MeHg-Induced Cytotoxicity Associated With Oxidative Stress and Early Calcium Mobility in Rat Cerebral Cortical...

Methylmercury (MeHg) is a potent neurotoxin that can cross the blood-brain barrier and disrupt neurological function in animals. Emerging evidence suggests that MeHg neurotoxicity may originate from compromised astrocytes, as they are strategically positioned to metabolize and process substances that enter the central nervous system. Thus, a better characterization of the timely cellular responses of astrocytes upon MeHg exposure is key to delineating the toxicology of MeHg. Here, MeHg exposure caused a transient increase in reactive oxygen species (ROS) and intracellular calcium concentration ([Ca²⁺]i), which peaked within 3 h and 30 min, respectively, in astrocytes. Further analyses indicated that the increase in [Ca²⁺]i after MeHg exposure might involve both extracellular Ca²⁺ influx and Ca²⁺ release from intracellular stores, as evidenced by alteration of Ca²⁺ dynamics in cells by targeting specific Ca²⁺ channels with blockers. Further cytotoxicity analyses revealed that antagonizing Ca²⁺-dependent signaling pathways and ROS levels markedly protected astrocytes against MeHg-induced cell death. Treatment with lipopolysaccharide improved cell survival under MeHg exposure, suggesting a reciprocal interaction of proinflammatory signaling and MeHg on [Ca²⁺]i kinetics and nitric oxide production. Collectively, our findings indicated that transient alterations in free radical and Ca²⁺ levels in astrocytes may be associated with MeHg-induced cytotoxicity. Targeting oxidative stress and Ca²⁺ signaling in astrocytes may provide potential strategies for mitigating MeHg-induced neurotoxicity.