# Reproductive and Developmental Toxicity of Dioxin

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $461,276

## Abstract

PROJECT SUMMARY
 Clinical management of urinary disorders costs Americans over four billion dollars annually, demanding
a better understanding of risk factors that underlie or contribute to these disorders. We provide compelling
evidence for a new paradigm that a man's fetal andneonatal environment determines his risk of developing
urinary complications of benign prostatic disease in adulthood. The proposed studies offer needed insight into
disease pathogenesis, incidence, and why some men develop urinary complications of benign prostate
hyperplasia (BPH) at a younger age or with more severe symptoms than others. Our preliminary results show in
utero and lactational (IUL) exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) causes severe urinary
dysfunction in mice susceptible to BPH. TCDD is a widespread contaminant, ubiquitous in serum of American
men, and a selective activator of the aryl hydrocarbon receptor (AHR), a receptor that can be activated by many
persistent organic pollutants. We isolated two potential mechanisms by which IUL TCDD exposure impairs
urinary function: by increasing sensory nerve fibers during lower urinary tract development and by enhancing
estrogen receptor signaling. We also discovered that age of mice at the time of TCDD exposure determines the
impact on mouse urinary function. Adult TCDD exposure has the opposite effect of IUL exposure - it protects
against urinary dysfunction in mice susceptible to urinary complications of BPH. These findings create a
remarkable opportunity to test whether AHR activation in the prostate and lower urinary tract of adult males is
therapeutic for urinary dysfunction. We synthesized novel selective AHR modulators (SAHRMs), verified their
potency in vitro, and will perform pre-clinical testing in vivo. This proposal's three specific aims will test the
following hypotheses: (1) IUL TCDD exposure increases the number of sensory nerve fibers in the prostate and
prostatic urethra, having a lasting effect on urinary function, (2) IUL TCDD exposure impairs urinary function
through a mechanism requiring stromal estrogen receptor-alpha (ERα), and (3) the impact of TCDD exposure
on urinary function differs depending on when exposure occurs, perinatal period versus adulthood. As part of
aim 3, we will also test the hypothesis that adult exposure to SAHRMs, which lack TCDD-like toxicity, offers
therapeutic benefit by reducing urinary dysfunction in BPH susceptible mice. By establishing a mechanistic
connection between TCDD exposure and urinary function, the proposed studies launch original lines of research
into a disease process never before linked to developmental origins or AHR signaling. We also expect to reveal
the AHR as a new therapeutic target for treating urinary complications of BPH, a disease against which current
drugs are only marginally effective.

## Key facts

- **NIH application ID:** 9975167
- **Project number:** 5R01ES001332-43
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** RICHARD Eugene PETERSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $461,276
- **Award type:** 5
- **Project period:** 1978-06-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975167

## Citation

> US National Institutes of Health, RePORTER application 9975167, Reproductive and Developmental Toxicity of Dioxin (5R01ES001332-43). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9975167. Licensed CC0.

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