SAT638 Understanding Heritable Metabolic Alterations Upon Paternal Preconception Nicotine Exposure

Disclosure: S.R. Aguiar: None. R. Chamorro-Garcia: None. Exposure to endocrine-disrupting chemicals (EDCs) found in our environment can increase the risk of susceptibility to metabolic diseases, such as obesity and type 2 diabetes. Tobacco products harbor a cluster of harmful EDCs that are inhaled by smokers and dispersed through the air. Previous research showed that tobacco exposure during pregnancy can lead to developmental alterations that increase the risk of metabolic disease in the offspring later into adulthood. Although global tobacco use is higher among men than women, little is known about how paternal exposure to tobacco products contribute to metabolic disease in future unexposed generations. Paternal preconception exposure to environmental factors have been shown to lead to increased risk of disease in future offspring, though mechanisms of these heritable alterations remain unclear. Our research focuses on determining the mechanisms through which paternal preconception exposure to tobacco-related chemicals, such as nicotine, lead to metabolic disease, and the underlying mechanism of epigenetic inheritance of these metabolic traits. We hypothesize that paternal nicotine exposure elicits alterations in the paternal germline (i.e., sperm) that are transferred to the zygote upon fertilization leading to metabolic alterations in unexposed offspring. We found that paternal preconception exposure to nicotine leads to insulin resistance and increased plasma ghrelin levels in F1 females. In F1 males, we found different metabolic alterations in the form of altered fasting glucose levels and decreased plasma glucagon levels. Taken together, our current data suggest that paternal preconception nicotine exposure may alter ghrelin signaling pathways that lead to metabolic disruption in F1 females, as well as alter glycogen mobilization in F1 males. To determine the mechanism behind these heritable metabolic alterations observed in paternal nicotine-exposed offspring, we will investigate small non-coding RNA populations in the sperm of nicotine-treated sires. We will characterize heritable alterations during early embryogenesis by whole genome transcriptomics. These approaches will identify the mechanisms behind heritable metabolic alterations observed in offspring paternally-exposed to nicotine, as well as indicate what specific transcripts are impacted during early embryogenesis that give rise to these phenotypes. This project will provide insights into the intergenerational metabolically disruptive effects of paternal tobacco use and the mechanism of inheritance that drives these phenotypes, ultimately providing more evidence to change tobacco policies and legislation. Presentation: Saturday, June 17, 2023