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Delineating mechanisms underlying azole-induced developmental toxicity using single cell transcriptomic approaches, genome editing tools, and alternative models

Award Number: R01ES033617
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Azoles are antifungal agents widely-used in clinical applications and agriculture. Despite evident exposures in humans, the developmental health risks associated with azole exposures during pregnancy remains undefined. In vertebrate models, azoles cause developmental toxicity, including a spectrum of congenital malformations. While the mechanisms are unresolved, azoles induce changes in the embryo that resemble excess bioavailability of all-trans retinoic acid (RA) due to similarities in adverse morphological and molecular phenotypes. In a spatiotemporal-dependent manner, RA regulates the transcription of hundreds of genes, several with known essential functions for embryonic development. Many environmental chemicals are suspected to cause developmental toxicity by disrupting RA signaling at different points in the pathway. As we transition towards alternative, animal-free approaches for developmental toxicity testing, delineating toxicological mechanisms associated with perturbations in key signaling pathways such as RA is warranted to establish appropriate in vitro and in silico testing models for identifying chemical hazards. In this project, we propose to leverage alternative models for developmental toxicity testing: rat whole embryo culture (WEC; Aim 1), zebrafish (Zf; Aim 2) embryo, and human embryonic stem cell (hESC; Aim 3) models and innovative molecular tools (e.g., single-cell RNA sequencing, CRISPR-Cas9), to investigate mechanisms linked with azole-induced developmental toxicity during a predefined susceptible window in embryogenesis (early organogenesis). We will determine conserved molecular, cellular, and morphological changes due to azole exposure and functional targets with roles in cell proliferation, differentiation and patterning. Results will be used to delineate an adverse outcome pathway (AOP) of azole-induced developmental toxicity. Finally, our study will be one of the first investigations to implement single-cell transcriptomics and multi-gene editing to link chemical exposures to adverse developmental outcomes on molecular, cellular and organism levels.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $795,032 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Environmental Health	000	4	1/6/2025	NON-COMPETING CONTINUATION	$711,294
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Environmental Health	001	4	1/7/2025	SUPPLEMENT FOR EXPANSION	$83,738
														Subtotal = $795,032

Issue Date FY: 2024 ( Subtotal = $823,817 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Environmental Health	000	3	12/28/2023	NON-COMPETING CONTINUATION	$713,475
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Environmental Health	001	3	2/12/2024	SUPPLEMENT FOR EXPANSION	$141,744
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Environmental Health	002	3	6/27/2024	SUPPLEMENT FOR EXPANSION	-$31,402
														Subtotal = $823,817

Issue Date FY: 2023 ( Subtotal = $773,620 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Environmental Health	000	2	12/23/2022	NON-COMPETING CONTINUATION	$715,653
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Environmental Health	001	2	8/22/2023	SUPPLEMENT FOR EXPANSION	$57,967
														Subtotal = $773,620

Issue Date FY: 2022 ( Subtotal = $715,222 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Environmental Health	000	1	3/4/2022	NEW	$715,222
														Subtotal = $715,222

Grand Total All Awards = $3,107,691

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Delineating mechanisms underlying azole-induced developmental toxicity using single cell transcriptomic approaches, genome editing tools, and alternative models

Award Number: R01ES033617

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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