Protein-based inheritance in mammals - there is growing evidence that environmental exposures to the father can affect the phenotype of his offspring and, in some cases, these effects can be adaptive

The Department of Health and Human Services National Institutes of Health Office of the Director awarded Texas Tech University Health Sciences Center $575,904 on September 1, 2026, under the Trans-NIH Research Support program (CFDA 93.310) to investigate protein-based transgenerational inheritance in mammals. The funded research examines how paternal environmental exposures transmit phenotypic changes to offspring across generations, with focus on establishing germ granules consisting of epigenetic modifying amyloids as the information carriers in mammalian sperm that convey environmental signals and corresponding phenotypes to offspring. The research builds on evidence that paternal exposures—including endocrine disruptors, nutritional stress, and dietary composition—produce measurable phenotypic effects in descendants, and seeks to determine the precise mechanisms by which spermatozoa incur and transmit transgenerational effects beyond classical epigenetic mechanisms such as DNA methylation, chromatin remodeling, and small noncoding RNAs. The award covers the period from September 1, 2026, through July 31, 2031, with place of performance in Lubbock, Texas.

Most notably, in utero exposure of male rats to the endocrine disruptor vinclozolin resulted in germ cell apoptosis and increased rates of cancers and neurological defects in offspring over several generations. Reduced nutrients have also been linked to transgenerational effects in humans with offspring of paternal grandfathers starved during wwii exhibiting increased rates of diabetes, cardiovascular disease, and obesity. A study in mice established that intergenerational inheritance can indeed occur through the male germline by showing changes in the expression of genes involved in lipid and cholesterol metabolism in the offspring of male mice FED a low protein diet. These studies supported the idea that epigenetic information carriers in sperm responded to the environmental stressors and transmitted new phenotypes across generations. Although the current paradigm suggests that classic epigenetic mechanisms including sperm DNA methylation, chromatin remodeling, and small noncoding rnas such as tsrnas may be involved and indeed changes have been observed, the challenge that still remains is precisely how transgenerational effects are incurred and transmitted by spermatozoa. In this proposal we seek to establish a new paradigm for transgenerational inheritance and propose that germ granules consisting of epigenetic modifying amyloids are the epigenetic information carriers in mammalian sperm that transmit environmental information and corresponding phenotype to offspring. While the idea may at first be considered extreme considering that we propose that the heritable information is based on a protein fold rather than on the genome itself, there is evidence to support that such idea is credible. This includes that 1) yeast have long used prion forming proteins to rapidly adapt to changing environmental conditions that can be passed on to future generations, including in some instances becoming hardwired by subsequent genetic changes; 2) the notable presence in mammals of regulatory proteins including DNA and RNA binding proteins that have prion domains and can form amyloid; 3) recent evidence of protein-based inheritance in c.elegans, the first evidence in a multi-cellular organism; and 4) our exciting preliminary data showing germ granules carrying epigenetic modifying proteins/amyloids are present in RAT spermatozoa. Using the RAT vinclozolin model, microinjection of fertilized RAT embryos, and recombinant proteins/cell culture we will determine if germ granules and their amyloids are epigenetic carriers of inheritance in mammals. Although high-risk, our studies will be transformative if successful and will reveal a unique mechanism by which environmental exposures can be linked to the inheritance of new phenotypes including human disease. Our studies will result in significant conceptual advances in epigenetics, inheritance, disease etiologies, and evolution.