Do structure‐activity relationships for the acute toxicity of pcbs and pbbs also apply for induction of hepatocellular carcinoma?

Robertson, Larry W.; Silberhorn, Eric M.; Glauert, Howard P.; Schwarz, Michael; Buchmann, Albrecht

doi:10.1002/etc.5620100603

Cited by 26 publications

(12 citation statements)

References 38 publications

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“…As seen in Figure 1, the development of mild hepatocyte vacuolation was observed as early as 36 hours and continued in severity at the later time points which agrees with previous studies (Robertson et al 1991). More pronounced vacuolation was seen at 3 days, which corresponds to increases seen in copper levels and ROS formation.…”

Section: Discussionsupporting

confidence: 92%

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

et al. 2015

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Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 umol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9 hr, 18 hr, 36 hr, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 hours with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein.

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Section: Discussionsupporting

confidence: 92%

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

et al. 2015

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“…PCBs are known for causing changes to gene expression, some of which have been linked to disruptions in lipid metabolism (Arzuaga et al , 2009). Steatosis is a prominent feature of PCB toxicity (Robertson et al , 1991). In our study as well, PCB 126-induced liver toxicity presented histologically as steatosis (Figures 5, 6A and Supplemental Figure 1) and the most promising of our findings was the reduction in lipid deposition in the livers of rats supplemented with NAC.…”

Section: Discussionmentioning

confidence: 99%

N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents

et al. 2012

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Potent aryl hydrocarbon receptor agonists like PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl) cause oxidative stress and liver pathology, including fatty liver. Our question was whether dietary supplementation with N-acetylcysteine (NAC), an antioxidant, can prevent these adverse changes. Male Sprague-Dawley rats were fed a standard AIN-93G diet (sufficient in cysteine) or a modified diet supplemented with 1.0% NAC. After one week, rats on each diet were exposed to 0, 1, or 5 μmol/kg body weight PCB 126 by ip injection (6 rats per group) and euthanized two weeks later. PCB-treatment caused a dose-dependent reduction in growth, feed consumption, relative thymus weight, total glutathione and glutathione disulfide (GSSG), while relative liver weight, glutathione transferase activity and hepatic lipid content were dose-dependently increased with PCB dose. Histologic examination of liver tissue showed PCB 126-induced hepatocellular steatosis with dose dependent increase in lipid deposition and distribution. Dietary NAC resulted in a reduction in hepatocellular lipid in both PCB groups. This effect was confirmed by gravimetric analysis of extracted lipids. Expression of CD36, a scavenger receptor involved in regulating hepatic fatty acid uptake, was reduced with high dose PCB treatment but unaltered in PCB-treated rats on NAC-supplemented diet. These results demonstrate that NAC has a protective effect against hepatic lipid accumulation in rats exposed to PCB 126. The mechanism of this protective effect appears to be independent of NAC as a source of cysteine/precursor of glutathione.

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“…Lipids appear to be removed from the plasma and accumulate in tissues in corn-oil–fed animals receiving PCB injection. A number of studies have reported an increase in liver and hepatic microsomal lipids (total lipids, phospholipids, neutral lipids, and cholesterol) after PCB administration (Asais-Braesco et al 1990; Garthoff et al 1977; Hinton et al 1978; Ishidate et al 1978; Robertson et al 1991). The amplified toxicity of linoleic acid and PCBs to endothelial cells could thus be mediated by cellular accumulation of this fatty acid and its subsequent transformation to toxic cytotoxic epoxide metabolites (Viswanathan et al 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Serum and aortic and liver tissues were obtained for analysis. According to our combined experience with several animal species, long-term intraperitoneal injections of 100–300 μmol/kg bw per injection are sufficient to initiate disease states, such as tumor promotion (Robertson et al 1991). In our preliminary studies, we saw adhesion molecule expression at 170 μmol/kg bw per injection; thus, this concentration was chosen for the present study.…”

Section: Methodsmentioning

confidence: 99%

Dietary Fat Interacts with PCBs to Induce Changes in Lipid Metabolism in Mice Deficient in Low-Density Lipoprotein Receptor

Hennig¹,

Reiterer²,

Toborek³

et al. 2005

Environ Health Perspect

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There is evidence that dietary fat can modify the cytotoxicity of polychlorinated biphenyls (PCBs) and that coplanar PCBs can induce inflammatory processes critical in the pathology of vascular diseases. To test the hypothesis that the interaction of PCBs with dietary fat is dependent on the type of fat, low-density lipoprotein receptor–deficient (LDL-R−/−) mice were fed diets enriched with either olive oil or corn oil for 4 weeks. Half of the animals from each group were injected with PCB-77. Vascular cell adhesion molecule-1 (VCAM-1) expression in aortic arches was non-detectable in the olive-oil–fed mice but was highly expressed in the presence of PCB-77. PCB treatment increased liver neutral lipids and decreased serum fatty acid levels only in mice fed the corn-oil–enriched diet. PCB treatment increased mRNA expression of genes involved in inflammation, apoptosis, and oxidative stress in all mice. Upon PCB treatment, mice in both olive- and corn-oil–diet groups showed induction of genes involved in fatty acid degradation but with up-regulation of different key enzymes. Genes involved in fatty acid synthesis were reduced only upon PCB treatment in corn-oil–fed mice, whereas lipid transport/export genes were altered in olive-oil–fed mice. These data suggest that dietary fat can modify changes in lipid metabolism induced by PCBs in serum and tissues. These findings have implications for understanding the interactions of nutrients with environmental contaminants on the pathology of inflammatory diseases such as atherosclerosis.

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Do structure‐activity relationships for the acute toxicity of pcbs and pbbs also apply for induction of hepatocellular carcinoma?

Cited by 26 publications

References 38 publications

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents

Dietary Fat Interacts with PCBs to Induce Changes in Lipid Metabolism in Mice Deficient in Low-Density Lipoprotein Receptor

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