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2017, Number 6

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Ann Hepatol 2017; 16 (6)

Long-Term, Low-Dose Exposure to Microcystin-LR Does not Cause or Increase the Severity of Liver Disease in Rodents

Labine M, Gong Y, Minuk GY

Language: English
References: 30
Page: 959-965
PDF size: 416.63 Kb.


ABSTRACT

Background. Acute exposure to high concentrations of microcystin-LR (MC-LR) can cause significant hepatocyte injury. Aim. To document the effects of long-term, low-dose MC-LR exposure on hepatic inflammation and fibrosis in mice with healthy and diseased livers. Material and methods. Male CD1 mice (N = 20/group) were exposed to 1.0 µg/L of MC-LR in drinking water; 1.0 µg/L MC-LR plus 300 mg/L of the hepatotoxin thioacetamide (MC-LR/TAA); or 300 mg/L TAA alone for 28 weeks. Liver biochemistry and histology were documented at the end of the study period. In addition, hepatic stellate cells (HSCs), were exposed in vitro to MC-LR (0.1-10,000 µg/L) and monitored for changes in cell metabolism, proliferation and activation. Results. Liver biochemistry and histology were essentially normal in MC-LR alone exposed mice. MC-LR/TAA and TAA alone exposed mice had significant hepatic inflammation and fibrosis but the extent of the changes were similar in the two groups. In vitro, MC-LR had no effect on HSC metabolism, proliferation or activation. Conclusion. Long-term, low-dose exposure to MC-LR is unlikely to lead to chronic liver disease in the setting of a normal liver or exacerbate existing liver disease in the setting of ongoing hepatitis.


REFERENCES

  1. Duy TN, Lam PK, Shaw GR, Connell DW. Toxicology and risk assessment of freshwater cyanobacterial (bluegreen algal) toxins in water. Rev Environ Contam Toxicol 2000; 163: 113-85.

  2. Carmichael WW. Health Effects of Toxin-Producing Cyanobacteria: The CyanoHABs. Human and Ecological Risk Assessment. An International Journal 2001; 7: 1393-407.

  3. Pouria S, de Andrade A, Barbosa J, Cavalcanti RL, Barreto VT, Ward CJ, Preiser W, et al. Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet 1998; 352: 21-6.

  4. Yuan M, Carmichael WW, Hilborn ED. Microcystin analysis in human sera and liver from human fatalities in Caruaru, Brazil 1996. Toxicon 2006; 48: 627-40.

  5. Falconer IR, Burch MD, Steffensen DA, Choice M, Coverdale OR. Toxicity of the blue green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs, as an animal model for human injury and risk assessment. Environ Toxicol Water Qual 1994; 9: 131-9.

  6. WHO. Algae and cyanobacteria in fresh water. In: Guidelines for safe recreational water environments. Vol 1. Coastal and fresh waters. Geneva, Switzerland: World Health Organization; 2003, p. 136-58.

  7. Guzman RE, Solter PF. Hepatic oxidative stress following prolonged sublethal microcystin LR exposure. Toxicol Pathol 1999; 27: 582-8.

  8. Runnegar M, Seward DJ, Ballatori N, Crawford JM, Boyer JL. Hepatic toxicity and persistence of ser/thr protein phosphatase inhibition by microcystin in the little skate Raja erinacea. Toxicol Appl Pharmacol 1999; 161: 40-9.

  9. Malbrouck C, Trausch G, Devos P, Kestemont P. Effect of microcystin-LR on protein phosphatase activity and glycogen content in isolated hepatocytes of fed and fasted juvenile goldfish Carassius auratus L. Toxicon 2004; 44: 927-32.

  10. Buratti FM, Scardala S, Funari E, Testai E. Human glutathione transferases catalyzing the conjugation of the hepatoxin microcystin-LR. Chem Res Toxicol 2011; 24: 926-33.

  11. Carvalho GM, Oliveira VR, Casquilho NV, Araujo AC, Soares RM, Azevedo SM, Pires KM, et al. Pulmonary and hepatic injury after sub-chronic exposure to sublethal doses of microcystin-LR. Toxicon 2016; 112: 51-8.

