Isothiocyanates Reduce Mercury Accumulation via an Nrf2-Dependent Mechanism during Exposure of Mice to Methylmercury

Abstract

Background: Methylmercury (MeHg) exhibits neurotoxicity through accumulation in the brain. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays an important role in reducing the cellular accumulation of MeHg.Objectives: We investigated the protective effect of isothiocyanates, which are known to activate Nrf2, on the accumulation of mercury after exposure to MeHg in vitro and in vivo.Methods: We used primary mouse hepatocytes in in vitro experiments and mice as an in vivo model. We used Western blotting, luciferase assays, atomic absorption spectrometry assays, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assays, and we identified toxicity in mice based on hind-limb flaccidity and mortality.Results: The isothiocyanates 6-methylsulfinylhexyl isothiocyanate (6-HITC) and sulforaphane (SFN) activated Nrf2 and up-regulated downstream proteins associated with MeHg excretion, such as glutamate-cysteine ligase, glutathione S-transferase, and multidrug resistance–associated protein, in primary mouse hepatocytes. Under these conditions, intracellular glutathione levels increased in wild-type but not Nrf2-deficient primary mouse hepatocytes. Pretreatment with 6-HITC and SFN before MeHg exposure suppressed cellular accumulation of mercury and cytotoxicity in wild-type but not Nrf2-deficient primary mouse hepatocytes. In comparison, in vivo administration of MeHg to Nrf2-deficient mice resulted in increased sensitivity to mercury concomitant with an increase in mercury accumulation in the brain and liver. Injection of SFN before administration of MeHg resulted in a decrease in mercury accumulation in the brain and liver of wild-type, but not Nrf2-deficient, mice.Conclusions: Through activation of Nrf2, 6-HITC and SFN can suppress mercury accumulation and intoxication caused by MeHg intake.

Neuroprotective Role of Quercetin against Arsenic Induced Oxidative Stress in Rat Brain

“…Under oxidative stress, the excessive ROS induces an increase in GST levels, and then GST metabolizes the toxic products of lipid peroxidation, and other molecules [50]. In our study, a significant decrease in the GST activity was observed after arsenic treatment, which usually occurs under extreme oxidative stress conditions [6].…”

DNA microarray analysis of human neuroblastoma SH-SY5Y cells exposed to methylmercury

“…We previously reported that MeHg activates NF-E2-related factor 2 (Nrf2), a transcription factor involved in cellular protection against MeHg toxicity in human neuroblastoma SH-SY5Y cells (Toyama et al, 2007(Toyama et al, , 2011. Although such a transcription factor is known to cooperatively regulate downstream genes responsible for antioxidant proteins, as well as phase II detoxification enzymes, and phase III transporters (Taguchi et al, 2011), alterations to the expression of Nrf2-related genes caused by MeHg exposure has not been documented.…”

siRNA-mediated silencing of the gene for heat shock transcription factor 1 causes hypersensitivity to methylmercury in HEK293 cells

“…Nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, has been reported as a biological defense factor against methylmercury toxicity (Toyama et al, 2007;Wang et al, 2009;Toyama et al, 2011). However, it is not clear which other transcription factors may be involved in reducing methylmercury toxicity.…”