2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin: Retinol acyltransferase transcription in the rat kidney

Pi Hoegberg, Carsten K. Schmidt, Heinz Nau, A. Catharine Ross, Reza Zolfaghari, Nicholas Fletcher, Christina Trossvik, Charlotte B. Nilsson, Helen Håkansson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalChemico-Biological Interactions
Volume145
Issue number1
DOIs
StatePublished - Mar 6 2003

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Transcription
Tretinoin
Rats
Kidney
Retinoids
Cytochrome P-450 CYP1A1
Cellular Retinol-Binding Proteins
Liver
Dioxins
Tissue
Metabolism
lecithin-retinol acyltransferase
1,4-dioxin
Polychlorinated Dibenzodioxins
Environmental Pollutants
Messenger RNA
Time and motion study
Enzymes
Cytochromes
Vitamin A

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Hoegberg, Pi ; Schmidt, Carsten K. ; Nau, Heinz ; Ross, A. Catharine ; Zolfaghari, Reza ; Fletcher, Nicholas ; Trossvik, Christina ; Nilsson, Charlotte B. ; Håkansson, Helen. / 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin : Retinol acyltransferase transcription in the rat kidney. In: Chemico-Biological Interactions. 2003 ; Vol. 145, No. 1. pp. 1-16.
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abstract = "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.",
author = "Pi Hoegberg and Schmidt, {Carsten K.} and Heinz Nau and Ross, {A. Catharine} and Reza Zolfaghari and Nicholas Fletcher and Christina Trossvik and Nilsson, {Charlotte B.} and Helen H{\aa}kansson",
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Hoegberg, P, Schmidt, CK, Nau, H, Ross, AC, Zolfaghari, R, Fletcher, N, Trossvik, C, Nilsson, CB & Håkansson, H 2003, '2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin: Retinol acyltransferase transcription in the rat kidney', Chemico-Biological Interactions, vol. 145, no. 1, pp. 1-16. https://doi.org/10.1016/S0009-2797(02)00157-6

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces lecithin : Retinol acyltransferase transcription in the rat kidney. / Hoegberg, Pi; Schmidt, Carsten K.; Nau, Heinz; Ross, A. Catharine; Zolfaghari, Reza; Fletcher, Nicholas; Trossvik, Christina; Nilsson, Charlotte B.; Håkansson, Helen.

In: Chemico-Biological Interactions, Vol. 145, No. 1, 06.03.2003, p. 1-16.

Research output: Contribution to journalArticle

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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

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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