicological potential -particularly in congested areas.These particles have multitude ways to enter the body, including adsorption via the www.intechopen.comExposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics 327 skin, the olfactoric nerve bundles (inducing neurodegenerative diseases), deposition within the respiratory tract (directly related to respiratory diseases), ingestion of cleared particle laden mucus (in combination with the former mode of entry, responsible of the wider organismic health problems).Redistribution of the cellularly absorbed particle load throughout the organism is achieved via the blood circulatory and the lymphatic system.Toxicity itself not only depends on the nature of the particle (solubility and hydrophobicity) but also on the surface structure, onto which volatile substances and radionuclides can adsorb.Since nano-sized particles exert more severe distressing effects on the cellular level than their coarser siblings, these aerosols significantly contribute to chronic disease patterns and epigenetic imprinting, which enables acquired lifestyle-related stress-response patterns to be passed on to subsequent generations.Due to the fact that these particles access secondary target organs along with their effects on the organismic level, they definitely will attain further toxico-medical attention in the near future.The availability of more and more products containing designed and engineered nano-particles and fibers, contributes to this dilemma as awareness of associated risks and benefits have not yet led to regulatory guidelines in order to limit side-effects of improper production methods, inadequate usage and irresponsible disposal of these materials.While the exact risk of aerosolized particles is still cumbersome to define, current scientific evidence already stresses the adverse effects of long-term exposure as it tilts the balance towards the emergence of so called "civil-societyrelated" diseases that so far were either considered harmless or not yet associated to these environmental stressors.While it is not always possible to assign a single detrimental aerosolized agent to a particular disease, the evidence given so far indicates that xenobiotic nano-aerosols along with the adsorbed cocktail of semi-/volatile organic compounds should be considered as promoters and modulators in the emergence of chronic diseases.This interrelation has scarcely been considered in the past.Since epigenotypic flexibility regards plasticity during embryonic development, the post-natal phase, and well into adulthood, it is not surprising that epigenetic imprinting due to airborne nano-aerosol exposure not only contributes to developmental disorders, but also to post-natal and even adult human diseases.This perspective will disproportionally challenges our existing medicare system.This Lamarckian-type of inheritance is achieved via various processes and involves in particular DNA-methylation, histone modifications, mRNA silencing and other regulatory interference mechanisms.Although it is well known that anthropogenic aerosols exert their effects on the cellular, tissue, organ, and organismic level, interference with the phylo-ontogenetic patterns, currently investigated in the field of epigenetics, open a new chapter to these issues.This line of argument may point towards a new understanding of health and disease, whereby the latter should just be regarded as an organismic proxy indicator in the attempt to attain a new organismic steady state.Hence, extended stress exposure (as is the case of environmental nano-aerosols) contain distressing agents that shift the constantly fluctuating homeostatic balance into new oscillating instabilities.However, the difference between these states lies in the fact that in the latter stages affected individuals increasingly feel physically less fit than in the former from which they have been kicked out of.

Fig. 5 .
Fig. 5. Exposure of human lung fibroblast to ceria nano-particles (arrows) of 20-50 nm in diameter.(a) Vesicles inside a fibroblast cell with ceria agglomerates.(b) A cluster of nano-particle agglomerates close to the cell membrane.(c) Nano-particles both inside the cell (vesicle) and outside are exclusively found in the form of agglomerates.(adoptedfrom   Limbach et al., 2005)