Does Methylmercury-Induced Hypercholesterolemia Play a Causal Role in Its Neurotoxicity and Cardiovascular Disease?

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 (40 mg/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.

Metabolism disrupting chemicals and metabolic disorders

“…In Bangladesh, drinking from arsenic contaminated wells was associated with increased ALT [578]. Chronic arsenic exposures were also associated with increased triglycerides in a cross-sectional study [579]; in rats, arsenic increased serum cholesterol, triglycerides, free fatty acids and phospholipids in association with increased oxidative stress and hepatic mitochondrial damage [580] as well as ALT when combined with an obesogenic agent [581, 582]. Lead and mercury exposures were associated with the fatty liver surrogate biomarker, ‘unexplained ALT elevation’ in adult NHANES [561]; and lead, but not mercury, was associated with ALT, plasma triglycerides and LDL, in Iranian adolescents [583].…”

The effect of a low iron diet and early life methylmercury exposure in Daphnia pulex

“…Past studies in humans and rodent models indicate that ID and MeHg exposure is associated with dyslipidemia (Nandyala et al, 2013; Stangl and Kirchgessner, 1998; Moreira et al, 2012). Previous studies in Caenorhabditis elegans and Drosophila melanogaster have demonstrated the utility of invertebrate model systems for understanding dysregulation of lipid metabolism in humans (Dourlen et al, 2015).…”

“…MeHg induced hypercholesterolemia in mice leads to cerebellar glial activation, suggesting MeHg induced dyslipidemia plays a role in both the cardio and neurotoxic effects of MeHg (Moreira et al, 2012). With regard to ID, triglyceride (TAG) serum levels were significantly elevated among Indian adults with ID compared to those who were not; subsequently, Fe therapy among the ID participants significantly decreased TAG levels after 3 months (Nandyala et al, 2013).…”

Mercury Exposure and Endothelial Dysfunction

“…42 In a similar experimental study, the mice treated for 21 days with a drinking solution of methyl mercury (40 mg/L) showed increased total and non-HDL plasma cholesterol levels, supporting the concept of mercury-induced cardiovascular toxicity. 43 Both population and animal studies signify that mercury exposure leads to CVDs, like hypertension, CHD, myocardial infarction, reduction in HRV, increase in sudden cardiac death, increase in carotid IMT and carotid obstruction, generalized atherosclerosis, renal dysfunction, renal failure and proteinuria, and an overall increase in the total cardiovascular mortality. 1,2,4,28,[44][45][46][47][48][49][50][51][52][53] The beginning event that triggers the development of consequent CVD is the functional disruption of the endothelium or endothelial dysfunction, and there is a growing data associating mercury exposure with endothelial dysfunction and higher risk of CVD.…”