Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic storage of retinol in rats with different dietary supplies of vitamin A (retinol)

Thunberg, Tuula; Ahlborg, Ulf G.; Håkansson, Helen; Krantz, Cilla; Monier, Mats

doi:10.1007/bf00293808

Cited by 75 publications

(10 citation statements)

References 41 publications

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“…Furthermore, few studies of TCDD hepatotoxicity have utilized a model system in which robust HSC activation would be expected to occur, so it is possible that TCDD-induced alterations in this population of cells have been inadvertently overlooked. Reports in the literature do indicate that a single dose of TCDD suppresses vitamin A storage in the rat liver, which is consistent with HSC activation (Thunberg et al , 1980; Hakansson and Hanberg, 1989). However, TCDD was found to have no effect on expression of the HSC activation marker, αSMA.…”

Section: Discussionsupporting

confidence: 74%

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice

Lamb

Cholico

et al. 2016

Toxicology and Applied Pharmacology

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro. The goal of this study was to determine how TCDD impacts HSC activation in vivo using a mouse model of experimental liver fibrosis. To elicit fibrosis, C57BL6/ male mice were treated twice weekly for 8 weeks with 0.5 ml/kg carbon tetrachloride (CCl4). TCDD (20 μg/kg) or peanut oil (vehicle) was administered once a week during the last 2 weeks. Results indicate that TCDD increased liver-body-weight ratios, serum alanine aminotransferase activity, and hepatic necroinflammation in CCl4-treated mice. Likewise, TCDD treatment increased mRNA expression of HSC activation and fibrogenesis genes, namely α-smooth muscle actin, desmin, delta-like homologue-1, TGF-β1, and collagen type I. However, TCDD treatment did not exacerbate fibrosis, nor did it increase the collagen content of the liver. Instead, TCDD increased hepatic collagenase activity and increased expression of matrix metalloproteinase (MMP)-13 and the matrix regulatory proteins, TIMP-1 and PAI-1. These results support the conclusion that TCDD increases CCl4-induced liver damage and exacerbates HSC activation, yet collagen deposition and the development of fibrosis may be limited by TCDD-mediated changes in extracellular matrix remodeling.

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Section: Discussionsupporting

confidence: 74%

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice

Lamb

Cholico

et al. 2016

Toxicology and Applied Pharmacology

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“…There is substantial evidence that TCDD treatment reduces vitamin A storage in the rodent liver (Hakansson and Ahlborg 1985; Hanberg et al 1996; Hanberg et al 1998; Håkansson and Hanberg 1989; Thunberg et al 1980). Reports that TCDD treatment suppressed vitamin A accumulation in HSCs by 30% without affecting the vitamin A content of parenchymal hepatocytes (Hakansson & Hanberg 1989) and inhibited the storage of newly ingested vitamin A in the liver (Hakansson and Ahlborg 1985) led us to speculate that TCDD would similarly suppress vitamin A storage in LX-2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…One compelling line of evidence stems from studies in which TCDD was found to reduce vitamin A accumulation in the rodent liver (Hanberg et al 1998; Håkansson and Ahlborg 1985; Håkansson and Hanberg 1989; Thunberg et al 1980). Loss of vitamin A was attributed to increased mobilization and excretion of retinoids from the liver, which coincided with increased kidney and serum retinoid concentrations (Håkansson and Ahlborg 1985).…”

Section: Introductionmentioning

confidence: 99%

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation

Harvey

Jurgensen

et al. 2016

Toxicology

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic hydrocarbon that elicits toxicity through the aryl hydrocarbon receptor (AhR). In the liver, gross markers of TCDD toxicity are attributed to AhR activation in parenchymal hepatocytes. However, less is known regarding the consequences of TCDD treatment on non-parenchymal cells in the liver. Hepatic stellate cells (HSCs) are non-parenchymal cells that store vitamin A when quiescent. Upon liver injury, activated HSCs lose this storage ability and instead function in the development and maintenance of inflammation and fibrosis through the production of pro-inflammatory mediators and collagen type I. Reports that TCDD exposure disrupts hepatic retinoid homeostasis and dysregulates extracellular matrix remodeling in the liver led us to speculate that TCDD treatment may disrupt HSC activity. The human HSC line LX-2 was used to test the hypothesis that TCDD treatment directly activates HSCs. Results indicate that exposure to 10 nM TCDD almost completely inhibited lipid droplet storage in LX-2 cells cultured with retinol and palmitic acid. TCDD treatment also increased LX-2 cell proliferation, expression of α-smooth muscle actin, and production of monocyte chemoattractant protein-1 (MCP-1), all of which are characteristics of activated HSCs. However, TCDD treatment had no effect on Col1a1 mRNA levels in LX-2 cells stimulated with the potent profibrogenic mediator, transforming growth factor-β. The TCDD-mediated increase in LX-2 cell proliferation, but not MCP-1 production, was abolished when phosphoinositide 3-kinase was inhibited. These results indicate that HSCs are susceptible to direct modulation by TCDD and that TCDD likely increases HSC activation through a multifaceted mechanism.

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“…In the Canadian study, EROD‐activities returned to background levels after a 13 weeks recovery period on a clean diet (Chu et al 1984). It is known that induction of the hepatic UDP‐GT activity requires considerably higher doses of TCDD as compared to EROD induction (Thunberg et al 1980; Santostefano et al 1998). The absence of correlation between the CDD/F‐TEQ intake and hepatic UDP‐GT activity in the present study is consistent with these data.…”

mentioning

confidence: 99%

Subchronic Toxicity of Baltic Herring Oil and its Fractions in the Rat II: Clinical Observations and Toxicological Parameters

Stern

Öberg

Casabona

et al. 2002

Pharmacology & Toxicology

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This study aimed to increase the knowledge about the toxicity of fish-derived organohalogen pollutants in mammals. The strategy chosen was to separate organohalogen pollutants derived from Baltic herring (Clupea harengus) fillet, in order to obtain fractions with differing proportions of identified and unidentified halogenated pollutants, and to perform a subchronic toxicity study in rats, essentially according to the OECD guidelines, at three dose levels. Nordic Sea lodda (Mallotus villosus) oil, with low levels of persistent organohalogen pollutants, was used as an additional control diet. The toxicological examination showed that exposure to Baltic herring oil and its fractions at dose levels corresponding to a human intake in the range of 1.6 to 34.4 kg Baltic herring per week resulted in minimal effects. The spectrum of effects was similar to that, which is observed after low-level exposure to pollutants such as chlorinated dibenzo-p-dioxins and dibenzofurans (CDD/F) and chlorinated biphenyls, despite the fact that these contaminants contribute to a minor part of the extractable organically bound chlorine (EOCl). The study confirmed previous findings that induction of hepatic ethoxyresorufin deethylase (EROD) activity takes place at daily intake levels 0.15 ng fish-derived CDD/F-TEQs/kg body weight. The study also demonstrated that hepatic vitamin A reduction takes place at somewhat higher daily exposure levels, i.e. 0.16-0.30 ng fish-derived CDD/F-TEQs/kg body weight. Halogenated fatty acids, the major component of EOCl, could not be linked to any of the measured effects. From a risk management point of view, the study provides important new information of effect levels for Ah-receptor mediated responses following low level exposure to organohalogen compounds from a matrix relevant for human exposure.

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Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic storage of retinol in rats with different dietary supplies of vitamin A (retinol)

Cited by 75 publications

References 41 publications

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation

Subchronic Toxicity of Baltic Herring Oil and its Fractions in the Rat II: Clinical Observations and Toxicological Parameters

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