# Retinoic Acid Signaling Disruption by Phthalates in Human and Rodent Fetal Testis

> **NIH NIH R00** · BROWN UNIVERSITY · 2020 · $234,374

## Abstract

This project, Retinoic Acid Signaling Disruption by Phthalates in Human and Rodent Fetal Testis, 
will improve male reproductive health by providing mechanistic information about disruption of a 
critical fetal testis developmental pathway by a ubiquitous class of environmental chemicals. 
Retinoic acid signaling regulates the entry of testicular germ cells into meiosis, and exogenous 
retinoic acid has dramatic effects on signaling pathways involved in gonadal sex determination and 
differentiation of the testis. Phthalates interact with retinoic acid signaling in the fetal testis 
in vitro. Phthalates and retinoic acid both cause adverse effects on the fetal seminiferous cord of 
multiple species. However, questions remain about the mechanisms responsible for the interaction 
and about the long-term effects of disrupting this signaling pathway. Fetal testis culture 
experiments have demonstrated that exogenous retinoic acid disrupts seminiferous cord development 
and signaling for sex determination, and that phthalates interact with retinoic acid to both 
enhance and inhibit some of these effects. R00 research will focus on comparisons between the rat 
fetal testis and both mouse and human fetal testis models (Specific Aim 1). This will
allow for important cross-species comparison with experiments in fetal testis cultures and cultured 
Sertoli cells. These experiments will quantify the response of the fetal testis to retinoic acid 
and phthalates using histology, immunohistochemistry, and gene expression as endpoints. Additional 
experiments will measure the impact of fetal phthalate and retinoic acid exposure on the mouse 
testis in later life, including development of the testis, spermatogenesis in adult mice, and 
changes in DNA methylation (Specific Aim 2). This will be a first step toward clarifying the 
mechanisms by which phthalate toxicity exerts persistent and potentially transgenerational effects 
by disrupting retinoic acid signaling in the fetal testis. This project is guided by the working 
hypothesis: phthalates interfere with fetal testicular development through disruption of retinoic 
acid signaling in the seminiferous cord.
The proposed experiments provide critical information about environmental exposures and effects on 
male reproductive health and serve the goal of this project: to describe the mechanism by which 
phthalates act on the retinoic acid signaling pathway to produce adverse outcomes during human 
fetal testicular development. This goal will be achieved by fulfilling the following Specific Aims. 
1: Compare the impact of disrupted retinoic acid signaling on testis development across species. 2: 
Identify persistent adverse outcomes of phthalate exposure mediated by altered retinoic acid signaling.

## Key facts

- **NIH application ID:** 9998947
- **Project number:** 5R00ES025231-05
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Daniel James Spade
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,374
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998947

## Citation

> US National Institutes of Health, RePORTER application 9998947, Retinoic Acid Signaling Disruption by Phthalates in Human and Rodent Fetal Testis (5R00ES025231-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998947. Licensed CC0.

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