The current paradigm in biology today is "Genetic Determinism", which suggests biology is determined controlled primarily by the DNA sequence and genetics. This includes areas such as evolutionary biology and medicine where genetic mutations are suggested as the principle mechanism involved. A large number of studies have suggested genetics cannot explain many forms of disease and most individuals with a disease do not appear to have genetic mutations (e.g. GWAS observations). The current proposal investigates environmental epigenetics as an additional causal factor for the etiology of disease. Epigenetics being the molecular factors around DNA that regulate genome activity, independent of DNA sequence. Epigenetic transgenerational inheritance refers to the germline propagation between generations of epigenetic states in the absence of direct exposure. The central theme of the Program involves the elucidation of the molecular mechanisms and etiology of epigenetic transgenerational inheritance of adult onset disease. The hypothesis to be tested is that environmental exposures during gonadal sex determination promotes abnormal epigenetic programming in the germ line that is transgenerationally transmitted to subsequent generations to induce adult onset diseases, and that subsequent generations potentially develop genetic mutations to facilitate the molecular etiology of epigenetic transgenerational inheritance. The objectives are to investigate the roles of DNA methylation and histone modifications (Aim 1), genetic mutations (Aim 2) and altered non-coding RNA (ncRNA) expression (Aim 3) in the etiology of epigenetic transgenerational inheritance (Aim 4). The research will determine how these different molecular mechanisms interact to initiate and maintain the epigenetic transgenerational inheritance of disease. Completion of the research will provide insights into the origins of disease, as well as new diagnostics and therapeutic strategies not previously considered.