Search

Author(s): Marshall, Adrienne; Kocher, Susan; Kerr, Amber; Stine, Peter | Abstract: Forests are shaped by the climates in which they grow. Climate has always changed over time, but many of the changes we now observe have not occurred in recent decades or even thousands of years. This faster rate of change can impact forest health in many ways. As a forest landowner, there are decisions you can make now about how you manage your land that will help you protect your forest against the likely effects of a changing climate. This publication can help you better understand the evolving science of climate change, the possible effects these changes will have on forests, and the actions you can take to better adapt your forests to the climate of the future.

Acetaminophen (APAP) overdose is the most frequent cause of adult acute liver failure. Susceptibility or resistance to APAP toxicity is most likely accounted for by the interplay of several factors. One factor important in multiple different chronic liver diseases that may play a role in APAP toxicity is elevated hepatic iron. Hereditary hemochromatosis is traditionally associated with hepatic iron overload. However, varying degrees of elevated hepatic iron stores observed in chronic hepatitis C and B, alcoholic liver disease and nonalcoholic fatty liver disease also have clinical relevance. We employed an animal model in which mice are fed a 3,5,5-trimethyl-hexanoyl-ferrocene (TMHF)-supplemented diet to evaluate the effect of elevated hepatic iron on APAP hepatotoxicity. Three hundred milligrams per kilogram APAP was chosen because this dosage induces hepatotoxicity but is not lethal. Since both excess iron and APAP induce oxidative stress and mitochondrial dysfunction, we hypothesized that the TMHF diet would enhance APAP hepatotoxicity. The results were the opposite. Centrilobular vacuolation/necrosis, APAP adducts, nitrotyrosine adducts, and a spike in serum alanine aminotransferase, which were observed in control mice treated with APAP, were not observed in TMHF-fed mice treated with APAP. Further analysis showed that the levels of CYP2E1 and CYP1A2 were not significantly different in TMHF-treated compared with control mice. However, the magnitude of depletion of glutathione following APAP treatment was considerably less in TMHF-treated mice than in mice fed a control diet. We conclude that a TMHF diet protects mice from moderate transient APAP-induced hepatotoxicity prior to the formation of APAP adducts, and one contributing mechanism is reduction in glutathione depletion.

Hepatocellular carcinoma (HCC), one of the most common causes of cancer death, is on the rise in the United States. HCC is a slow process occurring in the setting of liver cell injury that can be induced by oxidative stress leading to DNA damage and resulting in mutations that accumulate with time. Although many risk factors for HCC are known, the molecular pathogenesis of HCC is not well understood. In many chronic liver diseases that culminate in HCC, including hereditary hemochromatosis and chronic hepatitis C, excess iron deposition is observed. However, little is known about the effects of iron overload in the liver on cellular pathways. We generated a mouse model of chronic hepatic iron overload of liver by supplementing the diet with the iron donor 3,5,5-trimethyl-hexanoyl ferrocene (TMHF). Histological examination of livers from mice fed a TMHF diet for as long as 9 weeks showed no signs of inflammation or necrosis. Hepatocytes underwent expected physiological responses to iron in that ferritin levels were increased and hemosiderin accumulated with time. TMHF treated mice developed hepatomegaly and had elevated hepatic cyclin D1 and PCNA expression. TMHF treatment also resulted in a time-dependent decrease in hepatic levels of the antioxidant protein glutathione peroxidase 1 (GPX-1) but had no effect on Cu/Zn superoxide dismutase (SOD) or Mn-SOD. TMHF treatment also led to activation of β-catenin, induction of matrilysin (MMP7), and increased levels of cyp2b10. In this study, we tested the ability of selenium to specifically restore molecular and cellular changes induced by chronic hepatic iron overload. Mice were fed a diet supplemented with or without TMHF in the presence or absence of selenium for periods of time ranging from one to nine weeks. Selenium was provided as sodium selenite (15 ppm) or the synthetic organoselenium 1,4-phenylenebis (methylene) selenocyanate, p-XSC (15 ppm). Treatment of control mice, not fed TMHF, with selenium had no effect on the measured end points. As expected, supplementation with selenium in either form had no effect on TMHF induced ferritin expression or hemosiderin accumulation. However, dietary supplementation with selenium, simultaneously with TMHF treatment, markedly reduced TMHF mediated induction of cyclin D1 and PCNA expression and prevented iron mediated decrease in GPX-1 levels. Selenium had no effect on iron-induced hepatomegaly, activation of β-catenin, induction of MMP7, or increased cyp2b10. We conclude that (1) selenium restores the levels of the antioxidant defense enzyme GPX-1 and reduces iron induced stimulation of proliferation in a mouse model of hepatic iron overload; (2) the effects of selenium on these pathways occur by a mechanism other than simply reduction in hepatic iron levels; and (3) the effects of selenium are specific to some and not all iron-mediated changes in hepatic cellular signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1886.