Transcriptomic and epigenomic signatures distinguish high- and low-risk endotypes for liver tumor development.

Abstract

The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, Environmental Health Perspectives, 128 (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver tissue from mice that developed tumors (i.e., "high-risk") and equivalently exposed mice did not (i.e., "low-risk"). Blood transcriptomic signatures separated TBT-exposed from vehicle controls but did not discriminate between animals that developed tumors versus those that did not. However, uninvolved liver tissue of mice with tumors exhibited transcriptomic and epigenomic signatures distinct from liver tissue of mice without tumors and had many features in common with tumors. These high-risk transcriptomic and epigenomic features were also found in 10/26 TBT-exposed mice at 5 months, indicating that this risk signature preceded tumor development. Thus, while early life exposure to TBT exhibits variable penetrance for hepatic tumor development, indicating TBT exposure is not sufficient for liver tumorigenesis, increased risk for hepatic tumor development is linked to epigenomic and transcriptomic reprogramming of the liver induced by this EDC.