Plasticity of epigenomic aging creates vulnerabilities to early-life environmental exposures, reshaping adult cell- and direction-specific trajectories
To understand how early-life exposures shape health and disease trajectories across the lifecourse, the TaRGET II Consortium exposed mice from pre-conception through weaning to diverse environmental toxicants, followed by longitudinal epigenomic and transcriptomic profiling into adulthood.  These studies revealed that early-life exposures caused persistent epigenomic reprogramming and correlative disruption of the transcriptome.  Notably, for the xenoestrogen BPA, obesogen TBT, dioxin TCDD, and air pollutant PM2.5, 40–60% of the genes disrupted in their exposure signatures overlapped with genes differentially expressed during liver aging.  Epigenetic histone modifications at enhancers—and, to a lesser extent, promoters—emerged as key targets for this reprogramming.  Despite differing mechanisms of action, these 4 toxicants induced a polarized signature in the liver, characterized by cell- and direction-specific disruption of the aging transcriptome.  In hepatocytes, genes that typically increase with age, particularly those in metabolic pathways, were downregulated.  Conversely, in non-parenchymal cells, genes typically downregulated with age, including those involved in extracellular matrix production, were upregulated.  This polarized aging signature correlated strongly with liver transcriptomes from patients with liver disease and hepatocellular carcinoma (HCC), effectively distinguishing healthy from diseased human livers.  These findings demonstrate that the plasticity of epigenomic aging is vulnerable to early life environmental exposures, which can reprogram the epigenome, with lasting impacts on the transcriptome, and disease risk, later in life. Overall design: This dataset consists of ChIP-Seq data generated from the livers of 3-week, 5-month, or 10-month-old male mice in response to maternal exposure to vehicle (control) through weaning