# Epigenetic Mechanisms of Neurodevelopment in Prenatal Alcohol Exposure

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $59,157

## Abstract

ABSTRACT
Prenatal alcohol exposure (PAE) is a leading cause of preventable neurodevelopmental disability. One
contributing factor is impaired corticogenesis through alcohol’s suppression of neural progenitor cell (NPC)
proliferation. Ribosome biogenesis (RBG) is a critical regulator of cell cycle progression and its disruption
causes nucleolar stress and cell cycle arrest. Using whole-transcriptome sequencing and KEGG pathway
analysis, I identified ribosome biogenesis (RBG) as the single greatest downregulated pathway within the
alcohol-exposed fetal brain cortex (60 out of 70 ribosomal genes; p-adj = 1.86E-49). Transcriptional
suppression of RBG occurs through DNA methylation in CpG regulatory regions of ribosomal protein (RP)-
encoding genes and ribosomal DNA (rDNA). I found that 36 RP-encoding genes having attenuated expression
in the alcohol-exposed fetal cortex were also hypermethylated in their 5’ upstream regulatory regions. Choline
is an essential nutrient required for NPC proliferation and provides methyl groups for DNA methylation.
Prenatal supplemental choline restored methylation of cytosines in these RP-encoding genes. I hypothesize
that alcohol impairs NPC proliferation, at least in part, through hypermethylation of CpG regulatory regions in
RP-encoding genes and rDNA, and this leads to suppressed RBG, whereas prenatal choline supplementation
prevents these changes. To test this, I will administer alcohol, with and without choline supplementation, to
pregnant Nestin-CFPnuc transgenic mice during the peak proliferative phase of fetal cortical neurogenesis
(E10.5 – E14.5); I will study their NPCs at E14.5. Nestin-CFPnuc mice express cyan fluorescent protein (CFP)
specifically in NPCs, to facilitate their identification and isolation. In Aim 1, I will quantify proliferation and
monitor cell cycle progression in alcohol-exposed Nestin-CFP+ NPCs, and I will assess the ability of prenatal
choline to normalize their proliferation. In Aim 2, I will quantify RBG and nucleolar stress in alcohol-exposed
nestin-CFP+ NPCs and will assess whether prenatal choline reduces their nucleolar stress. Using targeted
knockdown, I will also confirm that reduced RBG is sufficient to decrease proliferation in otherwise-normal
NPCs. In Aim 3, I will quantify DNA methylation within the CpG regulatory regions of RP-encoding genes and
rDNA in alcohol-exposed NPCs and test the ability of choline to normalize their methylation. These studies
offer novel mechanistic insight into how PAE impairs NPC proliferation, and informs our understanding of how
prenatal choline may improve neurodevelopmental outcomes in PAE. Studies herein will develop my skills in
preclinical models of PAE and will deepen my expertise as an investigator with a niche in epigenetic and
nutrient interactions in PAE.

## Key facts

- **NIH application ID:** 10313081
- **Project number:** 1F32AA028684-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Olivia C Rivera
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $59,157
- **Award type:** 1
- **Project period:** 2021-06-02 → 2022-03-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313081

## Citation

> US National Institutes of Health, RePORTER application 10313081, Epigenetic Mechanisms of Neurodevelopment in Prenatal Alcohol Exposure (1F32AA028684-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10313081. Licensed CC0.

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