Epigenetic effects of paternal environmental exposures and experiences on offspring phenotypes

Recent decades have revealed increasing evidence for epigenetic inheritance through paternal environmental exposures and experiences, affecting offspring health outcomes across diverse species. Key epigenetic mediators in sperm may include DNA methylation, chromatin modifications, as well as small and long non-coding (nc)RNAs. Identified environmental influences extend beyond lifestyle factors (e.g., exercise, diet, alcohol, and nicotine use) to include stress, infections, pollutants, and other toxins. Evidence from humans, rodents, and other species suggests that various paternal exposures before conception substantially shape the phenotypes in offspring, via developmental modulation, including changes to brain and behavior, metabolism, endocrinology, and physiology. These findings raise concerns regarding human epigenetic inheritance, because the relevant environmental exposures have changed significantly in recent decades, potentially increasing the risk of future generations for various disorders ('transgenerational epigenopathy'). Here, we integrate evidence for paternal environmental exposures affecting offspring phenotypes, and associated epigenetic mechanisms, critically discussing potential implications for medicine and other scientific fields.