LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease

Autores
Schroeder, Mariana; Fuenzalida, Barbara; Yi, Nan; Shahnawaz, Saira; Gertsch, Jürg; Pellegata, Daniele; Ontsouka, Edgar; Leiva, Andrea; Gutiérrez, Jaime; Müller, Martin; Brocco, Marcela Adriana; Albrecht, Christiane
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring´s life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes present increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in girls. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.
Fil: Schroeder, Mariana. University of Bern; Suiza
Fil: Fuenzalida, Barbara. University of Bern; Suiza
Fil: Yi, Nan. University of Bern; Suiza
Fil: Shahnawaz, Saira. University Of Sargodha; Pakistán
Fil: Gertsch, Jürg. University of Bern; Suiza
Fil: Pellegata, Daniele. University of Bern; Suiza
Fil: Ontsouka, Edgar. University of Bern; Suiza
Fil: Leiva, Andrea. Universidad San Sebastián; Chile
Fil: Gutiérrez, Jaime. Universidad San Sebastián; Chile
Fil: Müller, Martin. Lindenhofgruppe; Suiza
Fil: Brocco, Marcela Adriana. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Albrecht, Christiane. University of Bern; Suiza
Materia
ENVIRONMENTAL STRESS
FETAL PROGRAMMING
METABOLIC DISEASE
MISCARRIAGE
PLACENTA
PREECLAMPSIA
SEX DIFFERENCES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/265950
Acceder
id CONICETDig_04696a9ca4fb4464ed8f8b15b2005fbf
oai_identifier_str oai:ri.conicet.gov.ar:11336/265950
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic diseaseSchroeder, MarianaFuenzalida, BarbaraYi, NanShahnawaz, SairaGertsch, JürgPellegata, DanieleOntsouka, EdgarLeiva, AndreaGutiérrez, JaimeMüller, MartinBrocco, Marcela AdrianaAlbrecht, ChristianeENVIRONMENTAL STRESSFETAL PROGRAMMINGMETABOLIC DISEASEMISCARRIAGEPLACENTAPREECLAMPSIASEX DIFFERENCEShttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring´s life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes present increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in girls. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.Fil: Schroeder, Mariana. University of Bern; SuizaFil: Fuenzalida, Barbara. University of Bern; SuizaFil: Yi, Nan. University of Bern; SuizaFil: Shahnawaz, Saira. University Of Sargodha; PakistánFil: Gertsch, Jürg. University of Bern; SuizaFil: Pellegata, Daniele. University of Bern; SuizaFil: Ontsouka, Edgar. University of Bern; SuizaFil: Leiva, Andrea. Universidad San Sebastián; ChileFil: Gutiérrez, Jaime. Universidad San Sebastián; ChileFil: Müller, Martin. Lindenhofgruppe; SuizaFil: Brocco, Marcela Adriana. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Albrecht, Christiane. University of Bern; SuizaW B Saunders Co-Elsevier Inc2024-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/265950Schroeder, Mariana; Fuenzalida, Barbara; Yi, Nan; Shahnawaz, Saira; Gertsch, Jürg; et al.; LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease; W B Saunders Co-Elsevier Inc; Metabolism-clinical And Experimental; 153; 4-2024; 1-130026-0495CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0026049524000192info:eu-repo/semantics/altIdentifier/doi/10.1016/j.metabol.2024.155793info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:50:54Zoai:ri.conicet.gov.ar:11336/265950instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:50:54.621CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
title LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
spellingShingle LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
Schroeder, Mariana
ENVIRONMENTAL STRESS
FETAL PROGRAMMING
METABOLIC DISEASE
MISCARRIAGE
PLACENTA
PREECLAMPSIA
SEX DIFFERENCES
title_short LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
title_full LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
title_fullStr LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
title_full_unstemmed LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
title_sort LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease
dc.creator.none.fl_str_mv Schroeder, Mariana
Fuenzalida, Barbara
Yi, Nan
Shahnawaz, Saira
Gertsch, Jürg
Pellegata, Daniele
Ontsouka, Edgar
Leiva, Andrea
Gutiérrez, Jaime
Müller, Martin
Brocco, Marcela Adriana
Albrecht, Christiane
author Schroeder, Mariana
author_facet Schroeder, Mariana
Fuenzalida, Barbara
Yi, Nan
Shahnawaz, Saira
Gertsch, Jürg
Pellegata, Daniele
Ontsouka, Edgar
Leiva, Andrea
Gutiérrez, Jaime
Müller, Martin
Brocco, Marcela Adriana
Albrecht, Christiane
author_role author
author2 Fuenzalida, Barbara
Yi, Nan
Shahnawaz, Saira
Gertsch, Jürg
Pellegata, Daniele
Ontsouka, Edgar
Leiva, Andrea
Gutiérrez, Jaime
Müller, Martin
Brocco, Marcela Adriana
Albrecht, Christiane
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ENVIRONMENTAL STRESS
FETAL PROGRAMMING
METABOLIC DISEASE
MISCARRIAGE
PLACENTA
PREECLAMPSIA
SEX DIFFERENCES
topic ENVIRONMENTAL STRESS
FETAL PROGRAMMING
METABOLIC DISEASE
MISCARRIAGE
PLACENTA
PREECLAMPSIA
SEX DIFFERENCES
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring´s life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes present increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in girls. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.
Fil: Schroeder, Mariana. University of Bern; Suiza
Fil: Fuenzalida, Barbara. University of Bern; Suiza
Fil: Yi, Nan. University of Bern; Suiza
Fil: Shahnawaz, Saira. University Of Sargodha; Pakistán
Fil: Gertsch, Jürg. University of Bern; Suiza
Fil: Pellegata, Daniele. University of Bern; Suiza
Fil: Ontsouka, Edgar. University of Bern; Suiza
Fil: Leiva, Andrea. Universidad San Sebastián; Chile
Fil: Gutiérrez, Jaime. Universidad San Sebastián; Chile
Fil: Müller, Martin. Lindenhofgruppe; Suiza
Fil: Brocco, Marcela Adriana. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Biotecnológicas; Argentina
Fil: Albrecht, Christiane. University of Bern; Suiza
description The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring´s life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes present increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in girls. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.
publishDate 2024
dc.date.none.fl_str_mv 2024-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/265950
Schroeder, Mariana; Fuenzalida, Barbara; Yi, Nan; Shahnawaz, Saira; Gertsch, Jürg; et al.; LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease; W B Saunders Co-Elsevier Inc; Metabolism-clinical And Experimental; 153; 4-2024; 1-13
0026-0495
CONICET Digital
CONICET
url http://hdl.handle.net/11336/265950
identifier_str_mv Schroeder, Mariana; Fuenzalida, Barbara; Yi, Nan; Shahnawaz, Saira; Gertsch, Jürg; et al.; LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease; W B Saunders Co-Elsevier Inc; Metabolism-clinical And Experimental; 153; 4-2024; 1-13
0026-0495
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0026049524000192
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.metabol.2024.155793
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613567918112768
score 13.070432

Publicaciones similares