Mercury-induced cognitive impairment in metallothionein-1/2 null mice

Abstract

Metallothioneins are central for the metabolism and detoxification of transition metals. Exposure to mercury during early neurodevelopment is associated with neurocognitive impairment. Given the importance of metallothioneins in mercury detoxification, metallothioneins may be a protective factor against mercury-induced neurocognitive impairment. Deletion of the murine metallothionein-1 and metallothionein-2 genes causes choice accuracy impairments in the 8-arm radial maze. We hypothesize that deletions of metallothioneins genes will make metallothionein-null mice more vulnerable to mercury-induced cognitive impairment. We tested this hypothesis by exposing MT1/MT2-null and wildtype mice to developmental mercury (HgCl 2 ) and evaluated the resultant effects on cognitive performance on the 8-arm radial maze. During the early phase of learning metallothionein-null mice were more susceptible to mercury-induced impairment compared to wildtype. Neurochemical analysis of the frontal cortex revealed that serotonin levels were higher in metallothionein-null mice compared to wildtype mice. This effect was independent of mercury exposure. However, dopamine levels in mercury exposed metallothionein-null mice were lower compared to mercury-exposed wildtype mice. This work shows that deleting metallothioneins increase the vulnerability to developmental mercury-induced neurocognitive impairment. Metallothionein effects on monoamine transmitters may be related to this cognitive effect.

Genetic polymorphisms affecting susceptibility to mercury neurotoxicity in children: Summary findings from the Casa Pia Children's Amalgam Clinical Trial

“…Since adverse neurobehavioral effects were found only among children having gene modifications, genexHg interactions are assumed to underlie these effects. In this regard, Hg directly affects dopaminergic (Eddins et al, 2008), serotonergic (Tsai et al, 1995) and other neurologic processes (Castoldi et al, 2008; Pieper et al, 2014), and these effects are likely to be exaggerated against enzyme or protein products of genetic variants that mediate or facilitate developing neurologic pathways. Of note, Hg 2+ directly impairs the enzymatic activity of CPOX4 (Li and Woods, 2009) and also likely inhibits preferentially the S-containing met forms of the COMT val158met enzyme and the BDNF val66met protein product, both of which play critical roles in neurologic development (Barnett et al, 2009; Burkhalter et al, 2003).…”

Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection

“…Therefore, we thought the observation of MT induction for studying the neurotoxic effect of thimerosal because of its high sensitivity to stress. MT-1 and MT-2 as acute-phase proteins are induced in both astrocytes and activated microglia by several stimuli, including mercury compounds, and protect the central nervous system from damage by functions such as antioxidative, anti-inflammatory, neurodegenerative, and apoptotic behavior in the brain (Eddins et al 2008), and Ambjørn et al (2008) suggested that MT induces neuronal differentiation and has a neuroprotective effect (Chung et al 2008). In contrast, it has been reported that MT-3 is first expressed in neurons, but MT-3 is also known to be expressed in astrocytes (Giralt et al 2001;Hozumi et al 2008).…”

Global gene expression profiling using heterologous DNA microarrays to analyze alterations in the transcriptome of Mus spretus mice living in a heavily polluted environment

“…Different isoforms of MTs participate in cellular responses to a wide range of stresses, highlighting their power to scavenge free radicals related to pollution environments and several age-associated pathologies such as cancer (Eddins et al 2008). Therefore, increased Mt1 expression (∼5-fold) might help to protect DRS animals in order to maintain homeostatic levels of essential metals (such as Zn, Mn, or Cu) and detoxifying non-essential metals (Cd or Pb) (Fig.…”