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

Abstract

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

Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort

“…This CpG site has been reported in Han et al (2021) which examined fetal malnutrition and its impact on pineal development, by observing patterns of melatonin production and assessing DNA methylation levels in a Chinese cohort. Network analysis found this CpG site involved in processes such as nervous system development and synapse assembly among others [ 53 ]. Further information regarding its function or role in influencing gene expression is yet to be elucidated.…”