Fetal malnutrition is associated with impairment of endogenous melatonin synthesis in pineal via hypermethylation of promoters of protein kinase C alpha and cAMP response element-binding.
fetal exposure
malnutrition
melatonin
methylation
Journal
Journal of pineal research
ISSN: 1600-079X
Titre abrégé: J Pineal Res
Pays: England
ID NLM: 8504412
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
revised:
26
07
2021
received:
04
05
2021
accepted:
20
08
2021
pubmed:
7
9
2021
medline:
14
1
2022
entrez:
6
9
2021
Statut:
ppublish
Résumé
This study investigated whether and how fetal malnutrition would influence endogenous melatonin synthesis, and whether such effect of fetal malnutrition would transmit to the next generation. We enrolled 2466 participants and 1313 of their offspring. The urine 6-hydroxymelatonin sulfate and serum melatonin rhythm were measured. Methylation microarray detection and bioinformatics analysis were performed to identify hub methylated sites. Additionally, rat experiment was performed to elucidate mechanisms. The participants with fetal malnutrition had lower 6-hydroxymelatonin sulfate (16.59 ± 10.12 μg/24 hours vs 24.29 ± 11.99 μg/24 hours, P < .001) and arear under curve of melatonin rhythm (67.11 ± 8.16 pg/mL vs 77.11 ± 8.04 pg/mL, P < .001). We identified 961 differentially methylated sites, in which the hub methylated sites were locating on protein kinase C alpha (PRKCA) and cAMP response element-binding protein (CREB1) promoters, mediating the association of fetal malnutrition with impaired melatonin secretion. However, such effects were not observed in the offspring (all P > .05). Impaired histomorphology of pineal, decreased melatonin in serum, pineal, and pinealocyte were also found in the in vivo and in vitro experiments (P < .05 for the differences of the indicators). Hypermethylation of 10 CpG sites on the PRKCA promoter and 8 CpG sites on the CREB1 promoter were identified (all P < .05), which down-regulated PRKCA and CREB1 expressions, leading to decreased expression of AANAT, and then resulting in the impaired melatonin synthesis. Collectively, fetal malnutrition can impair melatonin synthesis through hypermethylation of PRKCA and CREB1 promoters, and such effects cannot be transmitted to the next generation.
Substances chimiques
Protein Kinase C-alpha
EC 2.7.11.13
Melatonin
JL5DK93RCL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12764Subventions
Organisme : National Key R&D Program of China
ID : 2017YFC1307401
Organisme : Young Elite Scientists Sponsorship Program by CAST
ID : 2019QNRC001
Organisme : National Natural Science Foundation
ID : 82030100
Organisme : National Natural Science Foundation
ID : 82073534
Organisme : National Natural Science Foundation
ID : 81803227
Organisme : Open Research Fund for Top Disciplines of Public Health and Prevent Medicine at Ningxia Medical University
ID : 30181302
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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