Fisetin impedes developmental methylmercury neurotoxicity via downregulating apoptotic signalling pathway and upregulating Rho GTPase signalling pathway in hippocampus of F 1 generation rats

• Published in: International journal of developmental neuroscience 2018-10, Vol.69 (1), p.88-96
• Main Authors: Jacob, Sherin, Thangarajan, Sumathi
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - drug effects; Dose-Response Relationship, Drug; Electron Transport - drug effects; Female; Flavonoids - therapeutic use; Hippocampus - drug effects; Hippocampus - metabolism; MAP Kinase Signaling System - drug effects; Mercury - metabolism; Mercury Poisoning, Nervous System - drug therapy; Mercury Poisoning, Nervous System - psychology; Methylmercury Compounds; Neuroprotective Agents - therapeutic use; Pregnancy; Rats; Rats, Wistar; rho GTP-Binding Proteins - biosynthesis; rho GTP-Binding Proteins - genetics; Signal Transduction - drug effects
• ISSN: 0736-5748; 1873-474X
• DOI: 10.1016/j.ijdevneu.2018.07.002

Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F generation rats. Pregnant Wistar rats were grouped as Group I : administered with vehicle control, Group II: MeHg (1.5 mg/kg b.w), Group III: MeHg + Fisetin (10 mg/kg b.w), Group IV: MeHg + Fisetin (30 mg/kg b.w), Group V: MeHg + Fisetin (50 mg/kg b.w), Group VI: MeHg + Fisetin (70 mg/kg b.w), Group VII: Fisetin (30 mg/kg b.w) alone. Fisetin reduced mercury accumulation in offspring brain. In hippocampus, Fisetin preserved mitochondrial total thiol status, glutathione antioxidant system, mitochondrial metabolic integrity and respiratory chain activity. Fisetin ameliorated apoptotic signals by preventing Cytochrome c release, down regulating ERK 1/2 and Caspase 3 gene expression. Fisetin also upregulated mRNA expressions of RhoA/Rac1/Cdc42 in hippocampus. Predominant effect of Fisetin was to reduce mercury accumulation in offspring brain there by diminishing the toxic effect of MeHg. Hence we showed that, gestational intake of Fisetin (30 mg/kg b.w.) impedes developmental MeHg neurotoxicity by regulating mitochondrial apoptotic and Rho GTPase signalling molecules and by reducing the mercury accumulation in hippocampus of F generation rats.