Effects of Prenatal Stress and/or Forebrain ATRX Deficiency in C57BL/6 Mice on Cellular Metabolism, DNA Damage, ATM Promoter Methylation and Gene Expression

Abstract

Early life experiences and maternal care influence brain development, in areas that support stress regulation, cognition, and social behaviour. Studies suggest that sustained changes in gene expression in response to prenatal stress during the first week of postnatal development is mediated by changes in chromatin structure, DNA methylation and DNA damage pathways. Chromatin remodelling protein ATRX is regulated by maternal care and works to mediate Atm, a gene responsible for DNA damage detection. ATRX and ATM play a key role in gene expression regulation, which is in part regulated by mitochondrial dynamics and metabolic pathways. We examined mitochondrial function, reactive oxygen species generation, oxidative DNA damage, Atm gene expression and Atm promoter methylation in brain regions relevant to autistic-like behaviours using a mouse model with reduced Atrx expression. Our findings demonstrate that early life environment plays a role in mechanisms underlying metabolism, gene expression, DNA damage detection and ultimately neurodevelopment.