The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis

Abstract

Pre-existing and gestationally-developed diabetes mellitus have been linked with impaired metabolic function in placental villous trophoblast cells, that is thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia as an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that have been found to be impaired in diabetic placentae. Therefore, the current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased triglyceride and glycogen nutrient stores. However, specific functional readouts of metabolic enzyme activity and mitochondrial oxidative respiratory activity were not altered. We speculated that increased glycogen content may reduce free glucose available for oxidation and subsequently protect trophoblast cells from mitochondrial damage during acute high glucose exposures. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. Hyperglycemic exposure was associated with an altered transcriptomic profile (e.g. increased expression of ACSL1 (+1.36 fold-change (FC), HSD11B2 (+1.35 FC), and RPS6KA5 (+1.32 FC)), and metabolome profile (e.g. increased levels lactate (+2.72 FC), malonate (+3.74 FC), and riboflavin (+3.68 FC)) in BeWo cytotrophoblasts that further highlighted trophoblast metabolic function is modulated independently by hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolic function and nutrient storage, and these data continue to expand our knowledge on the mechanisms governing the development of placental dysfunction.