Studies on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A homeostasis

University dissertation from Stockholm : Karolinska Institutet, Institute of Enviromental Medicine

Abstract: Vitamin A (retinoids) is needed for normal vision, growth, reproduction, cell differentiation, embryonic development, and immune function. Retinoids exert their functions in the same way as classical hormones, as transcription factors acting via nuclear receptors. In addition, retinoids have been shown to have a key role in several other endocrine systems. It is therefore not surprising that tissue homeostasis of retinoids is well regulated. Dioxins are widespread, highly toxic, environmental pollutants. Their resistance to chemical and biological degradation, together with their lipophilicity, cause dioxins to be accumulated in the food chain. Humans are exposed to these substances mainly via food such as fatty fish, meat, and milk products. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin congener and also the most studied. The fact that dioxins disturb retinoid homeostasis has been known for quite some time. The aim of this thesis was to clarify the mechanisms behind the effects of TCDD on vitamin A homeostasis in rats, and to establish which effect of TCDD on vitamin A homeostasis is the critical one, resulting in the altered tissue levels of vitamin A and possibly also other effects. The results indicate that TCDD has minor effects on the intestinal absorption and processing of orally administered retinol, and on the hepatic uptake and processing of dietary vitamin A. The lower levels of hepatic retinyl esters in TCDD-treated rats may be due to a combination of increased mobilization of hepatic stores of vitamin A, and a severely decreased LRAT activity in the hepatic stellate cells. The increased mobilization is predicted to be an early as well as a major effect of TCDD, and it occurs even though TCDD does not increase the activity of three investigated hepatic retinyl ester hydrolases. TCDD causes increased protein levels of RBP in the liver, possibly by another mechanism than impaired release of RBP into circulation. The increased renal LRAT activity in TCDD-treated rats may be the cause of the observed increased renal levels of retinyl esters. It is possible that TCDD increases LRAT activity via a retinoic acid receptor-dependent mechanism. The increased retinoic acid levels in serum in TCDD-treated rats indicate the ability of TCDD to affect the homeostasis of this important signaling retinoid. An interference of TCDD with the retinoic acid signaling pathway may have many implications for basic cellular processes, resulting from changed expression of retinoid-responsive genes. Such an effect would be compatible with the hypothesis that at least some of the toxicity of TCDD is due to a perturbation of vitamin A metabolism.

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