title: New insights to the role of aryl hydrocarbon receptor in bone phenotype and in dioxin-induced modulation of bone microarchitecture and material properties.
abstract: Bone is a target for high affinity aryl hydrocarbon receptor (AHR) ligands, such as dioxins. Although bone morphology, mineral density and strength are sensitive endpoints of dioxin toxicity, less is known about effects on bone microarchitecture and material properties. This study characterizes TCDD-induced modulations of bone tissue, and the role of AHR in dioxin-induced bone toxicity and for normal bone phenotype. Six AHR-knockout (Ahr(-/-)) and wild-type (Ahr(+/+)) mice of both genders were exposed to TCDD weekly for 10 weeks, at a total dose of 200μg/kgbw. Bones were examined with micro-computed tomography, nanoindentation and biomechanical testing. Serum levels of bone remodeling markers were analyzed, and the expression of genes related to osteogenic differentiation was profiled using PCR array. In Ahr(+/+) mice, TCDD-exposure resulted in harder bone matrix, thinner and more porous cortical bone, and a more compact trabecular bone compartment. Bone remodeling markers and altered expression of a number of osteogenesis related genes indicated imbalanced bone remodeling. Untreated Ahr(-/-) mice displayed a slightly modified bone phenotype as compared with untreated Ahr(+/+) mice, while TCDD exposure caused only a few changes in bones of Ahr(-/-) mice. Part of the effects of both TCDD-exposure and AHR-deficiency were gender dependent. In conclusion, exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones and most notably, increased trabecular bone volume fraction in Ahr(+/+) mice. AHR is involved in bone development of a normal bone phenotype, and is crucial for manifestation of TCDD-induced bone alterations.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: maria.herlin@ki.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Herlin
authors.forename: Mikko A J
authors.initials: MA
authors.lastname: Finnilä
authors.forename: Peter
authors.initials: P
authors.lastname: Zioupos
authors.forename: Antti
authors.initials: A
authors.lastname: Aula
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Miettinen
authors.forename: Timo
authors.initials: T
authors.lastname: Jämsä
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.forename: Merja
authors.initials: M
authors.lastname: Korkalainen
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
authors.forename: Matti
authors.initials: M
authors.lastname: Viluksela
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D024042:Collagen Type I / Q000097:blood; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011347:Procollagen / Q000097:blood; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein / Q000235:genetics / Q000378:metabolism
chemical_list: C556357:Ahsg protein, mouse; D015415:Biomarkers; C570620:Col10a1 protein, mouse; C447413:Col2a1 protein, mouse; D024042:Collagen Type I; D024043:Collagen Type II; D024121:Collagen Type X; D009687:Nuclear Proteins; D010446:Peptide Fragments; D000072317:Polychlorinated Dibenzodioxins; D011347:Procollagen; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; C412229:Tfip11 protein, mouse; D042561:Vascular Endothelial Growth Factor B; D033921:Vesicular Transport Proteins; D060749:alpha-2-HS-Glycoprotein; C047202:procollagen Type I N-terminal peptide; C467482:vascular endothelial growth factor B, mouse
keywords: Aryl hydrocarbon receptor; Bone microstructure; Bone strength; Micro-computed tomography; Nanoindentation; Tissue quality