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Investigating neurodevelopmental toxicity of perfluoroalkyl acids and their derivatives in human brain organoids models

Award Number: R01ES033636
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/07/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Investigating neurodevelopmental toxicity of perfluoroalkyl acids and their derivatives in human brain organoids models - SUMMARY Per- and polyfluoroalkyl substances and their derivatives (PFAS) are industrial chemicals that are wide- spread in the environment, including blood serum of wildlife and humans. Their pervasiveness and long half-life raises the questions about their toxicity, especially with regards to the effect on the developing fetus. Several studies have demonstrated that these compounds cross the placenta, are found in the umbilical cord blood, and can cause neurodevelopmental abnormalities in the offspring of the exposed mothers, including early pregnancy loss, low birth weight, hyperactivity, decreased head circumference and behavior problems. However, the molecular mechanisms following PFAS exposure, such as dysregulated genes and pathways, especially in the context of human brain development, remain unexplored. Here, we are proposing to use human induced pluripotent stem cell (iPSC) derived models such as neural progenitor cells (NPCs), spheroids and brain cortical organoids, to fill in this knowledge gap. We hypothesize that PFAS impact early brain development by dysregulating transcriptional programs of NPCs that are involved in proliferation, cell cycle and survival. We also hypothesize that these early alterations will have significant impact on the formation of cortical networks. We are proposing the following Specific Aims to test these hypotheses: (1) Investigate dose- dependent impact of PFAS on neural progenitor cell cycle, cell viability and proliferation; (2) Perform genome- wide pooled genetic screens with CRISPRi/a sgRNA libraries to identify modifier genes and pathways upon PFAS treatment; (3) Validate the impact of PFAS on long-term neurodevelopment in cortical organoids models and identify cell populations impacted by PFAS. Our study will identify genes, molecular and cellular pathways dysregulated by PFAS exposure across various stages of brain development, modeled in vitro. It has a potential to uncover new mechanisms behind PFAS exposure, and to predict the impact of PFAS on developing human brain network function.


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: 2026 ( Subtotal = $607,486 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Environmental Health	000	5	12/18/2025	NON-COMPETING CONTINUATION	$607,486
														Subtotal = $607,486

Issue Date FY: 2025 ( Subtotal = $604,748 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Environmental Health	000	4	11/20/2024	NON-COMPETING CONTINUATION	$604,748
														Subtotal = $604,748

Issue Date FY: 2024 ( Subtotal = $602,132 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Environmental Health	000	3	11/29/2023	NON-COMPETING CONTINUATION	$602,132
														Subtotal = $602,132

Issue Date FY: 2023 ( Subtotal = $605,693 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Environmental Health	000	2	11/21/2022	NON-COMPETING CONTINUATION	$605,693
														Subtotal = $605,693

Issue Date FY: 2022 ( Subtotal = $606,887 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Environmental Health	000	1	2/4/2022	NEW	$606,887
														Subtotal = $606,887

Grand Total All Awards = $3,026,946

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Investigating neurodevelopmental toxicity of perfluoroalkyl acids and their derivatives in human brain organoids models

Award Number: R01ES033636

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/07/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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