# Sexually dimorphic epigenetic regulation of fetal brain development by environmental stressors

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $193,125

## Abstract

PROJECT SUMMARY
The prevalence of neurodevelopmental disorders of behavior and cognition such as autism spectrum disorders
(ASDs) is increased by prenatal exposure to pathogenic environmental stressors such as the anti-epileptic,
mood-stabilizing drug, valproic acid (VPA) and organophosphate insecticides such as chlorpyrifos. The under-
lying cellular and molecular mechanisms are not known. Many mental disorders are sexually dimorphic. Some
(e.g., ASD and ADHD) are more common in males whereas others (e.g., major depression and anxiety) are
more common in females. A goal of this research program is to investigate the biological basis for these sex
differences in fetal mouse brain exposed to environmental stressors during early gestation, prior to the appear-
ance of sex hormones. Published work by the PI has identified VPA-induced sex differences in the activating
epigenetic mark, H3K4me3, leading to sexually-dimorphic expression of Bdnf, the gene encoding brain-derived
neurotrophic factor. These studies with Bdnf establish an experimental paradigm for identifying other sexually-
dimorphic proteins that regulate brain development and that may mediate the pathogenic effects of environ-
mental stressors on brain development. An important clue to the underlying mechanism is that the enzymes
that regulate H3K4me3, the H3K4-demethylases, JARID1C and JARID1D, are encoded by genes on the X and
Y-chromosomes, respectively, and are therefore postulated to be differentially expressed in the two sexes. The
specific aims of this research program are to 1) identify genes involved in early brain development (in addition
to Bdnf) that are expressed differently in males and females in response to VPA due to sexually dimorphic
H3K4 trimethylation and 2) test the hypothesis that JARID1 gene expression and enzyme activity are greater in
males than in females, thereby providing a plausible mechanism for sexually dimorphic gene expression in the
fetal brain. Identification of such genes, particularly if found to be associated with one or more developmentally
relevant signaling pathways, will lead to a clearer understanding of the etiology of neurodevelopmental disor-
ders such as ASDs and provide the basis for future, hypothesis driven initiatives to determine the pathogenic
mechanisms of action of other environmental stressors acting during early gestation.

## Key facts

- **NIH application ID:** 9905527
- **Project number:** 5R21ES030137-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** BRUCE K KRUEGER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,125
- **Award type:** 5
- **Project period:** 2019-04-02 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905527

## Citation

> US National Institutes of Health, RePORTER application 9905527, Sexually dimorphic epigenetic regulation of fetal brain development by environmental stressors (5R21ES030137-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9905527. Licensed CC0.

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