Transgenerational effects of paternal exposures: the role of germline de novo mutations

Germline de novo mutations (DNMs) refer to spontaneous mutations arising during gametogenesis, resulting in genetic changes within germ cells that are subsequently transmitted to the next generation. While the impact of maternal exposures on germline DNMs has been extensively studied, more recent studies have begun to highlight the increasing importance of the effects of paternal factors. In this review, we have summarized the existing literature on how various exposures experienced by fathers affect the germline DNM burden in their spermatozoa, as well as their consequences for semen analysis parameters, pregnancy outcomes, and offspring health. A growing body of literature supports the conclusion that advanced paternal age (APA) correlates with a higher germline DNM rate in offspring. Furthermore, lifestyle choices, environmental toxins, assisted reproductive techniques (ART), and chemotherapy are associated with the accumulation of paternal DNMs in spermatozoa, with deleterious consequences for pregnancy outcomes and offspring health. Ultimately, our review highlights the clear importance of the germline DNM mode of inheritance, and the current understanding of how this is affected by various paternal factors. In addition, we explore conflicting reports or gaps of knowledge that should be addressed in future research.