SAT-156 Sex-Specific, Diet-Induced Metabolic Dysfunction in F1 Progeny as a Consequence of Maternal Adolescent Preconception Opioid Exposure

Abstract

Abstract Adverse metabolic conditions (obesity and type-2 diabetes) continue to be prevalent in developed nations. While the etiology of these diseases is multifactorial (i.e., genetic, environmental), parental exposures/experiences can also impart unfavorable metabolic phenotypes in future non-exposed progeny. We are currently in the midst of an opioid epidemic, with adolescents representing a growing population now exposed to this class of drugs. Endogenous opioids regulate reward- and motivation- related behaviors and chronic exposure to opioids significantly alter the brain’s reward system, an effect that can be transmitted across multiple generations. Indeed, data from animal models demonstrate that adolescent opioid exposure in females can impact their future progeny, even when that exposure occurs prior to conception. Effects observed in the offspring of morphine exposed females (MORF1) when compared to the offspring of saline exposed females (SALF1) include increased transcription of proopiomelanocortin (POMC) within the hypothalamic arcuate nucleus (ARC) of MORF1 offspring. POMC is differentially processed into several bioactive neuropeptides that play key roles in homeostatic and adaptive mechanisms. For example, β- endorphin (β-EP) and α- melanocyte stimulating hormone (α-MSH) regulate both reward/motivation and metabolic pathways, thus influencing reward liability as well as energy balance. Utilizing a preclinical model of preconception female adolescent opioid exposure, the current study demonstrates that when fed an obesogenic diet for 6-weeks, MORF1 offspring sex-specifically develop several deleterious metabolic effects; they consume more food, gain more weight, and develop fasting-induced hyperglycemia, hyperinsulinemia, and hypercorticosteronemia. MORF1 effects are associated with diet-specific alterations in ARC expression of neuropeptides known to regulate energy homeostasis. Further, while analysis across the POMC locus revealed no differences related to DNA methylation status in F1 male offspring at baseline, RNA sequencing of ARC tissue revealed an overall down-regulation of genes associated with synaptic plasticity in MORF1 males maintained on an obesogenic diet. Moreover, this transcriptional effect is coupled with an upregulation of inflammatory transcriptional networks. Thus, females adolescently exposed to morphine, conferred innate changes to the transcriptional response of the ARC to an obesogenic diet in the next generation. Such an effect induces the development of features suggestive of the emergence of metabolic syndrome in F1 offspring. Collectively, these findings suggest a potential confluence of two major global health issues (the opioid epidemic and metabolic syndrome) and provides evidence that maternal indices of opioid exposure can adversely influence metabolic predisposition in future progeny.