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

Area of Science:

• Environmental health
• Epigenetics
• Toxicology

Background:

• Early-life environmental exposures are critical determinants of adult health and disease.
• The long-term impact of these exposures on disease risk across the lifespan is not well understood.

Purpose of the Study:

• To investigate how early-life toxicant exposures durably reprogram the epigenome and influence age-associated gene expression trajectories.
• To determine if these reprogrammed states predispose to liver disease.

Main Methods:

• The TaRGET II Consortium exposed mice to diverse toxicants (BPA, TBT, TCDD, PM2.5) from pre-conception through weaning.
• Multi-omic profiling (epigenomics and transcriptomics) was performed on >800 liver samples from mice followed into adulthood.
• Analysis focused on identifying convergences in toxicant-induced epigenetic and transcriptional changes related to liver aging.

Main Results:

• Multiple toxicants converged on genes associated with liver aging, regardless of chemical class or mechanism.
• Histone modifications at enhancers were key targets, reprogramming liver aging-associated plasticity genes (LAAsP).
• Reprogramming led to bidirectional changes: repressed metabolic genes in hepatocytes and elevated extracellular matrix genes in non-parenchymal cells.

Conclusions:

• Early-life environmental exposures can hijack epigenomic aging plasticity, causing durable reprogramming of gene expression.
• These polarized transcriptional states foreshadow chronic liver disease and cancer.
• The identified LAAsP gene signature and polarized states effectively distinguished healthy from diseased human liver transcriptomes.