{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T05:56:52Z","timestamp":1763359012867,"version":"3.41.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>Smoking and particulate matter 2.5 (PM2.5) expose millions to cadmium (Cd), a toxic heavy metal linked to pro-inflammatory responses, oxidative stress, and disease pathogenesis. In the oral cavity, chronic Cd exposure contributes to the progression of periodontal diseases and oral cancers. However, the direct effect of Cd on oral tissues and the underlying mechanisms remains unclear. This study explored the impact of environmentally relevant concentrations of Cd on human gingival fibroblasts (HGFs) by evaluating cell viability, pro-inflammatory cytokine secretion (IL-6 and IL-8), COX-2 expression, and the activation of key signaling pathways: Akt, ERK1\/2, and JNK. Cd exposure significantly reduced HGF viability, elevated IL-6 and IL-8 secretion, and upregulated COX-2 expression. These effects were attenuated by inhibitors targeting Akt, ERK1\/2, and JNK pathways. By integrating cytokine profiling, COX-2 expression, and inhibitor-based pathway analysis, our study provides mechanistic insights into how low-level Cd exposure triggers early inflammatory responses in gingival fibroblasts. Our findings reveal that Cd exerts pro-inflammatory and cytotoxic effects on HGFs, which may play a role as one of the factors in the pathogenesis of smoking-related oral diseases. Targeting Akt, ERK1\/2, and JNK signaling pathways could offer therapeutic strategies to attenuate Cd-induced oral pro-inflammatory responses and tissue damage.<\/jats:p>","DOI":"10.3389\/ftox.2025.1583865","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T05:36:00Z","timestamp":1753248960000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cadmium decreases human gingival fibroblast viability and induces pro-inflammatory response associated with Akt and MAPK pathway activation"],"prefix":"10.3389","volume":"7","author":[{"given":"Tipparat","family":"Parakaw","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sirada","family":"Srihirun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathawut","family":"Sibmooh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nisarat","family":"Ruangsawasdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phisit","family":"Khemawoot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pornpun","family":"Vivithanaporn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,23]]},"reference":[{"key":"B1","article-title":"Salivary cadmium levels associated with smoking","volume-title":"IADR\/PER disease mechanisms - molecular genetics and oral manifestations","author":"Bertuzzo","year":"2003"},{"key":"B39","first-page":"798","article-title":"The endocrine disruptor cadmium modulates the androgen-estrogen receptors ratio and induces inflammatory cytokines in luminal (A) cell models of breast cancer","volume-title":"Endocrine","author":"Bimonte","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","first-page":"128346","DOI":"10.1016\/j.chemosphere.2020.128346","article-title":"Cadmium induced BEAS-2B cells apoptosis and mitochondria damage via MAPK signaling pathway","volume":"263","author":"Cao","year":"2021","journal-title":"Chemosphere"},{"key":"B3","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s10534-009-9268-6","article-title":"Cadmium effects on p38\/MAPK isoforms in MDA-MB231 breast cancer cells","volume":"23","author":"Casano","year":"2010","journal-title":"Biometals"},{"key":"B4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41389-020-0202-7","article-title":"Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells","volume":"9","author":"Chandrasekaran","year":"2020","journal-title":"Oncogenesis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"126704","DOI":"10.1016\/j.jhazmat.2021.126704","article-title":"Cadmium exposure triggers oxidative stress, necroptosis, Th1\/Th2 imbalance and promotes inflammation through the TNF-\u03b1\/NF-\u03baB pathway in swine small intestine","volume":"421","author":"Chen","year":"2022","journal-title":"J. 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