Refining the AOP for retinoid-induced teratogenicity: Insights into RAR/ RXR overactivation and RXR cross-talk with retinoic acid and thyroid hormone signaling

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F25%3A00085934" target="_blank" >RIV/00023001:_____/25:00085934 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14310/25:00143243 RIV/00159816:_____/25:00082257

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0166445X25003728?ref=pdf_download&fr=RR-2&rr=99dd02e3adcafc6d" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0166445X25003728?ref=pdf_download&fr=RR-2&rr=99dd02e3adcafc6d</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.aquatox.2025.107608" target="_blank" >10.1016/j.aquatox.2025.107608</a>

Result language

angličtina

Original language name

Refining the AOP for retinoid-induced teratogenicity: Insights into RAR/ RXR overactivation and RXR cross-talk with retinoic acid and thyroid hormone signaling

Original language description

Retinoic acid (RA), a vitamin A metabolite, plays a crucial and evolutionarily conserved role in vertebrate development. Chemical disruption of retinoid signaling can severely affect organisms; yet, despite its teratogenicity and pathway interactions, this disruption remains understudied. Increasing research aims to address these gaps by developing comprehensive frameworks like Adverse Outcome Pathways (AOPs). This study refines a previously proposed AOP network on retinoid-induced teratogenicity by: (1) empirically confirming over-activation of the Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR) heterodimer as the molecular initiating event (MIE), through morphological rescue of 5 dpf zebrafish co-exposed to all-trans Retinoic Acid (ATRA), a RAR ligand, and either BMS493 (RAR inverse agonist) or UVI3003 (RXR antagonist); (2) Identifying the window of sensitivity for MIE through time-stage co-exposure (4-24, 4-48, 4-72, and 4-120 hpf); (3) integrating key molecular and cellular events from existing knowledge. The study also brings new knowledge on how RXR signaling disruption contributes to RA and Thyroid Hormone (TH) signaling disruption using in vitro reporter assays and in vivo morphological endpoints. Results show that BMS493 and, unexpectedly, diclazuril (pesticide identified as a thyroid hormone receptor antagonist in vitro) inhibit Retinoic Acid Response Element (RARE) activity in vitro. UVI3003-ATRA co-exposure induced additive effect on RARE activity. UVI3003-TH co-exposure inhibited Thyroid Hormone Response Element activity. In zebrafish, co-exposure of ATRA with BMS493 or diclazuril rescued ATRA-induced malformations, i.e., craniofacial and tail malformations, and microphthalmia-confirming RAR/RXR overactivation as MIE. It also rescued posterior swim bladder inflation and retinal layer defects-revealing novel role for RAR/RXR in these phenotypes. Additionally, UVI3003-ATRA co-exposure increased zebrafish embryos mortality, and UVI3003 alone increased fluorescence expressed in thyrocytes of thyroglobulin-mCherry zebrafish. Altogether, these findings reveal RXR&apos;s involvement in endocrine crosstalk and highlight the critical role of retinoid signaling in developmental toxicity and the need for its inclusion in hazard assessment.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30108 - Toxicology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Aquatic Toxicology

ISSN

0166-445X

e-ISSN

1879-1514

Volume of the periodical

289

Issue of the periodical within the volume

December 2025

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

17

Pages from-to

"art. no. 107608"

UT code for WoS article

001606603800001

EID of the result in the Scopus database

2-s2.0-105020935591