title: Sex- and tissue-specific methylome changes in brains of mice perinatally exposed to lead.
abstract: Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend toward negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Sánchez-Martín
authors.affiliation: Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.affiliation: Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45219, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Landero-Figueroa
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Cecil
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D002874:Chromosome Mapping; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: D012333:RNA, Messenger; D007854:Lead
keywords: Brain; DNA methylation; Gene expression; Heavy metals; Lead