Cross-tissue molecular responses in the liver and blood after toxicant exposures

Exposure to toxic substances, particularly early in life, can perturb epigenomic marks linked to disease susceptibility. Human studies of environmental exposures often rely on surrogate tissues such as blood, but toxicant accumulation differs across organs and results in tissue-specific responses. Thus, understanding whether exposure-induced epigenomic alterations in surrogate tissues such as blood reflect changes in toxicant target tissues, such as liver, is essential for designing and interpreting environmental epigenetic studies. To address this knowledge gap, we systematically analyzed 1,013 multi-omics data from the TaRGET II Consortium, comparing molecular responses in mouse liver and blood following perinatal exposure to arsenic, lead, bisphenol A, tributyltin, di-2-ethylhexyl phthalate, tetrachlorodibenzo-p-dioxin, or air pollution in the form of particulate matter < 2.5μm (PM2.5). Most toxicant-induced molecular changes were tissue-specific, yet we identified a subset of co-regulated genes and regulatory elements in liver and blood in response to early-life exposure to toxicants. Moreover, we discovered that specific pathways, such as immune-related processes, were commonly affected by exposures in both tissues, and transcription factors, including Klf, Jun, Ets1, and Cebp, emerged as shared regulators. While molecular alterations are infrequently conserved between tissues following toxicant exposure, the shared alterations in transcription factors and biological pathways may provide a strategy to link effects in surrogate tissues to target tissues.