Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice.

Authors: Fader, Kelly A; Nault, Rance; Raehtz, Sandi; McCabe, Laura R; Zacharewski, Timothy R

Published In Toxicol Appl Pharmacol, (2018 Jun 01)

Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor (AhR) agonists have been shown to regulate bone development and remodeling in a species-, ligand-, and age-specific manner, however the underlying mechanisms remain poorly understood. In this study, we characterized the effect of 0.01-30 μg/kg TCDD on the femoral morphology of male and female juvenile mice orally gavaged every 4 days for 28 days and used RNA-Seq to investigate gene expression changes associated with the resultant phenotype. Micro-computed tomography revealed that TCDD dose-dependently increased trabecular bone volume fraction (BVF) 2.9- and 3.3-fold in male and female femurs, respectively. Decreased serum tartrate-resistant acid phosphatase (TRAP) levels, combined with a reduced osteoclast surface to bone surface ratio and repression of femoral proteases (cathepsin K, matrix metallopeptidase 13), suggests that TCDD impaired bone resorption. Increased osteoblast counts at the trabecular bone surface were consistent with a reciprocal reduction in the number of bone marrow adipocytes, suggesting AhR activation may direct mesenchymal stem cell differentiation towards osteoblasts rather than adipocytes. Notably, femoral expression of transmembrane glycoprotein NMB (Gpnmb; osteoactivin), a positive regulator of osteoblast differentiation and mineralization, was dose-dependently induced up to 18.8-fold by TCDD. Moreover, increased serum levels of 1,25-dihydroxyvitamin D3 were in accordance with the renal induction of 1α-hydroxylase Cyp27b1 and may contribute to impaired bone resorption. Collectively, the data suggest AhR activation tipped the bone remodeling balance towards bone formation, resulting in increased bone mass with reduced marrow adiposity.

PubMed ID: 29673856 Exiting the NIEHS site

MeSH Terms: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/biosynthesis; Adipocytes/drug effects; Adipocytes/metabolism; Adiposity/drug effects*; Age Factors; Animals; Basic Helix-Loop-Helix Transcription Factors/agonists; Basic Helix-Loop-Helix Transcription Factors/metabolism; Bone Marrow/drug effects*; Bone Marrow/metabolism; Bone Marrow/physiopathology; Bone Resorption/chemically induced; Bone Resorption/metabolism; Bone Resorption/physiopathology; Calcitriol/blood; Cancellous Bone/diagnostic imaging; Cancellous Bone/drug effects*; Cancellous Bone/metabolism; Cancellous Bone/physiopathology; Cathepsin K/metabolism; Dose-Response Relationship, Drug; Eye Proteins/metabolism; Female; Femur/diagnostic imaging; Femur/drug effects*; Femur/metabolism; Femur/physiopathology; Kidney/enzymology; Male; Matrix Metalloproteinase 13/metabolism; Membrane Glycoproteins/metabolism; Mice, Inbred C57BL; Osteoblasts/drug effects; Osteoblasts/metabolism; Osteoclasts/drug effects; Osteoclasts/metabolism; Osteogenesis/drug effects*; Polychlorinated Dibenzodioxins/toxicity*; Receptors, Aryl Hydrocarbon/agonists; Receptors, Aryl Hydrocarbon/metabolism; Tartrate-Resistant Acid Phosphatase/blood; Time Factors; X-Ray Microtomography

Back
to Top