title: Transgenic mice with a constitutively active aryl hydrocarbon receptor display a gender-specific bone phenotype.
abstract: Bone tissue homeostasis is governed by hormones, growth factors, and cytokines and can be distorted by environmental pollutants, such as ligands to the aryl hydrocarbon receptor (AhR). A transgenic mouse expressing a constitutively active aryl hydrocarbon receptor (CA-AhR), mimicking continuous low-dose exposure to AhR ligands, was used to explore potential long-term effects of these ligands on bone. The density, content, and dimensions of cortical and trabecular bone, as well as physical properties, were significantly altered in female transgenic mice, while almost no alterations were detected in males. Osteoclast volume density and serum level of C-telopeptide of type I collagen (CTX), reflecting osteoclast activity, were both increased by approximately 60% in female CA-AhR mice, while serum tartrate-resistant acid phosphatase (TRAP) 5b, reflecting osteoclast numbers, was unchanged. Subsequently, the resorption index (CTX/TRAP 5b) was increased by 90%, indicating increased osteoclast activity in female CA-AhR. Moreover, the protein level of the osteoclast collagenase cathepsin K was increased by 40% in bone extracts of female CA-AhR mice. The messenger RNA expression of several osteoclast- and osteoblast-associated genes was altered in female transgenic mice but not in males. Notably, early markers for osteoclast and osteoblast differentiation were normal, while the expression of functional markers of osteoclasts and osteoblasts were reduced. In conclusion, a low continuous activation of the AhR leads to a skeletal phenotype with increased bone resorption associated with more ductile bones in females but not in males. The results indicate the presence of an interaction between the AhR and a female-specific mechanism implicated in inhibition of osteoclast development and function. Female bone tissue appears more susceptible to dioxins and other AhR ligands than male bone tissue.
authors.affiliation: Division of Environmental Health Risk Assessment, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden. carolina.wejheden@ki.se
authors.forename: Carolina
authors.initials: C
authors.lastname: Wejheden
authors.forename: Sara
authors.initials: S
authors.lastname: Brunnberg
authors.forename: Sune
authors.initials: S
authors.lastname: Larsson
authors.forename: P Monica
authors.initials: PM
authors.lastname: Lind
authors.forename: Pia M
authors.initials: PM
authors.lastname: Lind
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.forename: Annika
authors.initials: A
authors.lastname: Hanberg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D056657:Cathepsin K / Q000378:metabolism; D002452:Cell Count; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D010010:Osteoclasts / Q000378:metabolism; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors
chemical_list: D015415:Biomarkers; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D056657:Cathepsin K