title: Effects of 2,3,7,8-tetrachloro-dibenzo-p-dioxin on the extracellular matrix of the thymus in juvenile marmosets (Callithrix jacchus).
abstract: 2,3,7,8-Tetrachloro-dibenzo-p-dioxin (TCDD) is an ubiquitously distributed xenobiotic. It has been postulated that the effects of TCDD on T-lymphocytes are mediated by modulation of the thymic microenvironment. There is growing evidence of a modified interplay between thymocytes and thymic epithelium related to changes in extracellular matrix (ECM) proteins. Eighteen male marmosets (Callithrix jacchus) were treated with single subcutaneous TCDD doses (1, 10, 100 ng/kg body weight) or vehicle and sacrificed 2 or 4 weeks thereafter. Thymus samples were stained with fluorescein isothiocyanate-conjugated antibodies for ECM proteins and examined immunohistochemically by semi-quantitative image analysis. Thymus samples of animals treated with 1 and 10 ng/kg were additionally analysed by Western blotting for ECM proteins, transforming growth factor-beta(1) (TGF-beta(1)) and integrin chain content (CD49a, CD49e, CD49f and CD29). Monkeys showed no overt signs of toxicity after TCDD treatment. Immunohistochemistry revealed an increase of ECM proteins at 100 ng/kg after 2 and 4 weeks. Western blotting confirmed immunohistochemistry showing a dose-dependent increase of several ECM proteins in animals treated with the lower TCDD doses of 1 and 10 ng/kg. Additionally, dose-dependent increases were observed in integrin chain and TGF-beta(1) contents. We demonstrated changes of thymic ECM in marmosets following low single TCDD doses. Combined with altered integrin expression and enhanced TGF-beta(1) stimulation our findings suggest a modified interplay between thymic epithelium and thymocytes. The extracellular matrix may play a more central role in mediating adverse effects of TCDD in organs than yet acknowledged.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité Campus Benjamin Franklin, Garystrasse 5, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Nottebrock
authors.forename: Kai
authors.initials: K
authors.lastname: Riecke
authors.forename: Matthias
authors.initials: M
authors.lastname: Kruse
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Ralf
authors.initials: R
authors.lastname: Stahlmann
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002144:Callithrix; D003094:Collagen / Q000378:metabolism; D003720:Densitometry; D004785:Environmental Pollutants / Q000633:toxicity*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
chemical_list: D004785:Environmental Pollutants; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D007797:Laminin; D000072317:Polychlorinated Dibenzodioxins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen