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New approach methodologies using stem cell morphogenesis models for preclinical developmental toxicity screening

Award Number: R03ES037055
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: 04/09/2026
PERIOD OF PERFORMANCE END DATE: 04/08/2028

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New approach methodologies using stem cell morphogenesis models for preclinical developmental toxicity screening - Proposal Abstract Traditionally, live animals have been used to assess the toxicity of candidate chemicals in pharmaceutical drug development. However, animal tests are increasingly scrutinized for being time- consuming, costly, and ethically challenging. This has driven demand for non-animal alternative tests, or new approach methodologies (NAMs). The recent FDA Modernization Act 2.0 supports this shift by permitting the adoption of validated NAMs in place of animal tests for safety assessments and regulatory approval of human trials. NAMs can serve as first-tier screening tools to identify potentially toxic drugs, allowing only those with no apparent toxicity to proceed to animal testing if necessary. This tiered approach could significantly reduce live animal use. To achieve this goal, rigorous validation of individual NAMs according to international standards is essential to ensure regulatory acceptance. The proposed project aims to establish validated NAMs for developmental and reproductive toxicity (DART) assessment using morphogenesis models derived from pluripotent stem cells. My lab has previously developed these morphogenesis models from mouse and human stem cells, which recapitulate key morphological and molecular events of early embryogenesis in vitro. In published studies, we showed that these models exhibit significant morphological and gene expression changes in response to chemicals known to cause birth defects or miscarriages. To validate these models as NAMs for DART assessment, we will apply the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline, which provides a list of reference drugs with comprehensive in vivo toxicokinetics data, such as rodent plasma concentrations linked to embryotoxicity and non-embryotoxicity. These data can serve as benchmarks to evaluate the effectiveness of NAMs in predicting embryotoxic drug concentrations in alignment with in vivo results. To accomplish our objective, we propose three Specific Aims. Aim 1 is to examine the impact of embryotoxic drug exposures on the gene expression profiles in the mouse morphogenesis model. Aim 2 is to enhance detection capabilities through molecular augmentation of the mouse morphogenesis model. Aim 3 is to examine the response of a human stem cell-based morphogenesis model in reference to available rodent toxicokinetics data. This project is significant in its potential to establish validated NAMs as non-animal alternatives for preclinical DART assessments. It is innovative in its use of advanced stem cell technology to model embryological processes, facilitating precise concentration-specific analyses aligned with high international standards.


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 = $156,500 )
2026	2026	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Environmental Health	000	1	4/9/2026	NEW	$156,500
														Subtotal = $156,500

Grand Total All Awards = $156,500

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New approach methodologies using stem cell morphogenesis models for preclinical developmental toxicity screening

Award Number: R03ES037055

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: 04/09/2026

PERIOD OF PERFORMANCE END DATE: 04/08/2028

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