Helsingin yliopisto


Helsingin yliopiston verkkojulkaisut

University of Helsinki, Helsinki 2006

Toxicity of dioxin to developing teeth and salivary glands

An experimental study

Anu Kiukkonen

Doctoral dissertation, June 2006.
University of Helsinki, Faculty of Medicine, Institute of Dentistry.

Dioxins are ubiquitous environmental poisons having unequivocal adverse health effects on various species. The majority of their effects are thought to be mediated by the aryl hydrocarbon receptor (AhR). Developing human teeth may be sensitive to dioxins and the most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is developmentally toxic to rodent teeth. Mechanisms of TCDD toxicity can be studied only experimentally.

The aim of the present thesis work was to delineate morphological end points of developmental toxicity of TCDD in rat and mouse teeth and salivary glands in vivo and in vitro and to characterize their cellular and molecular background.

Mouse embryonic teeth and submandibular gland explants were grown in organ culture without/with TCDD at various concentrations, examined stereomicroscopically and processed for histological examination. The effects of TCDD on cellular mechanisms essential for organogenesis were investigated. The expression of various genes eliciting the response to TCDD exposure or involved in tooth and salivary gland development was studied at the mRNA and/or protein levels by in situ hybridization and immunohistochemistry. Association of the dental effects of TCDD with the resistance of a rat strain to TCDD acute lethality was analyzed in two lactationally exposed rat strains. The effect of TCDD on rat molar tooth mineralization was studied in tissue sections.

TCDD dose- and developmental stage-dependently interfered with tooth formation. TCDD prevented early mouse molar tooth morphogenesis and altered cuspal morphology by enhancing programmend cell death, or apoptosis, in dental epithelial cells programmed to undergo apotosis. Cell proliferation was not affected. TCDD impaired mineralization of rat molar dental matrices, possibly by specifically reducing the expression of the mineralization-related dentin sialophosphoprotein gene shown in cultured mouse teeth. The impaired mineralization of rat teeth was accompanied by decreased expression of AhR and the TCDD-inducible xenobiotic-metabolozing enzyme P4501 A1 (CYP1A1), suggesting mediation of the TCDD effect by the AhR pathway. The severe interference by TCDD with rat incisor formation was independent of the genotypic variation of AhR determining the resistance of a rat strain to TCDD acute lethality. The impairment by TCDD of mouse submandibular gland branching morphogenesis was associated with CYP1A1 induction and involved blockage of EGF receptor signalling.

In conclusion, TCDD exposure is likely to have activated the AhR pathway in target organs with the consequent activation of other signalling pathways involving developmentally regulated genes. The resultant phenotype is organ specific and modified by epithelial-mesenchymal interactions and dependent on dose as well as the stage of organogenesis at the time of TCDD exposure. Teeth appear to be responsive to TCDD exposure throughout their development.

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Last updated 26.05.2006

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