title: Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity.
abstract: Epigenetic mechanisms are crucial to regulate the expression of different genes required for neuronal plasticity. Neurotoxic substances such as arsenic, which induces cognitive deficits in exposed children before any other manifestation of toxicity, could interfere with the epigenetic modulation of neuronal gene expression required for learning and memory. This study assessed in Wistar rats the effects that developmental arsenic exposure had on DNA methylation patterns in hippocampus and frontal cortex. Animals were exposed to arsenic in drinking water (3 and 36ppm) from gestation until 4 months of age, and DNA methylation in brain cells was determined by flow cytometry, immunohistochemistry and methylation-specific polymerase chain reaction (PCR) of the promoter regions of reelin (RELN) and protein phosphatase 1 (PP1) at 1, 2, 3 and 4 months of age. Immunoreactivity to 5 methyl-cytosine was significantly higher in the cortex and hippocampus of exposed animals compared to controls at 1 month, and DNA hypomethylation was observed the following months in the cortex at high arsenic exposure. Furthermore, we observed a significant increase in the non-methylated form of PP1 gene promoter at 2 and 3 months of age, either in cortex or hippocampus. In order to determine whether this exposure level is associated with memory deficits, a behavioral test was performed at the same age points, revealing progressive and dose-dependent deficits of fear memory. Our results demonstrate alterations of the methylation pattern of genes involved in neuronal plasticity in an animal model of memory deficit associated with arsenic exposure.
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Av. V. Carranza 2405, C.P. 78210 San Luis Potosí, Mexico.
authors.forename: Liborio
authors.initials: L
authors.lastname: Martínez
authors.forename: Verónica
authors.initials: V
authors.lastname: Jiménez
authors.forename: Christian
authors.initials: C
authors.lastname: García-Sepúlveda
authors.forename: Fátima
authors.initials: F
authors.lastname: Ceballos
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Delgado
authors.forename: Perla
authors.initials: P
authors.lastname: Niño-Moreno
authors.forename: Lesly
authors.initials: L
authors.lastname: Doniz
authors.forename: Víctor
authors.initials: V
authors.lastname: Saavedra-Alanís
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Castillo
authors.forename: Martha E
authors.initials: ME
authors.lastname: Santoyo
authors.forename: Roberto
authors.initials: R
authors.lastname: González-Amaro
authors.forename: María E
authors.initials: ME
authors.lastname: Jiménez-Capdeville
mesh_terms: D000367:Age Factors; D000818:Animals; D001151:Arsenic / Q000008:administration & dosage / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D018899:CpG Islands / Q000187:drug effects / Q000502:physiology*; D019175:DNA Methylation / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D000091042:Reelin Protein
chemical_list: D000091042:Reelin Protein; C000717129:Reln protein, rat; D001151:Arsenic