Periodontal Disease and Nuclear and Oxidative DNA Damage Periodontal Disease and Nuclear and Oxidative DNA Damage

Oral health is an important aspect of the overall health status of an individual. DNA damage has been associated with oral health and dental factors due to the increased of oxidative stress (OxS). DNA damage can produce a wide range of effects on human health. These effects could appear immediately, but others do not become evident much later. Chronic diseases have been study to understand their mechanisms, clinical implica - tions, and the development of secondary disease such as cancer. Periodontitis is one of the most common oral diseases. It is an inflammatory chronic infectious disease, which is characterized by the loss of supporting tissues and tooth loss caused by periodonto pathogens and long-term release of reactive oxygen species (ROS); thus, oxidative stress is increased during periodontitis. Oxidative stress can produce DNA damage, including the oxidation of nucleosides, which could cause DNA strand break. This oxidative dam - age leads the formation of micronuclei (MN) a marker of nuclear damage. Also, oxidative stress increased 8-hydroxy-2′-deoxyguanosine levels which are the most common stable product of oxidative DNA damage.


Introduction
DNA damage can generate many effects on human health and is the prime mechanism during carcinogenesis. Many of these effects could emerge directly, but others do not become evident until much later. Chronic diseases have been studied to understand their mechanisms of perpetuation of clinical complications and the development of secondary diseases such as cancer [1]. Oxidative stress (OxS) and, therefore, DNA damage has an important impact on the pathogenesis of chronic disease [2]. Periodontal diseases are inflammatory disorders characterized by gingival inflammation in which periodontopathic bacteria generate immunological inflammatory responses [3]. The OxS plays an important role in the pathogenesis of periodontitis, which can lead damage to genetic material [4]. Since periodontal disease is an example of the excess effects locally and systemically of OxS over production, the effect of periodontal disease over oxidative and nuclear DNA damage is the topic attended in this chapter.

Periodontitis
Moreover, dental caries, periodontal disease is one of the most prevalent oral diseases in the world and includes the major conditions gingivitis and periodontitis, which is a group of conditions affecting the supporting tissues of the teeth-the gingiva, periodontal ligament, cementum, and alveolar bone [1]. The reversible form of the disease, gingivitis, comprises inflammation of the gingival tissue without loss of alveolar bone. It is plaque induced and can be reversed with improved oral hygiene. In disease-susceptible individuals, gingivitis may develop into periodontitis, which is a chronic inflammatory condition of the gingiva causing destruction of connective tissue as well as of alveolar bone resulting in reduced support for the teeth and, ultimately, tooth loss (Figure 1) [5].
Periodontitis initiated by the complex interaction between the presence of periodontal pathogens (e.g., Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum) and host response [6]. Besides, the presence of periodontal pathogens associated with the progressive form of the disease, microbial by-products, the host immune response, environmental and behavior factors, and genetics may contribute the risk for developing periodontal disease [7].
Two main forms of periodontitis have been identified, chronic or aggressive, and are characterized by gingival inflammation and bleeding, periodontal pocket formation, destruction of connected tissues attachment, and alveolar bone loss. But, loss of connective tissue attachment is faster in aggressive periodontitis than in chronic periodontitis [8].
Moreover, the pathogenesis of periodontal diseases is mediated by the inflammatory response to bacteria in the dental biofilm. The inflammatory reaction that characterizes periodontitis is the complex interaction between periodontopathic bacteria and the host defense system, and its purpose is to protect the tissues from bacterial attack [6]. In periodontitis, neutrophil plays an important role in the initial host inflammation. Exaggerated neutrophil activity is the biological features characteristic of the periodontitis phenotype in agreement with a hyperinflammatory host response. Thus, reactive oxygen species (ROS) produced from neutrophil are implicated in the destruction of periodontal tissue; therefore, oxidative stress (OxS) is enhanced during periodontitis [9].

Free radicals (FR) and oxidative stress
A free radical (FR) is any molecular species that contains at least one unpaired electron. The unpaired electron increased the chemical reactivity of an atom or molecule that generates a high instability. Due to the increase in FR, oxidative stress (OxS) arises. The OxS has been defined as a disturbance in the balance between the production of reactive oxygen/ nitrogen species (ROS/RNS; FR) and the antioxidant defense system capacity to counteract their action [10]. The OxS occurs from an improved ROS/RNS generation or from a deterioration of the antioxidant protective ability. This process leads to the oxidation of biomolecules with consequent loss of its biological functions, whose manifestation is the potential oxidative damage to cells and tissues. Accumulation of ROS/RNS can result in several adverse effects such as lipid peroxidation, protein oxidation, and DNA damage (Figure 2) [11].

