Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease?

Eduardo Luiz Moreira, Jade De oliveira, Márcio Ferreira Dutra, Danúbia Bonfanti Santos, Carlos Alberto Gonçalves, Eliane Maria Goldfeder, Andreza Fabro De bem, Rui Daniel Prediger, Michael Aschner, Marcelo Farina

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLr-/-) mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLr-/- mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.

Original languageEnglish (US)
Pages (from-to)373-382
Number of pages10
JournalToxicological Sciences
Volume130
Issue number2
DOIs
StatePublished - Dec 2012
Externally publishedYes

Fingerprint

Hypercholesterolemia
Toxicity
Cardiovascular Diseases
Cholesterol
Dyslipidemias
Lipids
Probucol
Plasmas
Cardiovascular system
Environmental Pollutants
Food Chain
LDL Receptors
Cardiovascular System
Inbred C57BL Mouse
Knockout Mice
Neuroglia
LDL Cholesterol
Toxicology
Fish
Drinking

Keywords

  • Cardiovascular disease
  • Cholesterol
  • Dyslipidemia
  • Low-density lipoprotein receptor
  • Methylmercury
  • Neurotoxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

Moreira, E. L., De oliveira, J., Dutra, M. F., Santos, D. B., Gonçalves, C. A., Goldfeder, E. M., ... Farina, M. (2012). Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease? Toxicological Sciences, 130(2), 373-382. https://doi.org/10.1093/toxsci/kfs252

Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease? / Moreira, Eduardo Luiz; De oliveira, Jade; Dutra, Márcio Ferreira; Santos, Danúbia Bonfanti; Gonçalves, Carlos Alberto; Goldfeder, Eliane Maria; De bem, Andreza Fabro; Prediger, Rui Daniel; Aschner, Michael; Farina, Marcelo.

In: Toxicological Sciences, Vol. 130, No. 2, 12.2012, p. 373-382.

Research output: Contribution to journalArticle

Moreira, EL, De oliveira, J, Dutra, MF, Santos, DB, Gonçalves, CA, Goldfeder, EM, De bem, AF, Prediger, RD, Aschner, M & Farina, M 2012, 'Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease?', Toxicological Sciences, vol. 130, no. 2, pp. 373-382. https://doi.org/10.1093/toxsci/kfs252
Moreira, Eduardo Luiz ; De oliveira, Jade ; Dutra, Márcio Ferreira ; Santos, Danúbia Bonfanti ; Gonçalves, Carlos Alberto ; Goldfeder, Eliane Maria ; De bem, Andreza Fabro ; Prediger, Rui Daniel ; Aschner, Michael ; Farina, Marcelo. / Does methylmercury-induced hypercholesterolemia play a causal role in its neurotoxicity and cardiovascular disease?. In: Toxicological Sciences. 2012 ; Vol. 130, No. 2. pp. 373-382.
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