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Genetic and Cellular Toxicology of Dental Resin Monomers

¹ Department of Operative Dentistry and Periodontology, University of Regensburg, D-93042 Regensburg, Germany; and
² Department of Oral and Maxillofacial Sciences, University of Naples "Federico II", via S. Pansini 5, 80131-Naples, Italy

View larger version (19K): [in a new window]   Figure 1. Model of the induction of genotoxicity in mammalian cells by triethylene glycol dimethacrylate (TEGDMA) and cellular responses. DNA damage by TEGDMA may occur either directly, via covalent binding to nucleophilic centers of double-stranded DNA, or indirectly, via the generation of reactive oxygen species (ROS). The replication of damaged DNA causes gene mutations, but the successful repair of damaged DNA will lead to cell survival. Incomplete repair, however, as well as DNA double-strand breaks (dsb) as a result of blocked DNA replication, will cause cell-cycle delay or apoptosis in the case of severe and irreversible damage. Genotoxicity and cell-cycle delay are inhibited in the presence of the ROS scavenger N-acetylcysteine (NAC).

View larger version (9K): [in a new window]   Figure 2. Production of reactive oxygen species (ROS) and cell response. ROS are generated within the cell in mitochondria and peroxisomes, and by cytochrome P450 enzymes (CYP). The intracellular amounts of ROS also increase after exposure to UV light, ionizing radiation, or chemical agents, including dental resin monomers. The defense system against ROS includes endogenous and exogenous anti-oxidants (glutathione GSH, vitamins, N-acetyl-cysteine NAC) plus enzymatic activities. Cellular macromolecules such as lipids, proteins, and DNA may be damaged when the production of ROS is higher than the anti-oxidant capacity of the cells.

View larger version (25K): [in a new window]   Figure 3. Description of the phosphatidylinositol-3 kinase (PI3-K) pathway and the possible modulatory effect of triethylene glycol dimethacrylate (TEGDMA). Membrane receptors (ligand-dependent tyrosine kinase receptor, G-protein-coupled receptor) activate PI3-K to form the second-messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) by phosphorylating phosphatidylinositol-4,5-bisphosphate (PIP2). Then, PIP2 and PIP3 stimulate the phosphorylation (activation) of Akt (PKB/Akt). Akt is a key element in the control of substrates important for cell survival, cell cycle, protein synthesis, and metabolism. Activation of Akt by PI3-K is inhibited in the presence of TEGDMA. The possible links to elevated levels of reactive oxygen species (ROS) and a decrease in glutathione (GSH) levels remain to be elucidated. Tumor suppressor protein PTEN = phosphatase and tensin homologue; PH = pleckstrin homology; AFX, FKHR = forkhead transcription factors; BAD = pro-apoptotic factor of the Bcl-2 family; ASK-1 = apoptosis signal-regulating kinase 1; CREB = cAMP responsive element binding protein; IKK = inhibitor of NF-kappaB kinase; mTOR = mammalian target or rapamycin; GSK3 = glycogen synthase kinase 3; p21, p27 = cyclin-dependent kinase (cdk) inhibitors.