Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis

Woolbright, Benjamin L.; Williams, C. David; Ni, Hong‐Min; Kumer, Sean C.; Schmitt, Timothy M.; Kane, Bartholomew J.; Jaeschke, Hartmut

doi:10.1016/j.toxicon.2016.11.254

Cited by 33 publications

(20 citation statements)

References 49 publications

(67 reference statements)

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“…Some previous studies have confirmed hepatotoxicity, neurotoxicity, gastrointestinal toxicity, and reproductive toxicity of MC-LR [29][30][31][32]. However, the study of nephrotoxicity induced by prolonged oral exposure to MC-LR is rare.…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Exposure to Microcystin-LR on Kidney in Mice

Huang

et al. 2019

IJERPH

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Microcystin-LR (MC-LR) is a potent hepatotoxin, but a few studies suggested that it might also induce nephrotoxicity. However, nephrotoxicity induced by prolonged oral exposure to MC-LR is unknown. The aim of this study was to evaluate the potential influence of MC-LR on the kidney in mice following chronic exposure to MC-LR. In this study, we evaluated the nephrotoxicity of MC-LR in mice drinking water at different concentrations (1, 30, 60, 90, and 120 µg/L) for 6 months for the first time. The results showed that the kidney weights and the kidney indexes of mice were not altered in the MC-LR treated mice, compared with the control group. In addition, the renal function indicators revealed that the serum creatinine (SCr) levels were not significant changes after exposure to MC-LR. The blood urea nitrogen (BUN) levels were markedly decreased after exposure to 90 and 120 µg/L MC-LR for 3 months. The BUN levels were lower than that of the control group after exposure to 120 µg/L MC-LR for 6 months. The histopathological investigation revealed enlarged renal corpuscles, widened of kidney tubules, and lymphocyte infiltration in the interstitial tissue and the renal pelvis after exposure to 60, 90, and 120 µg/L MC-LR. Consequently, our results suggested that long-term exposure to MC-LR might be one important risk of kidney injury, which will provide important clues for the prevention of renal impairment.

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Section: Discussionmentioning

confidence: 99%

Effects of Chronic Exposure to Microcystin-LR on Kidney in Mice

Huang

et al. 2019

IJERPH

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“…MC-LR can accumulate in several tissues such as the liver, brain, ovary, intestine, kidney, and muscle [ 6 , 7 , 8 , 9 , 10 ]. The liver is the most affected organ in humans, followed by the gonads [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Ameliorates Microcystin-LR-Induced Testis Germ Cell Apoptosis in Rats via SIRT1 Signaling Pathway Activation

Liu

Zhang

Liu

et al. 2018

Toxins

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Microcystin-leucine arginine (MC-LR), a cyclic heptapeptide produced by cyanobacteria, is a strong reproductive toxin. Studies performed in rat Sertoli cells and Chinese hamster ovary cells have demonstrated typical apoptosis after MC-LR exposure. However, little is known on how to protect against the reproductive toxicity induced by MC-LR. The present study aimed to explore the possible molecular mechanism underlying the anti-apoptosis and protective effects of resveratrol (RES) on the co-culture of Sertoli–germ cells and rat testes. The results demonstrated that MC-LR treatment inhibited the proliferation of Sertoli–germ cells and induced apoptosis. Furthermore, sirtuin 1 (SIRT1) and Bcl-2 were inhibited, while p53 and Ku70 acetylation, Bax expression, and cleaved caspase-3 were upregulated by MC-LR. However, RES pretreatment ameliorated MC-LR-induced apoptosis and SIRT1 inhibition, and downregulated the MC-LR-induced increase in p53 and Ku70 acetylation, Bax expression, and caspase-3 activation. In addition, RES reversed the MC-LR-mediated reduction in Ku70 binding to Bax. The present study indicated that the administration of RES could ameliorate MC-LR-induced Sertoli–germ cell apoptosis and protect against reproductive toxicity in rats by stimulating the SIRT1/p53 pathway, suppressing p53 and Ku70 acetylation and enhancing the binding of Ku70 to Bax.

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“…Based on previous literature [53], in the present study we selected the administration dose of DON of 1 and 3 mg/kg feed and fed piglets for 4 weeks. Herein, DON at 1 mg/kg elevated the ALT and GGT levels, suggesting that DON may destroy the liver cell membrane, leading toleakage of enzymes from injured hepatocytes [54,55]. However, compared with the 1 mg/kg DON group, DON at 3 mg/kg decreased serum levels of ALT, AST and LDH, especially AST and LDH, suggesting that 3 mg/kg DON may lead to massive necrosis of liver cells or acute hepatitis, basically resulting in depletion of transaminase in the liver tissue [56,57].…”

Section: Donmentioning

confidence: 99%

Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver

Liu

Zhu

et al. 2020

Preprint

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Background Deoxynivalenol (DON) is an inevitable contaminant in animal feed and human food and can lead to decreased appetite and growth retardation in children and piglets, which are often used as models for children. Hepatotoxicity induced by DON is closely related to growth inhibition. Although many molecular mechanisms are related to the liver damage caused by DON, few studies have been done on cytochrome P450 (CYP450s) and DNA methylation, and the role of DNA methylation in growth inhibition of piglets was also unclear. Results In the present study, piglets were randomly assigned to the following three different dietary treatments for 4 weeks: control diet, diet containing 1 mg DON/kg feed, and diet containing 3 mg DON/kg feed. Compared to the control group, elevated alanine aminotransferase activity and globulin level were observed in DON groups; however, aspartate aminotransferase activity was decreased in 3 mg/kg DON group. DON exposure increased the mRNA expression of CYP450s including CYP1A1, CYP1A2, CYP2B22, CYP2C33, CYP2D25, CYP2E1, CYP3A22 and CYP3A39, in which DNA methylation was involved in the regulation of the expression of these enzymes. By estimating the benchmark dose value of the metabolic enzymes, CYP1A1 was found to be the most sensitive metabolic enzyme to evaluate the clinical liver injury caused by DON. DON upregulated the expression of DNA methyltransferases (DNMT1 and DNMT3B) in a dose-dependent manner, thus increasing the level of 5-mC in the whole genome. Notably, DON downregulated the expression of nicotinamide n-methyltransferase, possibly reducing the weight of the piglets. Additionally, 1 mg/kg DON decreased the expression of galanin-like peptide (GALP), while 3 mg/kg DON significantly increased the level of GALP through DNA methylation, thus affecting the appetite of the piglets. DON can significantly reduce the methylation level of insulin-like growth factor 1 (IGF-1) promoter and thus increase its expression. Conclusions Taken together, increased CYP450 expression and DNA methylation are important mechanisms of liver injury and growth inhibition induced by DON, which provide future reference values determination of antagonistic toxicity.

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Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis

Cited by 33 publications

References 49 publications

Effects of Chronic Exposure to Microcystin-LR on Kidney in Mice

Effects of Chronic Exposure to Microcystin-LR on Kidney in Mice

Resveratrol Ameliorates Microcystin-LR-Induced Testis Germ Cell Apoptosis in Rats via SIRT1 Signaling Pathway Activation

Dietary exposure of deoxynivalenol affected cytochrome P450 and growth related-gene expression via DNA methylation in piglet liver

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