Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype

Autores
Cisternas, Carla Daniela; Cortese, Maria Laura; Golynker, Ilona; Castillo-Ruiz, Alexandra; Forger, Nancy G.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.
Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Cortese, Maria Laura. Georgia State University; Estados Unidos
Fil: Golynker, Ilona. Georgia State University; Estados Unidos
Fil: Castillo-Ruiz, Alexandra. Georgia State University; Estados Unidos
Fil: Forger, Nancy G.. Georgia State University; Estados Unidos
Materia
ANTEROVENTRAL PERIVENTRICULAR NUCLEUS
BED NUCLEUS OF THE STRIA TERMINALIS
EPIGENETIC
MEDIAL PREOPTIC AREA
SEX DIFFERENCE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/129380

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network_name_str CONICET Digital (CONICET)
spelling Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotypeCisternas, Carla DanielaCortese, Maria LauraGolynker, IlonaCastillo-Ruiz, AlexandraForger, Nancy G.ANTEROVENTRAL PERIVENTRICULAR NUCLEUSBED NUCLEUS OF THE STRIA TERMINALISEPIGENETICMEDIAL PREOPTIC AREASEX DIFFERENCEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Cortese, Maria Laura. Georgia State University; Estados UnidosFil: Golynker, Ilona. Georgia State University; Estados UnidosFil: Castillo-Ruiz, Alexandra. Georgia State University; Estados UnidosFil: Forger, Nancy G.. Georgia State University; Estados UnidosEndocrine Society2020-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/129380Cisternas, Carla Daniela; Cortese, Maria Laura; Golynker, Ilona; Castillo-Ruiz, Alexandra; Forger, Nancy G.; Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype; Endocrine Society; Endocrinology; 161; 1; 1-2020; 1-270013-72271945-7170CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/endo/advance-article/doi/10.1210/endocr/bqz022/5631853info:eu-repo/semantics/altIdentifier/doi/10.1210/endocr/bqz022info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:39:47Zoai:ri.conicet.gov.ar:11336/129380instacron: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 09:39:48.004CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
title Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
spellingShingle Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
Cisternas, Carla Daniela
ANTEROVENTRAL PERIVENTRICULAR NUCLEUS
BED NUCLEUS OF THE STRIA TERMINALIS
EPIGENETIC
MEDIAL PREOPTIC AREA
SEX DIFFERENCE
title_short Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
title_full Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
title_fullStr Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
title_full_unstemmed Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
title_sort Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype
dc.creator.none.fl_str_mv Cisternas, Carla Daniela
Cortese, Maria Laura
Golynker, Ilona
Castillo-Ruiz, Alexandra
Forger, Nancy G.
author Cisternas, Carla Daniela
author_facet Cisternas, Carla Daniela
Cortese, Maria Laura
Golynker, Ilona
Castillo-Ruiz, Alexandra
Forger, Nancy G.
author_role author
author2 Cortese, Maria Laura
Golynker, Ilona
Castillo-Ruiz, Alexandra
Forger, Nancy G.
author2_role author
author
author
author
dc.subject.none.fl_str_mv ANTEROVENTRAL PERIVENTRICULAR NUCLEUS
BED NUCLEUS OF THE STRIA TERMINALIS
EPIGENETIC
MEDIAL PREOPTIC AREA
SEX DIFFERENCE
topic ANTEROVENTRAL PERIVENTRICULAR NUCLEUS
BED NUCLEUS OF THE STRIA TERMINALIS
EPIGENETIC
MEDIAL PREOPTIC AREA
SEX DIFFERENCE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.
Fil: Cisternas, Carla Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Cortese, Maria Laura. Georgia State University; Estados Unidos
Fil: Golynker, Ilona. Georgia State University; Estados Unidos
Fil: Castillo-Ruiz, Alexandra. Georgia State University; Estados Unidos
Fil: Forger, Nancy G.. Georgia State University; Estados Unidos
description Many neural sex differences are differences in the number of neurons of a particular phenotype. For example, male rodents have more calbindin-expressing neurons in the medial preoptic area (mPOA) and bed nucleus of the stria terminalis (BNST), and females have more neurons expressing estrogen receptor alpha (ERα) and kisspeptin in the ventromedial nucleus of the hypothalamus (VMH) and the anteroventral periventricular nucleus (AVPV), respectively. These sex differences depend on neonatal exposure to testosterone, but the underlying molecular mechanisms are unknown. DNA methylation is important for cell phenotype differentiation throughout the developing organism. We hypothesized that testosterone causes sex differences in neurochemical phenotype via changes in DNA methylation, and tested this by inhibiting DNA methylation neonatally in male and female mice, and in females given a masculinizing dose of testosterone. Neonatal testosterone treatment masculinized calbindin, ERα and kisspeptin cell number of females at weaning. Inhibiting DNA methylation with zebularine increased calbindin cell number only in control females, thus eliminating sex differences in calbindin in the mPOA and BNST. Zebularine also reduced the sex difference in ERα cell number in the VMH, in this case by increasing ERα neuron number in males and testosterone-treated females. In contrast, the neonatal inhibition of DNA methylation had no effect on kisspeptin cell number. We conclude that testosterone normally increases the number of calbindin cells and reduces ERα cells in males through orchestrated changes in DNA methylation, contributing to, or causing, the sex differences in both cell types.
publishDate 2020
dc.date.none.fl_str_mv 2020-01
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/11336/129380
Cisternas, Carla Daniela; Cortese, Maria Laura; Golynker, Ilona; Castillo-Ruiz, Alexandra; Forger, Nancy G.; Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype; Endocrine Society; Endocrinology; 161; 1; 1-2020; 1-27
0013-7227
1945-7170
CONICET Digital
CONICET
url http://hdl.handle.net/11336/129380
identifier_str_mv Cisternas, Carla Daniela; Cortese, Maria Laura; Golynker, Ilona; Castillo-Ruiz, Alexandra; Forger, Nancy G.; Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype; Endocrine Society; Endocrinology; 161; 1; 1-2020; 1-27
0013-7227
1945-7170
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://academic.oup.com/endo/advance-article/doi/10.1210/endocr/bqz022/5631853
info:eu-repo/semantics/altIdentifier/doi/10.1210/endocr/bqz022
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
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
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score 13.070432