Methylmercury Induces Metabolic Alterations in Caenorhabditis elegans: Role for C/EBP Transcription Factor

Caito, Samuel; Newell-Caito, Jennifer L.; Martell, Megan; Crawford, Nicole; Aschner, Michael

doi:10.1093/toxsci/kfz244

Cited by 12 publications

(27 citation statements)

References 81 publications

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“…Certain inconsistencies between the adipotropic effects of Hg reported in these two studies may be explained by the difference in the dose of metal exposure; higher dose 22 results in adipogenic response inhibition due to the potential toxic (including pro-oxidant) effects. In addition to the studies in mice demonstrating a significant impact of Hg exposure on PPARγ, our recent findings from a Caenorhabditis elegans model revealed a significant impact of 10 to 20 µM MeHg on lipid metabolism regulatory genes, including pro-adipogenic worm orthologs to human SREBP and C/EBPs 23 , due to MeHg being another regulator of adipogenesis. In contrast to the previously mentioned studies, one study demonstrated that in C57BL/6J mice orally exposed to 0.5 or 5 ppm MeHg (concentrations that failed to induce adipogenic gene expression in visceral adipose tissue), a reduction of adipose tissue cumulation was associated with MeHg-induced increase in hypothalamic pro-opiomelanocortin (POMC) expression 24 .…”

Section: Adipotropic Effects Of Heavy Metalsmentioning

confidence: 78%

Adipotropic effects of heavy metals and their potential role in obesity

Tinkov¹,

Aschner²,

Tao³

et al. 2021

Fac Rev

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Epidemiological studies demonstrated an association between heavy metal exposure and the incidence of obesity and metabolic syndrome. However, the particular effects of metal toxicity on adipose tissue functioning are unclear. Therefore, recent findings of direct influence of heavy metals (mercury, cadmium, and lead) and metalloid (arsenic) on adipose tissue physiology are discussed while considering existing gaps and contradictions. Here, we provide a literature review addressing adipose tissue as a potential target of heavy metal toxicity. Experimental in vivo studies demonstrated a significant influence of mercury, cadmium, lead, and arsenic exposure on body adiposity. In turn, in vitro experiments revealed both up- and downregulation of adipogenesis associated with aberrant expression of key adipogenic pathways, namely CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor gamma (PPARγ). Comparison of the existing studies on the basis of dose and route of exposure demonstrated that the effects of heavy metal exposure on adipose tissue may be dose-dependent, varying from increased adipogenesis at low-dose exposure to inhibition of adipose tissue differentiation at higher doses. However, direct dose-response data are available in a single study only for arsenic. Nonetheless, both types of these effects, irrespective of their directionality, contribute significantly to metabolic disturbances due to dysregulated adipogenesis. Particularly, inhibition of adipocyte differentiation is known to reduce lipid-storage capacity of adipose tissue, leading to ectopic lipid accumulation. In contrast, metal-associated stimulation of adipogenesis may result in increased adipose tissue accumulation and obesity. However, further studies are required to reveal the particular dose- and species-dependent effects of heavy metal exposure on adipogenesis and adipose tissue functioning.

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Section: Adipotropic Effects Of Heavy Metalsmentioning

confidence: 78%

Adipotropic effects of heavy metals and their potential role in obesity

Tinkov¹,

Aschner²,

Tao³

et al. 2021

Fac Rev

Self Cite

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“…Previously, we have shown that fat storage sites are increased by MeHg through two methods, BODIPY 493/503 and Nile Red [10]. As the Nile Red method amends itself to screening multiple treatment groups, we chose to quantify fat storage sites using this method.…”

Section: Nile Red Stainingmentioning

confidence: 99%

“…We have previously shown that MeHg increases the triglyceride content of N2 worms fed OP50 [10]. As HB101, HT115, and 2x cholesterol OP50 contained different lipid profiles to OP50, we were interested in whether the worms would accumulate lipids in response to MeHg at similar levels.…”

Section: Bacterial Diet Altered Lipid Accumulation In Response To Mehgmentioning

confidence: 99%

“…We have previously shown that MeHg induces the expression of several genes involved in lipid accumulation and metabolic disease [10]. MeHg increases the expression of cebp-1 (worm homolog of C/EBP) in worms fed OP50.…”

Section: Mehg-induced Pro-adipogenic Gene Transcription Is Diet-dependentmentioning

confidence: 99%

“…However it has been shown that elevated blood mercury levels are also associated with increased visceral adipose tissue [8], and that toenail mercury levels (a marker for chronic Hg exposure) are associated with the development of MS [9]. We have recently shown that MeHg significantly increased lipid storage, altered feeding behavior, and increased the transcription of MS-related genes in Caenorhabditis elegans (C. elegans) [10]. Mechanisms that lead to MeHg-induced dyslipidemia are not known.…”

Section: Introductionmentioning

confidence: 99%

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

Crawford

Martell

Nielsen

et al. 2021

Toxics

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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.

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