Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A storage in rat hepatic stellate cells

The polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), popularlycalled dioxins, are persistent pollutants with widespread occurrence in the environment aswell as in human food and tissues. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the mosttoxic dioxin, as well as other dioxin-like compounds induce a broad spectrum ofbiochemical and toxic effects, many of which occur at extremely low doses orconcentrations. Thus, there is a great need for an appropriate human health riskassessment However, due to several uncertainties, such as species differences in sensitiviyand the great number of dioxin-like compounds, it is urgent that the mechanisms behindthe toxic effects which are critical for human low-dose exposure are elucidated, i.e., effectson reproduction, fetal development, immune function, and tumour development. Theessential nutrient vitamin A, which acts as a hormone, is needed for proper reproduction,development, immune function, and can also affect tumour development. In addition,TCDD and other dioxin-like compounds interfere with the vitamin A homeostasis. Theinterference of dioxin-like compounds with vitamin A homeostasis may thus explain partof their toxicity. An apparent effect of TCDD on vitamin A is a long-lasting inhibition ofhepatic retinoid accumulation. The liver constitutes the major storage site for vitarnin Ain the body, but it also plays a central role in regulating retinoid homeostasis. The specificaim of the present study was to investigate possible mechanisms behind the inhibitoryeffect of TCDD on hepatic vitamin A accumulation in the rat. The results of the present study show that the TCDD-induced inhibition of vitamin Aaccumulation primarily occurs in the hepatic stellate cells which constitute the majorstorage site for vitamin A. A slow elimination of TCDD from hepatic cells is in accordancewith the long-lasting inhibition of TCDD on the hepatic vitamin A accumulation. Theimpaired ability of stellate cells to accumulate vitamin A was neither caused by an effectof TCDD on the number of stellate cells nor was their phenotype altered by TCDD. In thestellate ce s, TCDD nearly completely abolished the activity of LRAT, the enzyme whichcatalyses the esterification of retinol to retinyl esters for storage. The decreased LRATactivity correlates well with the reduced accumulation of vitamin A (particularly retinylesters) in these cells as well as in the liver as a whole. In the kidney, TCDD increased theLRAT activity, which can explain the increased renal retinyl ester levels. TCDD slightlydecreased the intestinal uptake of retinol into Iymph, particularly during the initial phaseof absorption. This decrease could also be explained by a corresponding decrease in theLRAT activity in the intestinal mucosa of TCDD-treated rats. In conclusion, the decreased LRAT activity in stellate cells is most probably a majorcontributing factor to the TCDD-induced inhibition of hepatic vitamin A accumulation.The lower uptake of vitamin A in the intestine of TCDD-treated rats, which also involvesa slightly depressed LRAT activity, may also contribute to the decreased hepatic vitaminA levels. Thus, a common feature for the effects of TCDD on vitamin A metabolismobserved in the present thesis is the tissue-specific altaation in the LRAT activity.Key words: Dioxin, TCDD, vitamin A, retinoids, lecithin:retinol acyltransferase,absorption, stellate celL hepatic vitamin A accumulation, intestinal lymph collectionDoctoral Thesis 1996 Annika HanbergISBN 91-628-1890-