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. 2017 Oct;58(8):540-550.
doi: 10.1002/em.22119. Epub 2017 Aug 19.

Perinatal Lead (Pb) Exposure Results in Sex and Tissue-Dependent Adult DNA Methylation Alterations in Murine IAP Transposons

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Free PMC article

Perinatal Lead (Pb) Exposure Results in Sex and Tissue-Dependent Adult DNA Methylation Alterations in Murine IAP Transposons

L Montrose et al. Environ Mol Mutagen. .
Free PMC article

Abstract

Epidemiological and animal data suggest that adult chronic disease is influenced by early-life exposure-induced changes to the epigenome. Previously, we observed that perinatal lead (Pb) exposure results in persistent murine metabolic- and activity-related effects. Using phylogenetic and DNA methylation analysis, we have also identified novel intracisternal A particle (IAP) retrotransposons exhibiting regions of variable methylation as candidate loci for environmental effects on the epigenome. Here, we now evaluate brain and kidney DNA methylation profiles of four representative IAPs in adult mice exposed to human physiologically relevant levels of Pb two weeks prior to mating through lactation. When IAPs across the genome were evaluated globally, average (sd) methylation levels were 92.84% (3.74) differing by tissue (P < 0.001), but not sex or dose. By contrast, the four individual IAPs displayed tissue-specific Pb and sex effects. Medium Pb-exposed mice had 3.86% less brain methylation at IAP 110 (P < 0.01), while high Pb-exposed mice had 2.83% less brain methylation at IAP 236 (P = 0.01) and 1.77% less at IAP 506 (P = 0.05). Individual IAP DNA methylation differed by sex for IAP 110 in the brain and kidney, IAP 236 in the kidney, and IAP 1259 in the kidney. Using Tomtom, we identified three binding motifs that matched to each of our novel IAPs impacted by Pb, one of which (HMGA2) has been linked to metabolic-related conditions in both mice and humans. Thus, these recently identified IAPs display tissue-specific environmental lability as well as sex-specific differences supporting an epigenetic link between early exposure to Pb and later-in-life health outcomes. Environ. Mol. Mutagen. 58:540-550, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: DNA methylation; Developmental Origins of Health and Disease (DOHaD); environmental epigenetics; intracisternal A particle (IAP); lead (Pb); retrotransposon; toxicoepigenetics.

Figures

Figure 1
Figure 1
Exposure paradigm for perinatal lead exposure. Dams were exposed to either control water or Pb-acetate water starting two weeks prior to mating through gestation until postnatal day 21 (PND21). Following this perinatal exposure, all pups were transitioned to control water until 10 months of age at which time matched kidney and brain tissues were collected for DNA extraction.

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