title: Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms.
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-/-) retained approximately 60-70% of their Vitamin A content compared to controls at 28 days. RAR and RXR knockout mice responded similarly to wildtype mice with respect to TCDD-induced retinoid disruption, with the exception of RXRbeta-/- mice which showed no decrease in hepatic Vitamin A concentration, suggesting that the role of RXRbeta in TCDD-induced retinoid disruption should be further investigated. Overall, the abnormal retinoid profile in the triple knockout mice (CI/CAI/CAII-/-), but not double knockout (CAI/CAII-/-) mice, suggests that a loss of CRBP I may account for the difference in retinoid profile in CI/CAI/CAII-/- mice, and is likely to result in an increased susceptibility to hepatic retinoid depletion following dioxin exposure.
authors.affiliation: Karolinska Institutet, Institute of Environmental Medicine, S-17177 Stockholm, Sweden.
authors.forename: Pi
authors.initials: P
authors.lastname: Hoegberg
authors.forename: Carsten K
authors.initials: CK
authors.lastname: Schmidt
authors.forename: Nick
authors.initials: N
authors.lastname: Fletcher
authors.forename: Charlotte B
authors.initials: CB
authors.lastname: Nilsson
authors.forename: Christina
authors.initials: C
authors.lastname: Trossvik
authors.forename: A
authors.initials: A
authors.lastname: Gerlienke Schuur
authors.forename: Abraham
authors.initials: A
authors.lastname: Brouwer
authors.forename: Heinz
authors.initials: H
authors.lastname: Nau
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D012176:Retinoids / Q000032:analysis / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D054840:Retinol-Binding Proteins, Cellular; D013045:Species Specificity; D013997:Time Factors; D014212:Tretinoin / Q000032:analysis / Q000378:metabolism
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin