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

Reprod Toxicol. 2021 Oct:105:25-43. doi: 10.1016/j.reprotox.2021.07.013. Epub 2021 Aug 4.


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.

Keywords: Adverse outcome pathway; Dioxin; Effect biomarkers; Endocrine disruption; Metabolism and endocrinology; Mode of action; Vitamin A; Weight of evidence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Cell Differentiation / drug effects
  • Cell Line
  • Environmental Pollutants / toxicity*
  • Female
  • Gene Expression / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism
  • Polychlorinated Dibenzodioxins / toxicity*
  • Receptors, Aryl Hydrocarbon / genetics
  • Tibia / drug effects*
  • Vitamin A / blood*


  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Vitamin A