Plasticity of Epigenomic and Transcriptomic Aging Reveals Common Targets for Reprogramming by Environmental Exposures

Environmental exposures during early life are increasingly recognized as key determinants of health and disease in adulthood (1) but how they durably shape disease risk across the lifecourse remains poorly understood. Here, we show early-life toxicants reprogram the epigenome and redirect age-associated transcriptional trajectories—polarizing cell-specific gene expression and predisposing to liver disease. The TaRGET II Consortium (2) exposed mice to diverse toxicants from pre-conception through weaning and followed individual animals though adulthood with multi-omic profiling. Analysis of >800 liver epigenomic and transcriptomic profiles from male and female mice revealed that despite differing chemical classes and mechanisms of action, multiple toxicants — BPA, TBT, TCDD, and PM2.5 — produced exposure signatures that converged on genes normally differentially expressed in the liver as animals aged. Histone modifications at enhancers emerged as key targets for epigenomic reprogramming of these liver aging-associated plasticity genes (LAAsP genes). Reprogrammed LAAsP genes exhibited a striking, bidirectional signature. In hepatocytes LAAsP genes that typically increase with age, such as those involved in metabolism, were repressed. Conversely, in non-parenchymal cells, LAAsP genes that normally decline with age, including those for extracellular matrix production, remained elevated. An attenuated LAAsP gene signature and polarized transcriptional states were mirrored in human liver disease and hepatocellular carcinoma and could effectively distinguished healthy from diseased human liver transcriptomes. Together, these findings demonstrate that early-life environmental exposures can hijack the plasticity of epigenomic aging, durably reprogram expression trajectories, and lock in polarized states that foreshadow chronic liver disease and cancer.