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Germline transmission of epigenetic alterations to offspring

Award Number: R01ES032452
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Germline transmission of epigenetic alterations to offspring - ABSTRACT: The overall goal of this research program is to delineate the role of germline epigenetic alterations (epimutations) in the onset and progression of inter-and transgenerational reproductive defects. So far, published scientific literature suggests that environmentally induced epigenetic alterations, mainly DNA methylation, histone modifications, and RNA modifications (epitranscriptome), are transmitted to subsequent generations via germline (eggs or sperm)1. However, the role of observed epimutations in the development of reproductive phenotypes is not well understood because of a lack of clear understanding of PGC to germline and germline-to soma transfer of reprogramming-resistant epimutations during the turnover of generations. Here in the proposed study, we are asking three big questions: a) Do germline epimutations establish age and developmental stage specifically in males? b) Do ancestrally established transgenerational epimutations predispose future generations to increased risks for reproductive impairment if exposed again to emerging environmental chemicals of concern? c) Is the role of the observed epimutations in the development of progression of phenotypic traits causative or correlative? This R01 research project will systematically answer these questions in three different aims. BPA will be used as a ubiquitous model endocrine-disrupting chemical (EDC), and Bisphenol S (BPS) will be used as an emerging contaminant of concern, and medaka fish as a comparative vertebrate animal model. Aim 1 will test the hypothesis that male germ cells at all stages of development are susceptible to BPA, the model EDC. Aim 2 will test the hypothesis that exposure of the F3 generation offspring with pre-existing epimutations to emerging contaminants will result in an increased incidence of reproductive impairment. Aim 3 will test the hypothesis that the EDC-induced epimutations are associated with reduced fertility in males and females and that these epimutations can be corrected by reprogrammable CRISPR-dCas9 epigenome editing in vivo. The project will identify footprints of the past exposure, determine the role of epimutations in reproductive impairment, determine whether inherited epimutations predispose current and future generations to increased risks of reproductive health due to exposure to emerging contaminants of concern, and provide significant insights into mechanisms underlying germline transmission of the epigenome and longitudinal health risks of exposure. Understanding of key time points during which epimutations transfer would provide insights into strategies for the mitigation of future estrogenic chemical-induced reproductive health effects in humans.


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 = $335,466 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Environmental Health	000	5	11/20/2024	NON-COMPETING CONTINUATION	$335,466
														Subtotal = $335,466

Issue Date FY: 2024 ( Subtotal = $345,153 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Environmental Health	000	4	11/20/2023	NON-COMPETING CONTINUATION	$345,153
2024	2023	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN ST	GREENSBORO	NC	27412	GUILFORD	USA	Environmental Health	001	2	6/21/2024	NON-COMPETING CONTINUATION	-$61,593
2024	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Environmental Health	002	3	6/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$61,593
														Subtotal = $345,153

Issue Date FY: 2023 ( Subtotal = $354,498 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Environmental Health	002	3	7/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$215,613
2023	2023	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Environmental Health	001	2	7/25/2023	NON-COMPETING CONTINUATION	-$179,786
2023	2023	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Environmental Health	000	2	11/17/2022	NON-COMPETING CONTINUATION	$318,671
														Subtotal = $354,498

Issue Date FY: 2022 ( Subtotal = $309,662 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Environmental Health	000	1	2/16/2022	NEW	$309,662
														Subtotal = $309,662

Grand Total All Awards = $1,344,779

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Germline transmission of epigenetic alterations to offspring

Award Number: R01ES032452

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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