Neurotoxicological mechanism of methylmercury induced by low-dose and long-term exposure in mice: oxidative stress and down-regulated Na+/K(+)-ATPase involved.
Methylmercury (MeHg), a potent neurotoxicant, easily passes through the blood-brain barrier (BBB), accumulates in the brain regions and causes severe irreversible damage. However, the neurotoxic effects and action mechanisms of MeHg are still unclear, especially in low-dose and long-term exposure. In this study, we attempted to explore the toxic effects of low-dose MeHg (0.05 mg/kg/day), which was the possible exposed dose by ingestion in MeHg-contaminated areas, on the time course of changes in locomotor activities and auditory brainstem response (ABR) system after administration for 7 consecutive weeks in mice. The results showed that the retention time on the rotating rod (60 rpm) was preferentially decreased after 1-week oral administration with MeHg. The locomotor activities parameters of ambulatory distances and stereotype-1 episodes were significantly increased and vertical-plane entries were progressively decreased after MeHg exposure in 3 consecutive weeks. Gradually progressive abnormality of ABR (increase in hearing thresholds, prolonged absolute and interwave latencies) was found during 4-6 weeks administration of MeHg. These impairments correlated with significant Hg accumulation and biochemical alterations in brain regions and/or other tissues, including the increase of lipid peroxidation (LPO) production, influence of Na+/K(+)-ATPase activities and nitric oxide (NO) levels were found. These findings provide evidence that the signaling of oxidative stress/Na+/K(+)-ATPase/NO plays a role in the underlying mechanisms of the neurotoxic effects induced by low-dose and long-term exposure of MeHg.
Huang
Chun-Fa
CF
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Hsu
Chuan-Jen
CJ
Liu
Shing-Hwa
SH
Lin-Shiau
Shoei-Yn
SY
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020262:Mercury Poisoning, Nervous System / Q000201:enzymology / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008767:Methylmercury Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013997:Time Factors
D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D009569:Nitric Oxide; D000254:Sodium-Potassium-Exchanging ATPase; C004925:methylmercuric chloride