TEGDMA-induced oxidative DNA damage and activation of ATM and MAP kinases

Eckhardt, Alexander; Gerstmayr, Nicol; Hiller, Karl‐Anton; Bolay, Carola; Waha, Claudia; Spagnuolo, Gianrico; Camargo, Carlos A.; Schmalz, Gottfried; Schweikl, Helmut

doi:10.1016/j.biomaterials.2008.12.045

Cited by 95 publications

(80 citation statements)

References 58 publications

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“…Resin monomers such as HEMA are responsible for the formation of DNA double-strand breaks. This genome damage leads to the activation of ataxia telangiectasia mutated (ATM) gene, a member of the phosphoinositide 3-kinase-like family of serine/threonine protein kinases, by autophosphorylation after long exposition periods to resin monomers (Eckhardt et al 2009). Ansteinsson et al (2011) demonstrated that in response to HEMA-induced DNA damage, a number of cell cycle checkpoints are activated leading to complex kinase-signalling networks that reduce the progression through the cell cycle and, in parallel, also mediate recruitment of DNA repair pathways.…”

Section: Hema-induced Dna Damagementioning

confidence: 99%

HEMA‐induced cytotoxicity: oxidative stress, genotoxicity and apoptosis

2014

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Gallorini M, Cataldi A, di Giacomo V. HEMA-induced cytotoxicity: oxidative stress, genotoxicity and apoptosis.International Endodontic Journal, 47, 813-818, 2014. Dental resin composites consist of organic polymers with inorganic fillers used as bonding resins and direct filling materials in dentine adhesives and as sealing agents for inlays, crowns and orthodontic brackets. Despite various modifications in the formulation, the chemical composition of composite resins includes inorganic filler particles and additives, which are incorporated into a mixture of an organic resin matrix. Among them, 2-hydroxyethylmethacrylate (HEMA) is one of the most frequently used. Several studies have attempted to clarify the mechanisms underlying HEMA cytotoxicity. Most of them support the hypothesis that this compound, once released in the oral environment, increases reactive oxygen species (ROS) production and oxidative DNA damage through double-strand breaks evidenced by in vitro presence of micronuclei. As a consequence, the glutathione detoxifying intracellular pool forms adducts with HEMA through its cysteine motif and inflammation begins to occur: transcription of early genes of inflammation such as tumour necrosis factor a or inducible cyclooxygenase up to the secretion of prostaglandins 2. These phenomena are counteracted by N-acetylcysteine (NAC), a nonenzymatic antioxidant, but not by vitamin E or other antioxidant. Consequently, NAC prevents HEMA-induced apoptosis acting as a direct ROS scavenger. This minireview collects the most significant papers on HEMA and tries to make an overview of its cytotoxicity on different cell types and experimental models.

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Section: Hema-induced Dna Damagementioning

confidence: 99%

HEMA‐induced cytotoxicity: oxidative stress, genotoxicity and apoptosis

2014

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“…P38 and JNK pathways are mainly activated by environmental stress including oxidative stress, but also by the bacterial lipopolysaccharide (LPS), and thus these kinases are also classified as stress-activated protein kinases (Matsuzawa and Ichijo, 2005). Differential activation of MAP-kinases p38, JNK, and ERK has also been described in the context of TEGDMA-and HEMA-induced apoptosis in different cell lines (Samuelsen et al, 2007;Spagnuolo et al, 2008;Eckhardt et al, 2009b).…”

Section: Map Kinasesmentioning

confidence: 99%

Toll-like Receptors, LPS, and Dental Monomers

2011

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Unreacted monomers released from dental resin-based composites at non-cytotoxic concentrations cause a depletion of glutathione and an increase of reactive oxygen species (ROS), leading to, e.g., DNA damage and apoptosis. ROS-sensitive MAP-kinases are activated by HEMA and TEGDMA. MAP-kinases are also involved in the bacteria-triggered cell responses of the innate immune system, e.g., after bacterial lipopolysaccharide (LPS) binding to the Toll-like receptor (TLR) 4. Therefore, both bacteria and monomers imply environmental stress to pulp tissue, and they may influence the target cell reactions in a combined way. In macrophages, cell-surface antigens and cytokines were up-regulated after exposure to LPS, but TEGDMA caused a significant down-regulation. Regulation was dependent on exposure time, indicating that LPS and TEGDMA act differently on MAP-kinases. Furthermore, the cell type played a decisive role. Inhibition of the immune response may result in a decrease in inflammatory symptoms and/or a reduced defense capacity against bacteria.

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“…ROS are the major agents responsible for endogenous DNA damage, which includes oxidation products of DNA bases and DNA strand breaks 11) . Previous own studies have shown that the microsomal degradation of (co)monomers [for example 2-hydroxyethyl methacrylate (HEMA)] can lead to the formation of epoxides, like 2,3-epoxymethacrylate, which are considered highly toxic and mutagenic substances [12][13][14][15][16] . In addition, (co)monomers can form ROS during their metabolization, that may be mutagenic and genotoxic [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

NAC ameliorates dental composite-induced DNA double-strand breaks and chromatin condensation

Styllou

Hickel

et al. 2017

Dental Materials Journal

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Released (co)monomers from dental composite components can induce DNA damage of which DNA double-strand breaks (DSBs) threaten genome integrity. Here, we tested whether the administration of the antioxidant N-acetylcysteine (NAC) is able to reduce the dental composite-induced DSBs in primary human gingiva fibroblasts. The dental composites Bis-GMA (bisphenol-Aglycerolate dimethacrylate), GMA (glycidyl methacrylate), HEMA (2-hydroxyethyl methacrylate) and TEGDMA (triethyleneglycol dimethacrylate) were found to induce co-localizing microscopic nuclear foci numbers of the DSB markers γ-H2AX and 53BP1 per cell in the order: GMA>Bis-GMA>TEGDMA>HEMA. Supplementation of (co)monomer-containing culture medium with NAC led to a significant reduction of resin-induced DSBs as well as to an amelioration of dental monomer-induced nuclear chromatin condensation in gingival fibroblasts. Thus, antioxidant treatment can reduce radical-induced chromatin and DNA damage and open avenues to mitigate genotoxic effects of dental composite compounds.

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TEGDMA-induced oxidative DNA damage and activation of ATM and MAP kinases

Cited by 95 publications

References 58 publications

HEMA‐induced cytotoxicity: oxidative stress, genotoxicity and apoptosis

HEMA‐induced cytotoxicity: oxidative stress, genotoxicity and apoptosis

Toll-like Receptors, LPS, and Dental Monomers

NAC ameliorates dental composite-induced DNA double-strand breaks and chromatin condensation

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