Methylmercury-Induced Metabolic Alterations in Caenorhabditis elegans Are Diet-Dependent

Abstract

Methylmercury (MeHg) is a well-known neurotoxicant; however, its role in metabolic diseases has been gaining wider attention. Chronic exposure to MeHg in human populations shows an association with diabetes mellitus and metabolic syndrome (MS). As the incidences of both obesity and MS are on the rise globally, it is important to understand the potential role of MeHg in the development of the disease. There is a dearth of information on dietary interactions between MeHg and lipids, which play an important role in developing MS. We have previously shown that MeHg increases food seeking behaviors, lipid levels, fat storage, and pro-adipogenic gene expression in C. elegans fed the standard OP50 Escherichia coli diet. However, we hypothesized that these metabolic changes could be prevented if the worms were fed a bacterial diet lower in lipid content. We tested whether C. elegans developed metabolic alterations in response to MeHg if they were fed two alternative E. coli strains (HT115 and HB101) that are known absorb significantly less lipids from their media. Additionally, to explore the effect of a high-lipid and high-cholesterol diet on MeHg-induced metabolic dysfunction, we supplemented the OP50 strain with twice the standard concentration of cholesterol in the nematode growth media. Wild-type worms fed either the HB101 or HT115 diet were more resistant to MeHg than the worms fed the OP50 diet, showing a significant right-hand shift in the dose–response survival curve. Worms fed the OP50 diet supplemented with cholesterol were more sensitive to MeHg, showing a significant left-hand shift in the dose–response survival curve. Changes in sensitivity to MeHg by differential diet were not due to altered MeHg intake in the worms as measured by inductively coupled mass spectrometry. Worms fed the low-fat diets showed protection from MeHg-induced metabolic changes, including decreased food consumption, lower triglyceride content, and lower fat storage than the worms fed either of the higher-fat diets. Oxidative stress is a common characteristic of both MeHg exposure and high-fat diets. Worms fed either OP50 or OP50 supplemented with cholesterol and treated with MeHg had significantly higher levels of reactive oxygen species, carbonylated proteins, and loss of glutathione than the worms fed the HT115 or HB101 low-lipid diets. Taken together, our data suggest a synergistic effect of MeHg and dietary lipid levels on MeHg toxicity and fat metabolism in C. elegans, which may affect the ability of MeHg to cause metabolic dysfunction.

Toxicity of Per- and Polyfluoroalkyl Substances to Nematodes

“…Furthermore, PFASs can cause obesity in C. elegans , with potential developmental, neurological, or reproductive effects. This is because, in healthy C. elegans , the neuroendocrine control of food sensing contributes to the balance of fat accumulation [ 52 ], and dietary structure, including lipid and cholesterol contents, is a primary determinant of C. elegans’ response to pollutants [ 53 ].…”

Application of Caenorhabditis elegans in Lipid Metabolism Research

“…Recently, using the enzymatic measurements of TAGs, the fat-reducing effects of some natural product, active ingredients, such as polysaccharides from Auricularia auricula [ 222 ], Volvariella volvacea [ 223 ], bitter melon [ 224 ] as well as phenolics from strawberry and raspberry [ 225 ], have been identified in C. elegans . In another study, Crawford and co-workers applied the enzymatic measurements of TGs and found that the lipid content of the diet could modify the lipid accumulation caused by methylmercury [ 226 ].…”

Association between Heavy Metals, Metalloids and Metabolic Syndrome: New Insights and Approaches

“…The differentiation of pre-adipocyte 3T3-L1 cells into mature adipocytes involves early induction of C/EBPβ transcription factor, which transactivates the expression of C/EBPα, PPARγ, and SREBP1 transcription factors, allowing for the expression of genes that are important for lipid storage and mobilization [ 238 ]. MeHg treatment of Caenorhabditis elegans has been shown to increase triglyceride content and lipid storage sites, as well as increase the expression of lipid storage, mobilization, and synthetic genes [ 239 , 240 ]. Interestingly, the effects of MeHg on lipid dysregulation could be modified by the bacterial diet fed to the worms [ 240 ], suggesting that dietary factors that the worms are exposed to at the same time as MeHg can affect the lipid dysregulation phenotype.…”

“…MeHg treatment of Caenorhabditis elegans has been shown to increase triglyceride content and lipid storage sites, as well as increase the expression of lipid storage, mobilization, and synthetic genes [ 239 , 240 ]. Interestingly, the effects of MeHg on lipid dysregulation could be modified by the bacterial diet fed to the worms [ 240 ], suggesting that dietary factors that the worms are exposed to at the same time as MeHg can affect the lipid dysregulation phenotype. MeHg-dependent lipid dysregulation in worms was associated with increased expression of cebp-1 (homolog to human C/EBP), nhr-49 (homolog to PPARγ), and sbp-1 (homolog to SREBP1) transcription factors [ 239 ].…”