Demonstration of in-situ apoptosis in mouse liver and kidney after short-term repeated exposure to fumonisin B1

Sharma, Raghubir P.; Dugyala, Raviprakash R.; Voss, Kenneth A.

doi:10.1016/s0021-9975(97)80084-9

Cited by 71 publications

(45 citation statements)

References 30 publications

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“…Fumonisin B 1 can cause fatty changes and disruption of sphingolipid metabolism in the liver. 11,39 We found more developed SER in hepatocytes from the treatment group than the control group. It is known that the SER has significant functions in lipid metabolism and detoxification processes; 34 under toxic conditions, therefore, excessive development of the SER is expected.…”

Section: Discussionmentioning

confidence: 68%

Microscopic Pathology of the Liver in Rats Fed a Fusarium Graminearum-Inoculated Diet

Özbek

2003

J Int Med Res

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Fusarium graminearum is a fungus frequently isolated from cereal grains. This study investigates the histopathological effects of dietary F. graminearum on rat liver. Treatment and control group rats were fed F. graminearum-inoculated and non-inoculated rice, respectively. After 14 days, all rats were sacrificed, and their livers analysed by electron and light microscopy. Electron microscopy of treatment group livers identified hepatocytes with well-developed smooth endoplasmic reticulum, swollen mitochondria, lipid accumulation, numerous vesicles containing electron-lucent materials and increased lysosomes. Many Kupffer's cells containing apoptotic bodies were also seen. Light microscopy identified hepatocytes from the treatment group with: cytoplasmic and nuclear pleomorphism; foci of necrosis; mononuclear cell infiltration; and presence of apoptotic bodies. These changes were absent in control rat livers indicating that dietary F. graminearum causes inflammation and parenchymal damage in the rat liver. This is the first histopathological study showing the association between F. graminearum and liver damage.

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Section: Discussionmentioning

confidence: 68%

Microscopic Pathology of the Liver in Rats Fed a Fusarium Graminearum-Inoculated Diet

Özbek

2003

J Int Med Res

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“…The relatively increased hepatotoxicity of fumonisin B 1 in Nos-KO was confirmed by microscopic evaluation of liver sections and the incidence of TUNELpositive nuclei in liver. The effects of fumonisin B 1 in murine liver included apoptotic hepatocytes and occasional mitotic figures scattered throughout the liver tissue with inflammatory changes characterized by anisocytosis and cytoplasmic vacuolation (Sharma et al, 1997;Voss et al, 1995); the effects were relatively prominent in the Nos-KO strain than the WT. Relative incidence of TUNEL-positive cells in liver of the two strains is illustrated in figure 4.…”

Section: Deletion Of Inos Increased Fumonisin B 1 Toxicity In Micementioning

confidence: 99%

“…The primary anti-PCNA antibodies (Sigma Chemical Co., St. Louis, MO) were incubated with tissue sections at 4°C overnight in a humid chamber, secondary antibodies applied and sections were stained with Vectorstain ABC kit (Vector Laboratories, Inc., Burlingame, CA, USA). The numbers of PCNA positive cells were counted under a microscope and normalized to the unit area as described (Sharma et al, 1997).…”

Section: Determination Of Apoptosis and Pcna Positive Cells In Livermentioning

confidence: 99%

“…Cells exposed to fumonisin B 1 in vitro and in vivo undergo a mixture of necrotic and apoptotic cell death (Tolleson et al, 1996). We have previously demonstrated increased apoptosis in liver and kidney of mice after a short-term treatment with fumonisin B 1 (Sharma et al, 1997); the hepatopathy and nephropathy were directly correlated with the accumulation of sphinganine in tissues .…”

Section: Introductionmentioning

confidence: 98%

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Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase

