# Exploring the Genetics of FASD in Complementary Mouse and Fish Models

> **NIH NIH U01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $283,974

## Abstract

Alcohol (ethanol) exposure during pregnancy is a well-recognized cause of birth defects and central nervous
system disturbances that lead to cognitive and behavioral problems across the lifespan. Although clusters of
physical features, in particular those involving the craniofacies, and neurobehavioral symptoms define fetal
alcohol spectrum disorders (FASDs), there is considerable variation in the consequences of prenatal alcohol
exposure. This variation impedes the accurate diagnosis of FASDs and confounds our complete understanding
of the damage that can be caused by alcohol exposure. While some of the individual differences in the
consequences of alcohol exposure are due to variations in the timing of exposure, genetic variability is a strong
modifier of the effects of ethanol exposure. Elucidating the genetic factors that confer risk and resilience has
been a slow process, usually accomplished by comparing ethanol’s effects among various strains of animals,
or by candidate gene approaches. Here, we propose a cross-species genetic analysis, utilizing state-of-the-art
whole transcriptomic sequencing (RNA-Seq), high-throughput CRISPR/Cas9 gene editing techniques, and
genetic screening to drive the discovery of novel candidate genes that modify susceptibility to early gestational
ethanol exposure. In Aim 1, RNA-Seq will be performed after ethanol or vehicle exposure in two closely related
mouse strains that differ in their susceptibility to the teratogenic effects of ethanol. This experiment will reveal a
number of genes that are differentially expressed in these “at risk” and “resilient” strains. Candidate genes are
then refined and tested for significant associations with craniofacial and neuroanatomical dysmorphology, as
well as neurobehavioral changes, using our zebrafish high-throughput screens, mouse MRI analysis (with
Hammond) and mouse behavioral phenotyping. The dual species approach affords a highly conserved FASD
model that is more relevant than studying either species alone. In Aim 2, we will perform an unbiased forward
genetic screen in zebrafish to identify mutations that suppress the teratogenicity of ethanol. The roles of these
genes will be tested in mice to identify conserved mechanisms of ethanol teratogenesis. These conserved
genetic mechanisms of ethanol teratogenesis can then be tested by CIFASD members Foroud, Hammond,
Mattson in human populations with prenatal ethanol exposure who vary in their craniofacial and
neurobehavioral manifestations. Likewise, human whole-exome sequencing experiments proposed by Dr.
Foroud will generate numerous candidate genes that will be tested and confirmed in our animal models for the
purpose of identifying conserved teratogenic mechanisms. These highly translational studies will significantly
contribute to our understanding of the genetic factors underlying the susceptibility to prenatal ethanol
exposure, which may be used to improve diagnosis, treatment, and prevention of FASD, as well as p...

## Key facts

- **NIH application ID:** 9940981
- **Project number:** 5U01AA021651-09
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** JOHANN K EBERHART
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $283,974
- **Award type:** 5
- **Project period:** 2012-08-10 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940981

## Citation

> US National Institutes of Health, RePORTER application 9940981, Exploring the Genetics of FASD in Complementary Mouse and Fish Models (5U01AA021651-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9940981. Licensed CC0.

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