Epigenetic and Non-epigenetic Role of SIRT1 in Fluoride-induced Cell Stress Administrative Supplement.

This is an application to the Administrative Supplements for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards (NOT-OD-23-032), granted for the PI's (Dr. Maiko Suzuki) parent R01 grant (R01DE027648) entitled “Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress”. The PI's overarching research objective in the dental-oral-craniofacial field is to identify environmental factors related to craniofacial pathophysiology and to develop novel preventive and therapeutic strategies for environmental factor-associated oral diseases, including tooth malformation, periodontitis and oral cancer. To attain the objective, in this supplement, the PI will develop the current R01 project into fluorinated compounds (per- and poly- fluoroalkyl Substances; PFAS), which are newly highlighted as environmental pollutants. PFAS are a large group of artificial fluorinated organic compounds that have generated increased public attention due to their toxicity and adverse health effects. The molecular mechanisms of PFAS effects on dental-oral-craniofacial pathophysiology are largely unidentified. In the parent R01 award, we focus on the molecular mechanisms of fluoride on enamel development. Our preliminary results demonstrated that, as well as fluoride, fluorinated organic compounds PFAS could cause adverse effects on enamel formation in vitro and in vivo. Recent studies have demonstrated the association between PFAS exposure and some types of cancer. However, the PFAS effects on Head and Neck Cancer (HNC) are largely unidentified. In this supplement, we propose to develop the parent research project into PFAS-mediated HNC pathology. The objective is to determine the biological effects of PFAS on HNC in vitro. Our preliminary data suggest that PFAS could promote HNC invasiveness and metastasis. We preliminary discovered that perfluorooctanoic acid (PFOA; a most studied PFAS) increased the expressions of epithelial-mesenchymal transition (EMT) markers and promoted cell migration (wound healing assay) in a murine squamous cell carcinoma cell line (SCC7) in vitro. SCC7 has been used as an oral cancer and head and neck cancer model in vitro and in vivo. Our previous study demonstrated that fluoride and PFOA increased ROS generation to cause oxidative stress in ameloblast-like cells. Based on our previous studies and preliminary data, we hypothesize that ROS may play a critical role in PFOA-mediated cancer EMT and cell migration. This hypothesis will be tested by the Aim: To determine the role of ROS in PFOA-mediated EMT and cell migration in murine and human oral squamous cell cancer (OSCC) cell lines in vitro. Upon successfully completing this proposed study, the results will provide new insights that PFAS could be considered a possible metastatic factor in HNC. Findings from this supplement and parental projects will improve our understanding of the health effects of fluorinated environmental factors (fluoride and PFAS) on enamel malformation and head and neck cancer pathophysiology.