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In vitro and whole animal evidence that methylmercury disrupts GABAergic systems in discrete brain regions in captive
Niladri Basu1, Anton M Scheuhammer, Kirsti Rouvinen-Watt
1Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA. niladri@umich.edu <niladri@umich.edu>
Abstract:
The effects of mercury (Hg) on key components of the GABAergic system were evaluated in discrete brain regions of captive juvenile male American mink (Neovison vison) using in vitro and in vivo (whole animal) experimental approaches. In vitro studies on cortical brain tissues revealed that inorganic Hg (HgCl(2); IC50=0.5+/-0.2microM) and methyl Hg (MeHgCl; IC50=1.6+/-0.2microM) inhibited glutamic acid decarboxylase (GAD; EC 4.1.1.15) activity. There were no Hg-related effects on [(3)H]-muscimol binding to GABA(A) receptors (IC50s>100microM). HgCl(2) (IC50=0.8+/-0.3microM) but not MeHgCl (IC50>100microM) inhibited GABA-transaminase (GABA-T; EC 2.6.1.19) activity. In a whole animal study, neurochemical indicators of GABAergic function were measured in brain regions (occipital cortex, cerebellum, brain stem, and basal ganglia) of captive mink fed relevant levels of MeHgCl (0 to 2microg/g feed, ppm) daily for 89d. No effects on GAD activity were measured. Concentration-dependent decreases in [(3)H]-muscimol binding to GABA(A) receptors and GABA-T activity were found in several brain regions, with reductions as great as 94% (for GABA(A) receptor levels) and 71% (for GABA-T activity) measured in the brain stem and basal ganglia. These results show that chronic exposure to environmentally relevant levels of MeHg disrupts GABAergic signaling. Given that GABA is the main inhibitory neurotransmitter in the mammalian nervous system, prolonged disruptions of its function may underlie the sub-clinical impacts of MeHg at relevant levels to animal health.
Insights
Methylmercury (MeHg) disrupts the GABAergic system, the brain's main inhibitory pathway. Chronic MeHg exposure in mink reduced GABA(A) receptor binding and GABA-transaminase activity, potentially impacting animal health.
Area of Science:
- Neurotoxicology
- Environmental Health
- Biochemistry
Background:
- Mercury (Hg) exposure is a global concern.
- The GABAergic system is crucial for mammalian nervous system function.
- Understanding Hg's impact on neurotransmitter systems is vital for assessing health risks.
Purpose of the Study:
- To investigate the effects of inorganic and methylmercury on the GABAergic system in American mink.
- To evaluate both in vitro and in vivo impacts of mercury on key GABAergic enzymes and receptors.
Main Methods:
- In vitro studies on cortical tissues to assess inhibition of glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T) by Hg.
- In vitro assessment of Hg effects on [(3)H]-muscimol binding to GABA(A) receptors.
- In vivo study involving chronic dietary methylmercury exposure in mink.
- Measurement of neurochemical indicators of GABAergic function in discrete brain regions post-exposure.
Main Results:
- In vitro, both inorganic and methylmercury inhibited GAD activity, while only inorganic mercury inhibited GABA-T.
- No Hg effects on [(3)H]-muscimol binding were observed in vitro.
- In vivo, chronic methylmercury exposure led to significant, concentration-dependent decreases in GABA(A) receptor binding and GABA-T activity in multiple brain regions, particularly the brain stem and basal ganglia.
- No effects on GAD activity were observed in vivo.
Conclusions:
- Chronic, environmentally relevant methylmercury exposure disrupts GABAergic signaling in mink.
- Reduced GABA(A) receptor binding and GABA-T activity indicate impaired inhibitory neurotransmission.
- These disruptions may underlie sub-clinical health impacts of methylmercury in animals.
