Methionine Stimulates Motor Impairment And Cerebellar Mercury Deposition in Methylmercury-Exposed Mice

Abstract

Methylmercury (MeHg) is a highly toxic environmental contaminant that produces neurological and developmental impairments in animals and humans. Although its neurotoxic properties have been widely reported, the molecular mechanisms by which MeHg enters the cells and exerts toxicity are not yet completely understood. Taking into account that MeHg is found mostly bound to sulfhydryl-containing molecules such as cysteine in the environment and based on the fact that the MeHg-cysteine complex (MeHg-S-Cys) can be transported via the L-type neutral amino acid carrier transport (LAT) system, the potential beneficial effects of L-methionine (L-Met, a well known LAT substrate) against MeHg (administrated as MeHg-S-Cys)-induced neurotoxicity in mice were investigated. Mice were exposed to MeHg (daily subcutaneous injections of MeHg-S-Cys, 10 mg Hg/kg) and/or L-Met (daily intraperitoneal injections, 250 mg/kg) for 10 consecutive days. After treatments, the measured hallmarks of toxicity were mostly based on behavioral parameters related to motor performance, as well as biochemical parameters related to the cerebellar antioxidant glutathione (GSH) system. MeHg significantly decreased motor activity (open-field test) and impaired motor performance (rota-rod task) compared with controls, as well as producing disturbances in the cerebellar antioxidant GSH system. Interestingly, L-Met administration did not protect against MeHg-induced behavioral and cerebellar changes, but rather increased motor impairments in animals exposed to MeHg. In agreement with this observation, cerebellar levels of mercury (Hg) were higher in animals exposed to MeHg plus L-Met compared to those only exposed to MeHg. However, this event was not observed in kidney and liver. These results are the first to demonstrate that L-Met enhances cerebellar deposition of Hg in mice exposed to MeHg and that this higher deposition may be responsible for the greater motor impairment observed in mice simultaneously exposed to MeHg and L-Met.

Antioxidant effects of Dendropanax morbifera Léveille extract in the hippocampus of mercury-exposed rats

“…MeHg exposure significantly decreased the rat hippocampal TSH level and GR activity, while GST activity was significantly lower than that of the control group. This result was consistent with previous studies indicating that sulfhydryl groups represented the main target of MeHg in biological systems [ 34 ] and that MeHg decreased glutathione levels in the cerebellum [ 48 ]. This result was also consistent with a previous study showing that the CHCl 3 fraction of the Dendropanax morbifera methanol extract exerted protective effects through its antioxidant activity, protection of mitochondria, and anti-apoptotic actions [ 49 ].…”

Mechanisms involved in the transport of mercuric ions in target tissues

“…Site-directed mutagenesis of LAT1 has been shown to cause a reduction in the cellular uptake of CH 3 Hg + , providing additional evidence for the hypothesis that CH 3 Hg- S -Cys is a substrate of LAT1 (Boado et al 2005). Taken together, these data provide strong support for the hypothesis that CH 3 Hg- S -Cys is taken into cells via one or both isoforms of System L. Interestingly, a recent study indicated that co-administration of methionine and CH 3 Hg + enhanced motor impairments in mice compared with administration of CH 3 Hg + alone (Zimmermann et al 2014). This finding suggests that a trans-stimulatory phenomenon may occur whereby the presence of additional substrate enhances the activity of the transporter so that more substrate, including CH 3 Hg + , is taken up by the carrier.…”

A brain proteome profile in rats exposed to methylmercury or thimerosal (ethylmercury)

“…The overproduction of ROS may trigger the cell to elevate antioxidants defenses in order to prevent cellular damage. Numerous studies demonstrated that neurons respond to MeHg exposure with enhanced ROS production, representing a key mechanism of cell damage Choi et al, 1996;Farina et al, 2011aFarina et al, , 2011bZimmermann et al, 2014), since the brain presents a highly susceptible tissue to oxidative stress due to its high rate of metabolism . In brain cells, Hg exposure modifies the physiological function of Figure 2.…”