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Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

Award Number: R01ES023316
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: 09/01/2013
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance - Studies in animal models linked gestational exposures to endocrine disrupting chemicals (EDCs) with the onset of disease in exposed and unexposed descendants. Many groups found such transgenerational effects of chemical exposures, which were proposed to be examples of epigenetic inheritance. Transgenerational effects of environmental exposures have substantial support in the literature. Yet the concept that responses to environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations remains controversial because the underlying mechanisms have not been explained satisfactorily. Understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental, unanswered question in biology. We developed a highly reproducible animal model for transgenerational inheritance of obesity. When pregnant F0 mouse dams were treated with environmentally-relevant (nM) doses of TBT via their drinking water throughout gestation, increased fat accumulation was detected in F1-F4 generation male descendants. Affected TBT-group males developed a transgenerational “thrifty phenotype”: they were resistant to fat loss during fasting, rapidly gained weight when dietary fat was increased and retained this fat even after being returned to a normal, low-fat diet. Our published and preliminary results led us to propose a new model for transgenerational inheritance - that prenatal TBT exposure altered higher-order chromatin structure (HOCS), changing secondary epigenetic modifiers that inhibited expression of insulin degrading enzyme (Ide) causing diet-induced hyperinsulinemia and obesity. Here we propose a comprehensive series of experiments designed to determine exactly how exposure of pregnant F0 dams to TBT alters HOCS in F1-F3 primordial germ cells (PGCs), why these changes are inherited, rather than reversed to the normal state, how these changes affect lower-level epigenetic regulators controlling expression of Ide and why does the phenotype only occur in males. Aim 1 will identify mechanisms that drive changes HOCS near the Ide gene and how these interact with lower-level epigenetic regulators to modulate Ide expression in the adult liver. Aim 2 tests whether epigenetic interventions, such as dissolving the HOCS alterations or releasing Ide expression from repression in PGCs or adults can prevent or reverse the transgenerational predisposition to male-specific metabolic phenotypes. Deciphering the underlying mechanisms will have profound implications for how the field views transgenerational inheritance and how future experiments are planned and conducted. This new understanding will be critical to explaining the etiology of non-communicable diseases such as obesity and type 2 diabetes, targeting their causes and ameliorating their effects. Our results will have broad implications for understanding epigenetic transmission of the effects of environmental stressors and could offer opportunities to incorporate considering prevention of transgenerational inheritance into risk assessment paradigms.


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 = $633,756 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	13	5/4/2026	NON-COMPETING CONTINUATION	$633,756
														Subtotal = $633,756

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	12	4/28/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	001	12	7/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $640,087 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	003	12	9/18/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	12	5/27/2024	NON-COMPETING CONTINUATION	$640,087
2024	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	002	11	5/30/2024	COMPETING CONTINUATION	$29,898
2024	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	001	10	5/30/2024	NON-COMPETING CONTINUATION	-$29,898
														Subtotal = $640,087

Issue Date FY: 2023 ( Subtotal = $660,457 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	002	11	7/3/2023	COMPETING CONTINUATION	$660,457
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	10	6/16/2023	NON-COMPETING CONTINUATION	$0
2023	2022	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Environmental Health	001	10	6/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $660,457

Issue Date FY: 2022 ( Subtotal = $584,633 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	10	4/29/2022	NON-COMPETING CONTINUATION	$584,633
														Subtotal = $584,633

Issue Date FY: 2021 ( Subtotal = $587,196 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	9	4/28/2021	NON-COMPETING CONTINUATION	$587,196
														Subtotal = $587,196

Issue Date FY: 2020 ( Subtotal = $589,708 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	8	4/13/2020	NON-COMPETING CONTINUATION	$589,708
														Subtotal = $589,708

Issue Date FY: 2019 ( Subtotal = $596,380 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	001	7	4/9/2019	NON-COMPETING CONTINUATION	$596,380
2019	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	5	3/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $596,380

Issue Date FY: 2018 ( