3,3′,4,4′-Tetrabromobiphenyl sensitizes rats to the hepatotoxic effects of endotoxin by a mechanism that involves more than tumor necrosis factor

Shedlofsky, Steve

doi:10.1016/0270-9139(91)90150-t

Cited by 2 publications

(1 citation statement)

References 12 publications

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“…We have also observed this effect in the rat as well. ,− Other groups have seen similar trends with PCB related compounds both in cells − and in animals. − Decrease in EROD activity seen with higher doses of PCB126 maybe the result of inhibition or inactivation of CYP1A1 by PCB126. Several papers have been published showing this trend in both marine animals and vertebrates. − …”

Section: Discussionsupporting

confidence: 73%

Does Dietary Copper Supplementation Enhance or Diminish PCB126 Toxicity in the Rodent Liver?

Lai

Klaren

et al. 2013

Chem. Res. Toxicol.

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Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 μmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats the hallmark signs of AhR activation were present, including increased cytochrome P-450 and lipid levels, and decreased glutathione. In addition a doubling of hepatic copper levels was seen and overall metals homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD) or increased (tyrosinase, metallothionein 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e. oxidative stress and steatosis, is clearly associated with disturbed metals homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other AhR agonists.

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Section: Discussionsupporting

confidence: 73%

Does Dietary Copper Supplementation Enhance or Diminish PCB126 Toxicity in the Rodent Liver?

Lai

Klaren

et al. 2013

Chem. Res. Toxicol.

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Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

Brown

Schultze

Holdan

et al. 1996

Environ Health Perspect

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After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.ImagesFigure 1.Figure 2. AFigure 2. BFigure 3.Figure 4. AFigure 4. BFigure 5.Figure 6.

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3,3′,4,4′-Tetrabromobiphenyl sensitizes rats to the hepatotoxic effects of endotoxin by a mechanism that involves more than tumor necrosis factor

Cited by 2 publications

References 12 publications

Does Dietary Copper Supplementation Enhance or Diminish PCB126 Toxicity in the Rodent Liver?

Does Dietary Copper Supplementation Enhance or Diminish PCB126 Toxicity in the Rodent Liver?

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

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