University of Oulu

Maria Herlin, Ismael Sánchez-Pérez, Javier Esteban, Merja Korkalainen, Xavier Barber, Mikko A.J. Finnilä, Gerd Hamscher, Bertrand Joseph, Matti Viluksela, Helen Håkansson, Bone toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the retinoid system: A causality analysis anchored in osteoblast gene expression and mouse data, Reproductive Toxicology, Volume 105, 2021, Pages 25-43, ISSN 0890-6238,

Bone toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the retinoid system : a causality analysis anchored in osteoblast gene expression and mouse data

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Author: Herlin, Maria1; Sánchez-Pérez, Ismael2; Esteban, Javier2;
Organizations: 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
2Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain
3Environmental Health Unit, Finnish Institute for Health and Welfare (THL), Kuopio, Finland
4Centro de Investigación Operativa, Universidad Miguel Hernández, Elche, Alicante, Spain
5Research Unit of Medical Imaging, Physics, and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
6Institute of Food Chemistry and Food Biotechnology, Justus Liebig University Giessen, 10 Giessen, Germany
7School of Pharmacy (Toxicology) and Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.2 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2021-09-29


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.

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Series: Reproductive toxicology
ISSN: 0890-6238
ISSN-E: 1873-1708
ISSN-L: 0890-6238
Volume: 105
Pages: 25 - 43
DOI: 10.1016/j.reprotox.2021.07.013
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
1172 Environmental sciences
217 Medical engineering
3111 Biomedicine
Funding: The authors gratefully acknowledge financial support for the European Commission R&D project BoneTox (QLK4-CT-2002-02528) and for contractual work by the Nordic Chemical Group (2016-023, 2017-003). The authors are solely responsible for the contents of this paper, which does not necessarily represent the opinion of the European Community.
Copyright information: © 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (