In Silico ApoE Isoform Interactions with Methylmercury (MeHg) and In Vivo MeHg Intoxication Effects on Epididymal White Fat Tissue and Liver Function in Young ApoE Knockout Mice

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.