ToxSci Advance Access published online on April 27, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi183
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1 Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-171 77 Stockholm, Sweden
* To whom correspondence should be addressed. This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumour promotion exposure protocol as previously described (Viluksela et al., 2000). Female rats (10/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (5/group) were identically maintained. After 20 weeks, the rats were killed and apolar retinoid levels determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and non-hepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D3) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dosedependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D3 was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-2 oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.
Received October 29, 2004
Accepted March 29, 2005
Endocrine Toxicology
Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment
2 Department of Food Toxicology, School of Veterinary Medicine, Hannover, D-30173 Hannover, Germany
3 National Public Health Institute, Department of Environmental Health, Kuopio, Finland
Helen Håkansson, E-mail: helen.hakansson{at}imm.ki.se
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