TY - JOUR
T1 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin
T2 - Retinol acyltransferase transcription in the rat kidney
AU - Hoegberg, Pi
AU - Schmidt, Carsten K.
AU - Nau, Heinz
AU - Ross, A. Catharine
AU - Zolfaghari, Reza
AU - Fletcher, Nicholas
AU - Trossvik, Christina
AU - Nilsson, Charlotte B.
AU - Håkansson, Helen
N1 - Funding Information:
The authors wish to thank Dr Deborah Grove, director of the Nucleic Acids Facility, Pennsylvania State University, for assistance with the real-time PCR analysis, and Natalia Stern and Sara Sundén for additional assistance. This study has been carried out with financial support from the Commission of the European Communities, specific RTD programme ‘FAIR-Agriculture and Fisheries’, FAIR-CT97-3220, ‘Retinoids (vitamin A) interaction with organohalogen food residues: mechanisms, biomarkers, and implication for developmental toxicity’. It does not necessarily reflect its views and in no way anticipates the Commission's future policy in this area. The work was also financially supported by the Foundation for Strategic Environmental Research (grant 98657); by funds from Karolinska Institutet and the Swedish Environmental Protection Agency, and by NIH grants DK-46869 and CA-90214.
PY - 2003/3/6
Y1 - 2003/3/6
N2 - Vitamin A (retinoids) has an essential role in development and throughout life of humans and animals. Consequently, effects of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on retinoid metabolism may be contributory to its toxicity. This study was performed to clarify the mechanism behind dioxin-induced retinyl ester formation in the rat kidney. In addition we investigated the possible role of CYP1A1 in dioxin-induced all-trans-retinoic acid (atRA) formation. Male Sprague-Dawley rats were exposed to a single oral dose of TCDD in a combined dose-response and time-course study, with doses ranging from 0.1 to 100 μg/kgbw and time points from 1 to 28 days. Levels of atRA and the expression of two potentially retinoic acid (RA)-controlled proteins critically involved in retinoid storage regulation, lecithin: retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP I), were analyzed in liver and kidney. The expression and activity of cytochrome P4501A1 (assayed as ethoxyresorufin-O-deethylase activity) was assessed to gain insight into its potential role in RA synthesis. There was a significant increase in LRAT mRNA expression in the kidney, whereas no such increase could be observed in the liver, despite significantly increased atRA levels in both tissues. This suggests a tissue-specific regulation of LRAT by TCDD that may be dependent on other factors than atRA. Neither CRBP I mRNA nor protein levels were altered by TCDD. The time-course relationship between CYP1A1 activity and atRA levels in liver and kidney does not exclude a role of CYP1A1 in TCDD-induced RA synthesis. The observed altered regulation of the retinoid-metabolizing enzyme LRAT, together with the low doses and short time required by TCDD to change tissue RA levels, suggest that enzymes involved in retinoid metabolism are specific and/or direct targets of TCDD.
AB - Vitamin A (retinoids) has an essential role in development and throughout life of humans and animals. Consequently, effects of the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on retinoid metabolism may be contributory to its toxicity. This study was performed to clarify the mechanism behind dioxin-induced retinyl ester formation in the rat kidney. In addition we investigated the possible role of CYP1A1 in dioxin-induced all-trans-retinoic acid (atRA) formation. Male Sprague-Dawley rats were exposed to a single oral dose of TCDD in a combined dose-response and time-course study, with doses ranging from 0.1 to 100 μg/kgbw and time points from 1 to 28 days. Levels of atRA and the expression of two potentially retinoic acid (RA)-controlled proteins critically involved in retinoid storage regulation, lecithin: retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP I), were analyzed in liver and kidney. The expression and activity of cytochrome P4501A1 (assayed as ethoxyresorufin-O-deethylase activity) was assessed to gain insight into its potential role in RA synthesis. There was a significant increase in LRAT mRNA expression in the kidney, whereas no such increase could be observed in the liver, despite significantly increased atRA levels in both tissues. This suggests a tissue-specific regulation of LRAT by TCDD that may be dependent on other factors than atRA. Neither CRBP I mRNA nor protein levels were altered by TCDD. The time-course relationship between CYP1A1 activity and atRA levels in liver and kidney does not exclude a role of CYP1A1 in TCDD-induced RA synthesis. The observed altered regulation of the retinoid-metabolizing enzyme LRAT, together with the low doses and short time required by TCDD to change tissue RA levels, suggest that enzymes involved in retinoid metabolism are specific and/or direct targets of TCDD.
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U2 - 10.1016/S0009-2797(02)00157-6
DO - 10.1016/S0009-2797(02)00157-6
M3 - Article
C2 - 12606150
AN - SCOPUS:0344643040
SN - 0009-2797
VL - 145
SP - 1
EP - 16
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1
ER -