# Main Research Component 1: Prenatal alcohol exposure: sex differences in effects on adolescent ethanol drinking, anxiety and associated neural circuitry

> **NIH NIH P50** · STATE UNIVERSITY OF NY,BINGHAMTON · 2020 · $295,199

## Abstract

PROJECT SUMMARY/ABSTRACT
MAIN RESEARCH COMPONENT 1
Alcohol consumption by pregnant women remains a startlingly common occurrence, despite the well-known
potential consequences for the health of exposed children. This is true even when alcohol consumption is
moderate, leading some to conclude that there is no safe level of alcohol consumption during pregnancy. One
of the most reproducible consequences of even low to moderate levels of prenatal alcohol exposure (PAE) is a
heightened ethanol preference and consumption in offspring, a phenomenon found in both humans and animal
models. Recent evidence from preclinical research has found consistent evidence of a sex-biased effect, with
male offspring showing a greater PAE-induced increase in ethanol consumption and preference than females.
This effect is observed even when PAE occurs prior to gonadal differentiation (before gestational day 12 in
rodents), suggesting that a non-gonadal sex-biasing factor must be responsible. This project tests the
hypothesis that genetic differences between males and females (sex chromosome complement and associated
differences in expression dosage of X vs. Y chromosome genes) moderate PAE effects. This hypothesis will
be tested using Four-Core genotype mice, in which the normal relationship between sex chromosome
complement and gonadal sex has been broken; the four core genotypes thus include XX females, XY females,
XY males and XX males. We will use this model to systematically test the prediction that XY genotype,
irrespective of gonads and gonadally-derived steroids, is associated with heightened PAE-induced escalation
of adolescent ethanol intake and heightened anxiety-like behaviors, and that these behavioral effects reflect
disturbed inhibitory synaptic signaling via reduced alpha-1-containing GABAA receptor function in the medial
central nucleus of the amygdala. Additional studies will test the hypothesis that differential expression of
kdm6a - an X chromosome escapee – contributes to the differential responses of XX and XY individuals to
PAE. Collectively, these studies will define the mechanisms underlying the sex-biased response to gestational
alcohol exposure and may reveal molecular pathways and neural circuits that confer susceptibility to this
common environmental insult with pervasive effects on brain and behavior.

## Key facts

- **NIH application ID:** 10006507
- **Project number:** 5P50AA017823-12
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** J. DAVID JENTSCH
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $295,199
- **Award type:** 5
- **Project period:** 2009-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006507

## Citation

> US National Institutes of Health, RePORTER application 10006507, Main Research Component 1: Prenatal alcohol exposure: sex differences in effects on adolescent ethanol drinking, anxiety and associated neural circuitry (5P50AA017823-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006507. Licensed CC0.

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