Craniofacial and dental toxicity of dioxins: developmental phenotypes and mechanistic insights.

Background: Dioxins are persistent environmental pollutants with high lipophilicity and long half-lives, enabling their accumulation in biological tissues and ecosystems. Among them, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and extensively studied chemical. Human exposure occurs primarily through contaminated food, cigarette smoke, and industrial emissions, posing significant health risks. Objective: This review summarizes the effects of dioxins, particularly TCDD, on craniofacial and dental development and discusses recent findings on the mechanisms underlying these effects. Methods: A narrative review of experimental studies in animal models, Results: In the developing palate, TCDD impairs mesenchymal proliferation, shelf elevation, and fusion, resulting in cleft palate involving various mechanisms such as oxidative stress, apoptosis, epigenetic changes, and suppression of TGF-β and Wnt signaling. Craniofacial bone development is also affected, with reduced ossification, altered mineralization, and impaired osteoblast differentiation. These outcomes are largely mediated by aberrant aryl hydrocarbon receptor (AhR) activation. However, other pathways, such as retinoic acid and vitamin D signaling, have also been found to have roles in these outcomes. Furthermore, genetic background modulates susceptibility, as shown by strain-specific differences and the protective role of AhR repressors. TCDD disrupts odontogenesis in a stage- and dose-dependent manner, leading to enamel hypoplasia, molar agenesis, dentin defects, and increased caries susceptibility. Conclusion: Dioxins, particularly TCDD, are potent developmental toxicants affecting multiple craniofacial tissues. Their effects are driven by dysregulation of several critical signaling pathways, with AhR acting as the central mediator. Given their long half-life and bioaccumulation, dioxins remain a relevant public health threat.