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

Abstract

The polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), popularly called dioxins, are persistent pollutants with widespread occurrence in the environment as well as in human food and tissues. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, as well as other dioxin-like compounds induce a broad spectrum of biochemical and toxic effects, many of which occur at extremely low doses or concentrations. Thus, there is a great need for an appropriate human health risk assessment. However, due to several uncertainties, such as species differences in sensitivity and the great number of dioxin-like compounds, it is urgent that the mechanisms behind the toxic effects which are critical for human low-dose exposure are elucidated, i.e., effects on reproduction, fetal development, immune function, and tumour development. The essential 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. The interference of dioxin-like compounds with vitamin A homeostasis may thus explain part of their toxicity. An apparent effect of TCDD on vitamin A is a long-lasting inhibition of hepatic retinoid accumulation. The liver constitutes the major storage site for vitamin A in the body, but it also plays a central role in regulating retinoid homeostasis. The specific aim of the present study was to investigate possible mechanisms behind the inhibitory effect of TCDD on hepatic vitamin A accumulation in the rat.

The results of the present study show that the TCDD-induced inhibition of vitamin A accumulation primarily occurs in the hepatic stellate cells which constitute the major storage site for vitamin A. A slow elimination of TCDD from hepatic cells is in accordance with the long-lasting inhibition of TCDD on the hepatic vitamin A accumulation. The impaired ability of stellate cells to accumulate vitamin A was neither caused by an effect of TCDD on the number of stellate cells nor was their phenotype altered by TCDD. In the stellate ce s, TCDD nearly completely abolished the activity of LRAT, the enzyme which catalyses the esterification of retinol to retinyl esters for storage. The decreased LRAT activity correlates well with the reduced accumulation of vitamin A (particularly retinyl esters) in these cells as well as in the liver as a whole. In the kidney, TCDD increased the LRAT activity, which can explain the increased renal retinyl ester levels. TCDD slightly decreased the intestinal uptake of retinol into Iymph, particularly during the initial phase of absorption. This decrease could also be explained by a corresponding decrease in the LRAT activity in the intestinal mucosa of TCDD-treated rats.

In conclusion, the decreased LRAT activity in stellate cells is most probably a major contributing 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 involves a slightly depressed LRAT activity, may also contribute to the decreased hepatic vitamin A levels. Thus, a common feature for the effects of TCDD on vitamin A metabolism observed in the present thesis is the tissue-specific alteration in the LRAT activity.