Maria Herlin, Helen Hǻkansson, Bertrand Joseph (Institute of Environmental Medicine, Karolinska Institutet, Stockholm), Ismael Sánchez-Pérez, Javier Esteban (Instituto de Bioingeniería, Universidad Miguel Hernández de Elche), Merja K. Korkalainen, Matti Viluksela (Environmental Health Unit, Finnish Institute for Health and Welfare (THL), Kuopio, Finland), Xavier Barber (University Miguel Hernández of Elche), Mikko Arttu Jalmari Finnilä (Research Unit of Medical Imaging, Physics, and Technology, Faculty of Medicine, University of Oulu) and Gerd Hamscher (Institute of Food Chemistry and Food Biotechnology, Justus Liebig University Giessen)
Abstract: Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.