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In Silico ApoE Isoform Interactions with Methylmercury (MeHg) and In Vivo MeHg Intoxication Effects on Epididymal
Synara C Lopes1, Vitória K Felix Monteiro1, Paola Caroline L Leocádio2
1Laboratory of the Biology of Tissue Healing and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, CE60430-270, Brazil.
Abstract:
MeHg neurotoxicity is well recognized; however, less is known about its effects on metabolism. Here, we integrated in silico and in vivo approaches to investigate MeHg interactions with apolipoprotein E (ApoE) and their metabolic consequences. Computational analyses revealed that human ApoE2 and ApoE3 isoforms establish stable Hg-S bonds with MeHg, while ApoE4 showed no stable binding, suggesting reduced mercury retention capacity. In addition, we evaluated the impact of MeHg intoxication (20 mg/L in drinking water for 20 days) on the liver and epididymal white fat (EWF) in young ApoE knockout (ko) and wild-type mice. Hg levels in hair, liver, and EWF were measured. We also evaluated body weight gain, plasma triglycerides, total cholesterol, and liver injury by assessing steatosis score, SOD, TBAR, AST, and ALT activities. To evaluate EWF, we analyzed adipocyte diameter, plasma leptin levels, and metabolomics. Hg levels were markedly higher among intoxicated mice. ApoE ko mice had higher Hg concentrations in hair but lower levels in liver and EWF than wild-type controls. Among wild-type mice, MeHg compromised weight gain and increased liver TBAR compared to nonchallenged controls. Among nonintoxicated mice, ApoE deficiency significantly increased triglycerides, cholesterol, and liver transaminases, accompanied by reduced EWF wet weight, SOD activity, and leptin levels. MeHg, together with ApoE deficiency, elevated cholesterol, triglycerides, hepatic transaminases, and TBARS. We found distinct EWF metabolite activity in different scenarios of ApoE deficiency and MeHg intoxication, highlighting increased cardiovascular risk when both challenges occur. Further studies are needed to clarify these mechanisms and identify key nutritional interventions.
Insights
Methylmercury (MeHg) neurotoxicity is known, but its metabolic effects are unclear. This study shows MeHg interacts differently with apolipoprotein E (ApoE) variants, impacting mercury retention and increasing cardiovascular risk when combined with ApoE deficiency.
Area of Science:
- Environmental Toxicology
- Metabolic Biochemistry
- Neuroscience
- Genetics
Background:
- Methylmercury (MeHg) is a potent neurotoxin with poorly understood metabolic impacts.
- Apolipoprotein E (ApoE) plays a crucial role in lipid metabolism and may influence MeHg toxicity.
- Understanding MeHg-ApoE interactions is vital for assessing metabolic and cardiovascular risks.
Purpose of the Study:
- To investigate the interaction between MeHg and different human ApoE isoforms (ApoE2, ApoE3, ApoE4) using in silico methods.
- To evaluate the in vivo metabolic consequences of MeHg intoxication in ApoE knockout (ko) and wild-type mice.
- To assess the combined effects of MeHg exposure and ApoE deficiency on liver and adipose tissue metabolism and cardiovascular risk markers.
Main Methods:
- In silico molecular docking to analyze MeHg binding to ApoE isoforms.
- In vivo study involving MeHg intoxication in ApoE ko and wild-type mice.
- Measurement of mercury levels, body weight, plasma lipids (triglycerides, cholesterol), liver enzymes (AST, ALT), oxidative stress markers (SOD, TBAR), adipocyte size, leptin, and metabolomics in liver and epididymal white fat (EWF).
Main Results:
- ApoE2 and ApoE3 showed stable mercury-sulfur bonds with MeHg in silico, unlike ApoE4.
- MeHg intoxication increased mercury levels in tissues and elevated liver TBAR in wild-type mice.
- ApoE deficiency alone increased plasma lipids and liver enzymes; combined with MeHg, it exacerbated these effects and altered EWF metabolomics, indicating increased cardiovascular risk.
Conclusions:
- ApoE isoforms exhibit differential binding affinities for MeHg, influencing mercury retention.
- MeHg exposure and ApoE deficiency synergistically increase metabolic disturbances and cardiovascular risk factors.
- Further research is needed to elucidate mechanisms and identify nutritional interventions for mitigating MeHg toxicity and associated metabolic risks.
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