Chemico-Biological Interactions 156 (2005) 25–39 Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms Pi Hoegberg a,1 , Carsten K. Schmidt a,2 , Nick Fletcher a,1 , Charlotte B. Nilsson a,3 , Christina Trossvik a , A. Gerlienke Schuur b , Abraham Brouwer c , Heinz Nau e , Norbert B. Ghyselinck d , Pierre Chambon d , Helen H˚ akansson a,∗ a Karolinska Institutet, Institute of Environmental Medicine, S-17177 Stockholm, Sweden b Centre for Substances and Risk Assessment, National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands c Institute of Environmental Studies, Free University Amsterdam, 1081 HV Amsterdam, The Netherlands d InstitutdeG´ en´ etique et Biologie Mol´ eculaire et Cellulaire (IGBMC) and Institut Clinique de la Souris (ICS), F-67404 Illkirch Cedex, France e School of Veterinary Medicine Hannover, D-30173 Hannover, Germany Received 3 January 2005; received in revised form 16 June 2005; accepted 27 June 2005 Available online 18 August 2005 Abstract We have investigated the role of Vitamin A (retinoid) proteins in hepatic retinoid processing under normal conditions and during chemical stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical known to interfere with retinoid turnover and metabolism. Three separate studies were performed in wildtype control mice and transgenic mice that lack one or more isoforms of retinoic acid receptors (RAR), retinoid X receptors (RXR), or intracellular retinoid-binding proteins (CRABP I, CRABP II, CRBP I). Body and organ weight development was monitored from 2 weeks of age to adult, and hepatic levels of retinyl esters, retinol, and retinoic acid were investigated. In addition, hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a recently discovered retinoid metabolite that has proven sensitive to both TCDD exposure and Vitamin A status, were also determined. Mice absent in the three proteins CRBP I, CRABP I, and CRABP II (CI/CAI/CAII -/- ) displayed significantly lower hepatic retinyl ester, retinol, and all-trans-retinoic acid levels compared to wildtype mice, whereas the liver concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid was considerably higher. After treatment with TCDD, hepatic total retinoids were almost entirely depleted in the CI/CAI/CAII -/- mice, whereas wildtype mice and mice lacking CRABP I, and CRABP II (CAI/CAII -/- ) ∗ Corresponding author. E-mail address: helen.hakansson@imm.ki.se (H. H˚ akansson). 1 Present address: Karolinska Institutet, Department of Biosciences at Novum, S-141 57 Huddinge, Sweden. 2 Present address: Safety Assessment, AstraZeneca R&D S ¨ odert¨ alje, 151 85 S ¨ odert¨ alje, Sweden. 3 Present address: Technologiezentrum Wasser Karlsruhe, Abteilung Analytik, Karlsruher Str. 84, 76139 Karlsruhe, Germany. 0009-2797/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2005.06.006