title: Methylmercury-induced developmental toxicity is associated with oxidative stress and cofilin phosphorylation. Cellular and human studies.
abstract: Environmental exposure to methylmercury (MeHg) during development is of concern because it is easily incorporated in children's body both pre- and post-natal, it acts at several levels of neural pathways (mitochondria, cytoskeleton, neurotransmission) and it causes behavioral impairment in child. We evaluated the effects of prolonged exposure to 10-600nM MeHg on primary cultures of mouse cortical (CCN) and of cerebellar granule cells (CGC) during their differentiation period. In addition, it was studied if prenatal MeHg exposure correlated with altered antioxidant defenses and cofilin phosphorylation in human placentas (n=12) from the INMA cohort (Spain). Exposure to MeHg for 9days in vitro (DIV) resulted in protein carbonylation and in cell death at concentrations ≥200nM and ≥300nM, respectively. Exposure of CCN and CGC to non-cytotoxic MeHg concentrations for 5 DIV induced an early concentration-dependent decrease in cofilin phosphorylation. Furthermore, in both cell types actin was translocated from the cytosol to the mitochondria whereas cofilin translocation was found only in CGC. Translocation of cofilin and actin to mitochondria in CGC occurred from 30nM MeHg onwards. We also found an increased expression of cortactin and LIMK1 mRNA in CGC but not in CCN. All these effects were prevented by the antioxidant probucol. Cofilin phosphorylation was significantly decreased and a trend for decreased activity of glutathione reductase and glutathione peroxidase was found in the fetal side of human placental samples from the highest (20-40μg/L) MeHg-exposed group when compared with the low (<7μg/L) MeHg-exposed group. In summary, cofilin dephosphorylation and oxidative stress are hallmarks of MeHg exposure in both experimental and human systems.
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Caballero
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Nair
authors.initials: N
authors.lastname: Olguin
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Campos
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.affiliation: CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO - Universitat Jaume I - Universitat de València, Valencia, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Ballester
authors.affiliation: CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO - Universitat Jaume I - Universitat de València, Valencia, Spain.
authors.forename: Maria-Jose
authors.initials: MJ
authors.lastname: Lopez-Espinosa
authors.affiliation: CIBER Epidemiología y Salud Pública (CIBERESP), Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO - Universitat Jaume I - Universitat de València, Valencia, Spain.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Llop
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Rodríguez-Farré
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain. Electronic address: csenqi@iibb.csic.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Suñol
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D002658:Developmental Disabilities / Q000139:chemically induced*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D050050:Protein Carbonylation / Q000187:drug effects
chemical_list: D051339:Actin Depolymerizing Factors; D008767:Methylmercury Compounds; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D025261:Mitochondrial Proton-Translocating ATPases; C546989:mt-Atp8 protein, mouse; D005978:Glutathione
keywords: Actin; Cofilin; Cultured neurons; Human placenta; Methylmercury; Mitochondria; Oxidative stress