The Developmental Origins of Health and Disease hypothesis states that in utero and early life exposures and experiences can dictate health throughout adulthood. The connection between environmental exposures and offspring health has historically been explored with respect to maternal exposures during pregnancy and, more recently, pre-pregnancy. However, while the prenatal environment is crucial for proper offspring health, the potential for paternal preconception exposures to influence growth and development has long been overlooked. With infertility and developmental problems on the rise and people choosing to postpone childbearing, the importance of considering both parents to understand offspring health holistically is of utmost importance. However, even when the importance of paternal exposures is accepted, understanding them apart from maternal exposures can be prohibitively difficult.Paternal preconception exposures can alter sperm epigenetics, which regulate gene expression in early embryonic development. DNA methylation has been widely studied for changes associated with environmental and lifestyle factors, and these changes have been observed in sperm as well as somatic cells. Animal studies provide useful insight, but given species differences, more human-like models are necessary to gain a more comprehensive understanding. Here, we demonstrate how an in vitro model for human spermatogenesis can recapitulate human sperm DNA methylation patterns observed after exposure to a brominated flame retardant. Further using this model, we expand the study of environmentally mediated effects on sperm methylation to include more common paternal preconception exposures: cannabis and perfluoroalkyl substances. This model provides a unique opportunity to experimentally study human sperm DNA methylation patterns in response to environmental exposures while also providing the ability to assess mechanisms and study mixtures and many different doses in a cost-effective manner. The results of these studies provide valuable information and direction for future studies on human sperm samples and a compelling argument to consider paternal exposures when attempting to associate environmental toxicants and offspring health measures.