Background: Environmentally induced epigenetic transgenerational inheritance of adult onset disease involvesa variety of phenotypic changes, suggesting a general alteration in genome activity.Results: Investigation of different tissue transcriptomes in male and female F3 generation vinclozolinversus control lineage rats demonstrated all tissues examined had transgenerational transcriptomes.The microarrays from 11 different tissues were compared with a gene bionetwork analysis. Althougheach tissue transgenerational transcriptome was unique, common cellular pathways and processes wereidentified between the tissues. A cluster analysis identified gene modules with coordinated geneexpression and each had unique gene networks regulating tissue-specific gene expression andfunction. A large number of statistically significant over-represented clusters of genes wereidentified in the genome for both males and females. These gene clusters ranged from 2-5 megabasesin size, and a number of them corresponded to the epimutations previously identified in sperm thattransmit the epigenetic transgenerational inheritance of disease phenotypes.Conclusions: Combined observations demonstrate that all tissues derived from the epigenetically altered germline develop transgenerational transcriptomes unique to the tissue, but common epigenetic controlregions in the genome may coordinately regulate these tissue-specific transcriptomes. This systemsbiology approach provides insight into the molecular mechanisms involved in the epigenetictransgenerational inheritance of a variety of adult onset disease phenotypes.