  12. He J, Li G, Chen J, Lin J, Zeng C, Chen J, Deng J, et al. Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study. Arch Toxicol 2017; 91: 465-80.

  13. Elleman TC, Falconer IR, Jackson AR, Runnegar MT. Isolation, characterization and pathology of the toxin from a Microcystis aeruginosa (= Anacystis cyanea) bloom. Aust J Biol Sci 1978; 31: 209-18.

  14. Frangez R, Kosec M, Sedmak B, Beravs K, Demsar F, Juntes P, Pogacnik M, et al. Subchronic liver injuries caused by microcystins. Pflugers Arch 2000; 440: R103-104.

  15. Milutinovic A, Zorc-Pleskovic R, Petrovic D, Zorc M, Suput D. Microcystin-LR induces alterations in heart muscle. Folia Biol (Praha) 2006; 52: 116-8.

  16. Duy TN, Lam PK, Shaw GR, Connell DW. Toxicology and risk assessment of freshwater cyanobacterial (bluegreen algal) toxins in water. Rev Environ Contam Toxicol 2000; 163: 113-85.

  17. Carmichael WW. Health Effects of Toxin-Producing Cyanobacteria: The CyanoHABs. Human and Ecological Risk Assessment. An International Journal 2001; 7: 1393-407.

  18. Pouria S, de Andrade A, Barbosa J, Cavalcanti RL, Barreto VT, Ward CJ, Preiser W, et al. Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet 1998; 352: 21-6.

  19. Yuan M, Carmichael WW, Hilborn ED. Microcystin analysis in human sera and liver from human fatalities in Caruaru, Brazil 1996. Toxicon 2006; 48: 627-40.

  20. Falconer IR, Burch MD, Steffensen DA, Choice M, Coverdale OR. Toxicity of the blue green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs, as an animal model for human injury and risk assessment. Environ Toxicol Water Qual 1994; 9: 131-9.

  21. WHO. Algae and cyanobacteria in fresh water. In: Guidelines for safe recreational water environments. Vol 1. Coastal and fresh waters. Geneva, Switzerland: World Health Organization; 2003, p. 136-58.

  22. Guzman RE, Solter PF. Hepatic oxidative stress following prolonged sublethal microcystin LR exposure. Toxicol Pathol 1999; 27: 582-8.

  23. Runnegar M, Seward DJ, Ballatori N, Crawford JM, Boyer JL. Hepatic toxicity and persistence of ser/thr protein phosphatase inhibition by microcystin in the little skate Raja erinacea. Toxicol Appl Pharmacol 1999; 161: 40-9.

  24. Malbrouck C, Trausch G, Devos P, Kestemont P. Effect of microcystin-LR on protein phosphatase activity and glycogen content in isolated hepatocytes of fed and fasted juvenile goldfish Carassius auratus L. Toxicon 2004; 44: 927-32.

  25. Buratti FM, Scardala S, Funari E, Testai E. Human glutathione transferases catalyzing the conjugation of the hepatoxin microcystin-LR. Chem Res Toxicol 2011; 24: 926-33.

  26. Carvalho GM, Oliveira VR, Casquilho NV, Araujo AC, Soares RM, Azevedo SM, Pires KM, et al. Pulmonary and hepatic injury after sub-chronic exposure to sublethal doses of microcystin-LR. Toxicon 2016; 112: 51-8.

  27. He J, Li G, Chen J, Lin J, Zeng C, Chen J, Deng J, et al. Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study. Arch Toxicol 2017; 91: 465-80.

  28. Elleman TC, Falconer IR, Jackson AR, Runnegar MT. Isolation, characterization and pathology of the toxin from a Microcystis aeruginosa (= Anacystis cyanea) bloom. Aust J Biol Sci 1978; 31: 209-18.

  29. Frangez R, Kosec M, Sedmak B, Beravs K, Demsar F, Juntes P, Pogacnik M, et al. Subchronic liver injuries caused by microcystins. Pflugers Arch 2000; 440: R103-104.

  30. Milutinovic A, Zorc-Pleskovic R, Petrovic D, Zorc M, Suput D. Microcystin-LR induces alterations in heart muscle. Folia Biol (Praha) 2006; 52: 116-8.




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