The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis.
Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cel...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0283118 |
| _version_ | 1827963542377070592 |
|---|---|
| author | Zachary J W Easton Xian Luo Liang Li Timothy R H Regnault |
| author_facet | Zachary J W Easton Xian Luo Liang Li Timothy R H Regnault |
| author_sort | Zachary J W Easton |
| collection | DOAJ |
| description | Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are 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 is 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 are altered in term diabetic placentae. 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 glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. 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. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1, HSD11B2, RPS6KA5, and LAP3 and reduced mRNA expression of CYP2F1, and HK2, concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction. |
| first_indexed | 2024-04-09T17:00:59Z |
| format | Article |
| id | doaj.art-abb3808fc5774427bb627ef594590fc5 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T17:00:59Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-abb3808fc5774427bb627ef594590fc52023-04-21T05:32:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01183e028311810.1371/journal.pone.0283118The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis.Zachary J W EastonXian LuoLiang LiTimothy R H RegnaultPre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are 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 is 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 are altered in term diabetic placentae. 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 glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. 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. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1, HSD11B2, RPS6KA5, and LAP3 and reduced mRNA expression of CYP2F1, and HK2, concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction.https://doi.org/10.1371/journal.pone.0283118 |
| spellingShingle | Zachary J W Easton Xian Luo Liang Li Timothy R H Regnault The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. PLoS ONE |
| title | The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. |
| title_full | The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. |
| title_fullStr | The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. |
| title_full_unstemmed | The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. |
| title_short | The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. |
| title_sort | impact of hyperglycemia upon bewo trophoblast cell metabolic function a multi omics and functional metabolic analysis |
| url | https://doi.org/10.1371/journal.pone.0283118 |
| work_keys_str_mv | AT zacharyjweaston theimpactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT xianluo theimpactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT liangli theimpactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT timothyrhregnault theimpactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT zacharyjweaston impactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT xianluo impactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT liangli impactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis AT timothyrhregnault impactofhyperglycemiauponbewotrophoblastcellmetabolicfunctionamultiomicsandfunctionalmetabolicanalysis |