Interaction between dolutegravir and folate transporters and receptor in human and rodent placenta.
Dolutegravir
antiretroviral therapy
folate deficiency
folate transport
neural tube defects
placenta
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jan 2022
Jan 2022
Historique:
received:
28
07
2021
revised:
27
10
2021
accepted:
07
12
2021
pubmed:
27
12
2021
medline:
1
4
2022
entrez:
26
12
2021
Statut:
ppublish
Résumé
Due to the critical role of folates in neurodevelopment, it is important to understand potential interactions between anti-HIV drugs used during pregnancy, and folate delivery pathways in the placenta. This study investigates the effect of dolutegravir (DTG) exposure on the functional expression of the reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor-α (FRα) in the placenta. Human placental cell lines, human placental explants, and a pregnant mouse model treated with clinically relevant concentrations of DTG were used. Gene and protein expression were assessed by qPCR, immunoblot and immunohistochemical assays. Folate transport function was measured by applying radioisotope-based transport assays. In placental cells, clinically relevant DTG exposure for 3h or 6h was associated with a modest but significant reduction in the expression of RFC and PCFT both at the mRNA and protein levels, as well as decreased uptake of RFC and PCFT substrates [ These findings demonstrate a potential interaction between DTG and folate transport pathways in the placenta, particularly in vivo, under folate deficient conditions, potentially impacting folate delivery to the foetus in the context of DTG-based ART during pregnancy. Funded by Ontario HIV Treatment Network, grant #506657; and Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, award #R01HD104553.
Sections du résumé
BACKGROUND
BACKGROUND
Due to the critical role of folates in neurodevelopment, it is important to understand potential interactions between anti-HIV drugs used during pregnancy, and folate delivery pathways in the placenta. This study investigates the effect of dolutegravir (DTG) exposure on the functional expression of the reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor-α (FRα) in the placenta.
METHODS
METHODS
Human placental cell lines, human placental explants, and a pregnant mouse model treated with clinically relevant concentrations of DTG were used. Gene and protein expression were assessed by qPCR, immunoblot and immunohistochemical assays. Folate transport function was measured by applying radioisotope-based transport assays.
FINDINGS
RESULTS
In placental cells, clinically relevant DTG exposure for 3h or 6h was associated with a modest but significant reduction in the expression of RFC and PCFT both at the mRNA and protein levels, as well as decreased uptake of RFC and PCFT substrates [
INTERPRETATION
CONCLUSIONS
These findings demonstrate a potential interaction between DTG and folate transport pathways in the placenta, particularly in vivo, under folate deficient conditions, potentially impacting folate delivery to the foetus in the context of DTG-based ART during pregnancy.
FUNDING
BACKGROUND
Funded by Ontario HIV Treatment Network, grant #506657; and Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, award #R01HD104553.
Identifiants
pubmed: 34954655
pii: S2352-3964(21)00565-X
doi: 10.1016/j.ebiom.2021.103771
pmc: PMC8715299
pii:
doi:
Substances chimiques
Folic Acid Transporters
0
Heterocyclic Compounds, 3-Ring
0
Oxazines
0
Piperazines
0
Pyridones
0
dolutegravir
DKO1W9H7M1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103771Subventions
Organisme : NICHD NIH HHS
ID : R01 HD104553
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests LS received personal support for participating in a ViiV organized Think Tank. The authors have no further competing interests related to this study.