Journal Article

Genome-Wide Alteration of Histone H3K9 Acetylation Pattern in Mouse Offspring Prenatally Exposed to Arsenic

Koldamova, Radosveta, Carter, Alexis, Saleem, Muzamil, Fitz, Nicholas F., Schug, Jonathan, Shiva, Sruti, Barchowsky, Aaron, Lefterov, Iliya, Cronican, Andrea A.

2013

Overview

Chronic exposure to arsenic in drinking water, especially in utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well as memory impairment. Several epidemiological studies have demonstrated cognitive and learning deficits in children with early exposure to low to moderate levels of arsenic, but pathogenic mechanisms or etiology for these deficits are poorly understood. Since in vivo studies show a role for histone acetylation in cognitive performance and memory formation, we examined if prenatal exposure to arsenic causes changes in the epigenomic landscape. We exposed C57Bl6/J mice to 100 μg/L arsenic in the drinking water starting 1 week before conception till birth and applied chromatin immunoprecipitation followed by high-throughput massive parallel sequencing (ChIP-seq) to evaluate H3K9 acetylation pattern in the offspring of exposed and control mice. Arsenic exposure during embryonic life caused global hypo-acetylation at H3K9 and changes in functional annotation with highly significant representation of Krüppel associated box (KRAB) transcription factors in brain samples from exposed pups. We also found that arsenic exposure of adult mice impaired spatial and episodic memory, as well as fear conditioning performance. This is the first study to demonstrate: a) genome wide changes in H3K9 acetylation pattern in an offspring prenatally exposed to arsenic, and b) a connection between moderate arsenic exposure and cognitive impairment in adult mice. The results also emphasize the applicability of Next Generation Sequencing methodology in studies aiming to reveal the role of environmental factors, other than dietary restriction, in developmental reprogramming through histone modifications during embryonic development.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetates / Acetylation / Acetylation - drug effects / Animals / Annotations / Arsenic / Arsenic - toxicity / Biology / Brain / Carrier Proteins - genetics / Carrier Proteins - metabolism / Children / Chromatin / Chronic exposure / Cognitive ability / Cognitive Dysfunction - etiology / Cognitive Dysfunction - genetics / Cognitive Dysfunction - metabolism / Cognitive impairment / Deoxyribonucleic acid / Diet / Dietary restrictions / DNA / DNA binding proteins / DNA methylation / Drinking behavior / Drinking Water / Embryogenesis / Embryonic development / Embryonic growth stage / Environmental factors / Epidemiology / Epigenetics / Etiology / Exposure / Fear conditioning / Female / Genome-Wide Association Study / Genomes / Genomics / Histones / Histones - genetics / Histones - metabolism / House mouse / Immunoprecipitation / Impairment / In vivo methods and tests / Intrauterine exposure / Learning / Learning strategies / Male / Memory / Memory Disorders - chemically induced / Memory Disorders - genetics / Memory Disorders - metabolism / Metabolism / Mice / Mice, Inbred C57BL / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Occupational health / Offspring / Perinatal exposure / Pregnancy / Prenatal experience / Prenatal exposure / Prenatal Exposure Delayed Effects / Progeny / Proteins / Repressor Proteins - genetics / Repressor Proteins - metabolism / Spatial memory / Studies / Transcription factors / Young adults