# Prenatal arsenic exposure alters transcriptional, post-transcriptional and post-translational programming of the glucocorticoid system in a sexually dimorphic manner

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $335,363

## Abstract

Project Summary
Developmental exposure to inorganic arsenic has been associated with several adverse health effects, including
reduction in cognitive performance and increased rates of psychiatric disorders. Altered programming of the
glucocorticoid receptor (GR) could account for many of the long-lasting consequences of arsenic. While the
impact of arsenic exposure on the epigenome has been studied in the context of cancer research, the influence
of this toxicant in the developing brain, particularly as it relates to epigenetics, is not well understood.
In our previous work, we found that male offspring exposed to 50 ppb arsenic prenatally (PAE) had decreased
expression of both GR protein and mRNA in brain. Female PAE mice were resistant to arsenic induced changes
in GR protein despite elevations in GR (Nr3c1) mRNA. In assessing epigenetic mechanisms, we found PAE
affected levels of histone3 lysine4 trimethylation (H3K4me3) as well as several noncoding RNAs (miRs and
lncRNA) in a sex-dependent manner. The goal of this competing renewal is to demonstrate that changes in
transcriptional, posttranscriptional and posttranslational regulation result in PAE sex-dependent effects at a
molecular, physiological and behavioral level.
Specific Aim 1 will test the hypothesis that PAE alters histone modifications that control the
transcription of stress-related genes during fetal development in a sex-specific manner. We will
assess histone posttranslational modifications (HPTMs), H3K4 me3/ H3K27 me3, histone writers and erasers,
and associated genes by western and sequential ChIP-qPCR techniques. We will confirm a functional link by
pharmacologically altering specific histone marks at embryonic day 12.5 (E12.5).
Specific Aim 2 will test the hypothesis that PAE alters the posttranscriptional regulation of
stress-related mRNA levels through micro-RNAs (miRs) during fetal development in a sex-
specific manner. These experiments will assess miR expression using qPCR and miR-RIP to target the GR
signaling system. We will confirm a functional link using LNA microRNA mimics and LNA-antimiR at E12.5.
Specific Aim 3 will test the hypothesis that PAE alters the posttranslational regulation of stress-
related proteins through long noncoding RNA (lncRNA) during fetal development in a sex-
specific manner. These experiments will assess growth arrest-specific 5 (Gas-5) expression at E12-18. We
will confirm a functional link to the GR system using LNA-GAPmer and LNA–antimir approaches.
Specific Aim 4 will test the mechanistic link between PAE-induced transcriptional,
posttranscriptional and/or posttranslational changes and the functional outcomes in the adult
animal. These experiments will assess the impact of interventions identified in Aims 1-3 on arsenic-induced
deficits: corticosterone response, learning and depression.

## Key facts

- **NIH application ID:** 9898373
- **Project number:** 5R01ES019583-09
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** ANDREA M ALLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,363
- **Award type:** 5
- **Project period:** 2010-12-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898373

## Citation

> US National Institutes of Health, RePORTER application 9898373, Prenatal arsenic exposure alters transcriptional, post-transcriptional and post-translational programming of the glucocorticoid system in a sexually dimorphic manner (5R01ES019583-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9898373. Licensed CC0.

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