Environmental exposures to the father can be transmitted to his offspring through the germline, resulting in inherited phenotypes including diseases such as obesity, diabetes, and cancer. Although changes in DNA methylation, histone modifications, and small RNAs have been observed, the epigenetic carrier in sperm is still unknown. Because of the significant impact on human health and accompanying economic consequences, it is critical to identify the germline carriers that respond to environmental stress and transmit this information. To answer this question we used an established rat model for transgenerational inheritance and discovered that in male germ cells TDP43 and AR, two clinically relevant proteins involved in human disease, assembled into highly stable aggregates known as amyloid, following exposure to the endocrine disruptor vinclozolin. Further, TDP43 and AR amyloids correlated with a phenotype of germ cell apoptosis in the vinclozolin-exposed males. Most importantly, germ cells from the sons and grandsons of the exposed males also contained amyloids despite their not being directly exposed to the environmental toxin. These results led us to hypothesize that amyloids may function as epigenetic carriers of inheritance. In this project we will use TDP43 and AR as molecular models to investigate if an amyloid-based mechanism of inheritance occurs in mammals. If successful, our studies will result in conceptual advances regarding the role of the environment in the origins of disease, how some diseases are inherited, and how species evolve. Deliverables will include manuscripts, scientific presentations, and trained personnel. We will share results/practical knowledge of amyloid-based inheritance and data sets for future work describing prion switching as a common mechanism to control function and how amyloids may mediate complex disease states.
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