EPIGENETIC ORIGINS OF DISEASE AND
IMPACT OF ENVIRONMENTAL TOXICANTS IN
IRAQ THEATER OF OPERATIONS
| Transgenerational effects of environmental factors (i.e. toxicants), such as pesticides, plastics and environmental compounds, significantly amplify the impact and health hazards of these toxicants. The transgenerational nature of the actions of these compounds requires a permanent epigenetic alteration of the germ-line. The current proposal is designed to investigate the actions of several different mixtures of environmental compounds relevant to the military (e.g. pesticide, herbicide, explosive residue mixtures). A comparison to the actions of the fungicide vinclozolin (i.e. antiandrogen endocrine disruptor used in the fruit industry) will be made as a positive control. A rodent model (i.e. rat) system is used to assess the potential actions of the compounds of interest. Previously, we have demonstrated that the endocrine disruptor vinclozolin exposure during embryonic gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that then induces a transgenerational adult onset disease state of male infertility, prostate disease, kidney disease, immune abnormalities and tumor development. The objective of the proposed research is to determine the actions of several mixtures of environmental compounds relevant to the military on the potential to promote transgenerational disease states and lterations in the epigenome. THE HYPOTHESIS TESTED IS THAT TRANSIENT EXPOSURE AT CRITICAL TIMES DURING DEVELOPMENT TO SPECIFIC MIXTURES OF ENVIRONMENTAL COMPOUNDS WILL PROMOTE AN ALTERATION IN THE EPIGENOME THAT SUBSEQUENTLY PROMOTES ADULT ONSET DISEASE, AND IF THE MALE GERM-LINE IS EPIGENTICALLY MODIFIED THAT TRANSGENERATIONAL DISEASE PHENOTYPES WILL BE INDUCED. Several generations of progeny from exposed F0 gestating females will be collected (F1-F3) to assess effects on adult onset disease, while the F3 generation will be the focus for transgenerational modification in the epigenome. A correlation with epigenetic modification with adult onset disease will be made as proof of concept for the epigenetic transgenerational phenotype and development of epigenetic biomarkers for disease. Once this is established in the rodent model future studies will consider analysis of epigenetic biomarkers in relevant human cohorts. The experimental approach to test the above hypothesis consists of the following specific aims: 1) Investigate the transgenerational effects of environmental compounds on adult onset disease; 2) Investigate the transgenerational effects of environmental compounds on the epigenome; 3) Correlation of the transgenerational disease phenotypes with the epigenome modifications to potentially identify epigenetic biomarkers of exposure and disease. Completion of the proposed research will determine how several mixtures of environmental compounds relevant to the military influence transgenerational adult onset disease in the F1, F2 and F3 generations of exposed gestating females and pubertally exposed animals. The transgenerational effects on the epigenome will also be determined and correlated to identify potential epigenetic biomarkers for disease and exposure. Insights into the role of epigenetics in environment-genome interactions will be provided. The role of epigenetics in adult onset disease etiology and actions of environmental compounds will be elucidated. The biohazard and potential health problems associated with the different environmental compound mixtures will be determined. This information can then be used by the military to assess if problems with exposure exist and the potential epigenetic biomarkers can be used to monitor exposure. |