2007

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Fumonisin B 1 , a natural mycotoxin, is an inhibitor of ceramide synthase causing marked dysregulation of sphingolipid metabolism in cells. This mycotoxin causes accumulation of free sphingoid bases (sphingosine and dihydrosphingosine or sphinganine) and their metabolites, important messengers involved in signal transduction leading to either cell survival or death. Free sphingoid bases are known apoptotic molecules whereas their respective 1-phosphates are protective. We previously reported that fumonisin B 1 caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT). Fumonisin B 1 also increased inducible nitric oxide synthase (iNOS) expression. In the current study we employed mice strain with the targeted deletion of iNOS gene (Nos-KO) to evaluate the role of nitric oxide (NO) on fumonisin B 1 -induced hepatotoxicity. The Nos-KO mice exhibited increased hepatotoxicity after subacute fumonisin B 1 exposure compared to their wild type counterparts, the liver regeneration was lower in Nos-KO compared to that in the WT mice. Increased hepatotoxicity in Nos-KO was not related to the extent of free sphingoid base accumulation after fumonisin B 1 treatment; however, it was accompanied by a lack of fumonisin B 1 -induced SPHK induction. The fumonisin B 1 -induced SPT was unaffected by lack of iNOS gene. Deletion of iNOS gene did not prevent fumonisin B 1 -dependent induction of inflammatory cytokines, namely tumor necrosis factor α, interferon γ and interleukin-12. The lack of fumonisin B 1 -induced SPHK induction in Nos-KO was supported by a similar effect on phosphorylated metabolites of sphingoid bases; the equilibrium between sphingoid bases and their phosphates is maintained by SPHK. We therefore conclude that iNOS induction produced by fumonisin B 1 modulates SPHK activity; the lack of iNOS prevents generation of sphingosine 1-phosphate and deprives cells from its protective effects.

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“…Liver and kidney are also targets in mice (74,84,85 (84). They found terminal deoxynucleotidyl transferase-mediated nickend labeling (TUNEL)-positive cells in the renal tubules of males (females were not examined) given subcutaneous injections of FB 1 for 5 consecutive days ( Figure 5).…”

Section: Hepatic and Renal Toxicity In Other Laboratory Speciesmentioning

confidence: 99%

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

Voss

Riley

Norred

et al. 2001

Environ Health Perspect

121

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Fumonisins are produced by Fusarium moniliforme F. verticillioides) and other Fusarium that grow on corn worldwide. They cause fatal toxicoses of horses and swine. Their effects in humans are unclear, but epidemiologic evidence suggests that consumption of fumonisin-contaminated corn contributes to human esophageal cancer in southern Africa and China. Much has been learned from rodent studies about fumonisin B1(FB1), the most common homologue. FB1 is poorly absorbed and rapidly eliminated in feces. Minor amounts are retained in liver and kidneys. Unlike other mycotoxins, fumonisins cause the same liver cancer promotion and subchronic (studies (3/4) 90 days) liver and kidney effects as (italic)F. moniliforme. FB 1 induces apoptosis of hepatocytes and of proximal tubule epithelial cells. More advanced lesions in both organs are characterized by simultaneous cell loss (apoptosis and necrosis) and proliferation (mitosis). Microscopic and other findings suggest that an imbalance between cell loss and replacement develops, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide synthase, and disrupt sphingolipid metabolism and, theoretically, sphingolipid-mediated regulatory processes that influence apoptosis and mitosis. Liver sphingolipid effects and toxicity are correlated, and ceramide synthase inhibition occurs in liver and kidney at doses below their respective no-observed-effect levels. FB1 does not cross the placenta and is not teratogenic in vivoin rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses. These data have contributed to preliminary risk evaluation and to protocol development for carcinogenicity and chronic toxicity studies of FB1 in rats and mice.

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Demonstration of in-situ apoptosis in mouse liver and kidney after short-term repeated exposure to fumonisin B1

Cited by 71 publications

References 30 publications

Microscopic Pathology of the Liver in Rats Fed a Fusarium Graminearum-Inoculated Diet

Microscopic Pathology of the Liver in Rats Fed a Fusarium Graminearum-Inoculated Diet

Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

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