Nuclear and oxidative DNA damage
DNA is chemically unstable and vulnerable to oxidation, due to its susceptibility to endogenous and exogenous damage. The endogenous genotoxic agents are mainly produced by cellular metabolism and composed of ROS and RNS, estrogen metabolites, and aldehydes produced by lipid peroxidation [12,13]. The OxS leads to different lesions in DNA, including direct modification of nucleotide bases, training sites a purinic/a pyrimidinic, single strand break, the oxidation of nucleosides, which could cause DNA strand breaks; this type of damage could have teratogenic or carcinogenic consequences [14].
One method for measuring DNA nuclear damage is the micronuclei (MN) assay [15][16][17]. MN are extranuclear bodies originated from chromosome fragments or whole chromosome that spontaneously or because of clastogenic (agents who broke chromosome) or aneuploidogenic (disrupted the spindle apparatus) agents that were not incorporated into the nucleus after cell division (Figure 3) [18]. The MN formation leads to cell death, genomic instability, or cancer development. Therefore, the increased in MN frequency is linking to environmental and occupational exposure to genotoxic agents, lifestyle, genetic profile cancer, and occurrence of other diseases, and MN screening is considered as a biomarker of DNA nuclear damage [19].
On the other hand, different markers of oxidative DNA damage have been identified. The most popular markers were designed for lipid peroxidation, such as malondialdehye (MDA), oxidized low-density lipoprotein (LDL), MDA-modified LDL, among other. In recent years, 8-hydroxy-2′-deoxyguanosine (8-OHdG or 8-oxodG) has appeared as a marker of oxidative stress in body fluids [20]. The 8-OHdG is the most common stable product of oxidative DNA damage caused by ROS. Among all purine and pyridine bases, guanine is most susceptible to oxidation. Hydroxyl radical addition to the eighth position of the molecule leads to the formation of guanine-modified product 8-OHdG (Figure 4) [21]. Oxidative-modified DNA in the form of 8-OHdG can be quantified to indicate the extent damage to genetic material is the most frequent and most mutagenic lesion in nuclear DNA and is important in mutagenesis and carcinogenesis processes [22].

Periodontitis and OxS: nuclear and oxidative DNA damage
The OxS plays an important role in the pathology of several diseases, including arthritis, Alzheimer's disease, diabetes, Parkinson's disease, and more recently periodontitis. The OxS is a phenomenon that occurs within the periodontal disease and has been linked with both onset of periodontal tissue destruction [23] and systemic inflammation [24]. Inflammatory periodontal disease resulting in tissue damage is mediated by ROS which are formed during the phagocytosis of periodontopathic bacteria by polymorphonuclear leukocytes. ROS generation can occur through different mechanisms such as protein disruption, lipid peroxidation, induction of proinflammatory cytokines, and DNA damage [22]. Therefore, periodontitis is associated with OxS which in turn can lead to nuclear and oxidative DNA damage and thus the formation of MN and 8-OHdG [25].
Some authors have been demonstrated that individual with periodontal disease exhibited an increase in the frequency of MN, which is directly related to DNA damage [25][26][27]. Similarly, elevated MN frequency has been reported in patients with cancer [28], rheumatoid arthritis [29], autoimmune diseases [30], and premature aging syndrome [31]. The presence of MN in a cell is an indicator of DNA damage and genetic instability, and it could be associated with the collateral complications in these patients and with future risk of cancer development in humans.
On the other hand, 8-OHdG level has been studies in oral pathologies, including periodontal disease [25,[32][33][34][35] and oral cancer [36]. As described above, in periodontitis OxS because of the formation of ROS, which is stimulated by neutrophils, produce damage of the bonesupporting tissues. The exceeds of ROS levels, the reduction of antioxidant enzyme activity, and defects in DNA reparation mechanism led to increased oxidative DNA damage [35].
8-OHdG is used as a standard biomarker of oxidative-induced DNA damage mainly because of its reliable detectability. Elevated levels of 8-OHdG from cancer patients compared with healthy subjects have been observed in lung cancer [37], basal cell carcinoma [38], colorectal cancer [39], bladder cancer [40], and renal cell carcinoma [41]. With respect to periodontitis, published data on oxidative damage to DNA have been reported by many authors around the world who investigated 8-OHdG levels in the saliva of periodontitis patients [4,25,33,34]. These studies demonstrated that salivary levels of 8-OHdG in samples from periodontitis patients were significantly higher than those from periodontally healthy controls and indicated that salivary 8-OHdG levels may be a useful marker for disease activity and may be indirectly reflect disease severity parameters [4,25,33,34].
Also, a study report significant positive correlation between MN frequency (a marker of nuclear damage) and 8-OHdG enzyme levels in subjects with periodontitis. This finding could suggest that these variables are associated and can be hypothesized that they could be linked in the development of periodontal disease [25]. The augmented 8-OHdG levels might indicate early oxidative mitochondrial DNA damage [33], and mitochondrial DNA undertakes OxS early than nuclear DNA [42].

Conclusion
Periodontal diseases are prevalent in human populations and represent a significant public health problem [43], and oxidative damage plays an important function in the pathogeny of the disease [9]. Nuclear and oxidative DNA damage area increased in subjects with periodontal disease, and genetic damage is a critical event not only in the initiation phase but also in the promotion and progression phases, which could be related to carcinogenesis events. Moreover, recent studies have associated periodontitis with some cancer including head and neck cancer [44], pancreatic cancer [45], colon cancer [46], and orodigestive cancers [47], which are relevant to the control of this disease and to promote the importance of good oral health.