# DEVELOPMENTAL TOXICITY OF ORGANOPHOSPHATE-BASED FLAME RETARDANTS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $337,018

## Abstract

In 2005, the commercial polybrominated diphenyl ether (PBDE) mixture known as PentaBDE – a widely used
brominated flame retardant (FR) – was voluntarily phased out in the United States due to concerns about
persistence, bioaccumulation, and toxicity. Due to increased use as PentaBDE replacements for low-density
polyurethane foam in numerous products, organophosphate-based FRs (OPFRs) have now been detected at
concentrations comparable to and, in some cases, higher than total PBDE concentrations within indoor dust,
suggesting that chronic human exposure to these alternative flame retardants following migration from treated
end-use products is common within the United States. Using zebrafish as a model, our long-term goal is to
identify xenobiotic-mediated pathways that contribute to adverse outcomes during early embryonic
development. Consistent with this long-term goal, the overall objective of this application is to continue
uncovering the mechanism of developmental toxicity for two high-production volume OPFRs commonly
detected at elevated concentrations within indoor environments. Our central hypotheses are that tris(1,3-
dichloro-2-propyl) phosphate (TDCPP, a chlorinated phosphate ester) disrupts DNA methylation during
cleavage and, consequently, delays epiboly progression from late-blastula through gastrula, whereas triphenyl
phosphate (TPP, an unsubstituted aryl phosphate ester) activates peroxisome proliferator-activated receptor γ
(PPARγ) – a major target for TPP-induced binding and activation – within the developing embryonic heart
during pharyngula, resulting in disruption of normal retinoic acid receptor (RAR)/retinoid X receptor (RXR)-
mediated signaling and inhibition of cardiac looping. Based on studies conducted within our laboratory over the
last five years, these hypotheses will be tested by pursuing two comprehensive specific aims: 1) Identify how
TDCPP-induced disruption of DNA methylation during cleavage delays epiboly progression from late-blastula
through gastrula; and 2) Identify how TPP-induced PPARγ activation disrupts RAR-RXR signaling and blocks
cardiac looping during heart morphogenesis. The proposed research is innovative because we will (1) leverage
the power and versatility of the zebrafish embryo model; (2) leverage our extensive expertise with automated
image acquisition and analysis; (3) for the first time, rely on bisulfite amplicon sequencing and whole-mount
methylation-specific fluorescence in situ hybridization to assess DNA methylation dynamics within zebrafish
embryos; and (4) for the first time, develop a stable transgenic reporter zebrafish line that will allow us and
other investigators to identify potential PPARγ ligands in vivo. This contribution is significant because it (1)
begins to address key uncertainties about mechanisms of developmental OPFR toxicity; (2) helps prioritize
targeted, mechanism-focused evaluations using prenatal developmental toxicity studies within rodents and
epidemiological stu...

## Key facts

- **NIH application ID:** 9868310
- **Project number:** 5R01ES027576-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** David C. Volz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,018
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868310

## Citation

> US National Institutes of Health, RePORTER application 9868310, DEVELOPMENTAL TOXICITY OF ORGANOPHOSPHATE-BASED FLAME RETARDANTS (5R01ES027576-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868310. Licensed CC0.

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