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Dynamic shift in trophoblast nucleos(t)ide metabolism, transport, and adenosine signaling during gestion and preterm birth

ABSTRACT: This study investigates the role of nucleos(t)ide metabolism, transport, and adenosine signaling in placental development and spontaneous preterm birth (PTB). We analyzed gene expression in human placentas, primary trophoblasts, BeWo cells and rat placentas across different gestational stages to understand metabolic adaptations and stress responses To understand the role of nucleos(t)ide metabolism (de novo synthesis and salvage patways), transport, and adenosine signaling in placental development and the adaptive response during spontaneous preterm birth (PTB), we analyzed gene expression in first-trimester and term human placentas, PTB placentas, primary human trophoblasts, and BeWo cells. Additionally, we examined rat placentas at different gestation days (GD12, GD15, and GD20) to provide developmental context and validate findings from human samples. Our results highlight the upregulation of nucleos(t)ide metabolism and adenosine signaling during placental growth and trophoblast differentiation (cytotrophoblast to syncytiotrophoblast), with further metabolic shifts in PTB placentas, particularly in pyrimidine de novo synthesis, purine salvage, and adenosine metabolism, suggesting an adaptive stress response. Additionally enhanced and also adenosine signaling and nucleoside transport was observed. This integrated approach provides novel insights into the metabolic regulation of placental function under both normal and pathological conditions

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE291205 | GEO | 2025/03/08

REPOSITORIES: GEO

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Project description:Pre-existing and gestationally-developed diabetes mellitus during pregnancy have been linked to impaired metabolic function in the villous trophoblast layer of the placenta. These metabolic impairments have been thought to mediate an increased risk of early life metabolic disease development in the exposed offspring. Previous research using the BeWo trophoblast cell line has suggested that independently, hyperglycemia is an important modulator of placental metabolic function in diabetic pregnancies. However, the direct impacts of hyperglycemia on specific aspects of placental metabolic function known to be impaired in diabetic pregnancies including nutrient storage and mitochondrial respiration, are largely unknown. The current study, therefore, utilized functional readouts of metabolic enzyme activity and endpoint readouts of nutrient storage in conjunction with multi-omics analysis (transcriptomics and metabolomics) in BeWo trophoblasts cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the impacts of elevated glucose levels on placental metabolic function. While metabolic enzyme activities and mitochondrial oxidative respiratory function were not altered following 72 hours of hyperglycemia, increased triglyceride and glycogen nutrient stores were observed in the high-glucose exposed BeWo trophoblasts. We speculated that the increased nutrient stores serve to modulate intracellular glucose levels and may reduce the amount of glucose available for oxidation and subsequently protect trophoblast cells from mitochondrial damage during acute high glucose exposures. Additionally, hyperglycemic-culture conditions in BeWo trophoblasts were associated with an altered transcriptomic profile highlighted by altered mRNA expression of metabolic enzymes as well as with an altered metabolome profile highlighted by an intracellular accumulation of lactate, malonate, and riboflavin. Overall, the results demonstrate that exposure to excess glucose modulates placental metabolism and nutrient storage and highlights that increased glucose abundance is an important independent regulator of placental function in diabetic pregnancies.

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Dynamic shift in trophoblast nucleos(t)ide metabolism, transport, and adenosine signaling during gestion and preterm birth

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