Paternal programming of fetoplacental and offspring metabolic disorders.

The alarming increase in the prevalence of metabolic pathologies is of worldwide concern and has been linked not only to genetic factors but also to a large number of non-genetic factors. In recent years, there has been increasing interest in the study of the programming of metabolic diseases, such as type 2 diabetes mellitus (T2DM) and obesity, by paternal exposure, a paradigm termed "Paternal Origins of Health and Disease" (POHaD). This term derives from the better known "Developmental Origins of Health and Disease" (DOHaD), which focuses on the involvement of the maternal intrauterine environment and complications during pregnancy associated with the health and disease of the offspring. Studies on paternal programming have documented environmentally induced epigenetic modifications in the male germline and in seminal plasma, which lead to intergenerational and transgenerational phenotypes, evident already during fetoplacental development. Studies with animal models at both ends of the nutritional spectrum (undernutrition or overnutrition) have been performed to understand the possible mechanisms and signaling pathways leading to the programming of metabolic disorders by exploring epigenetic changes throughout the life of the offspring. The aim of this review was to address the evidence of the programming of fetoplacental developmental alterations and metabolic pathologies in the offspring of males with metabolic disorders and unhealthy exposures, highlighting the mechanisms involved in such programming and looking for paternal interventions to reduce negative health outcomes in the offspring.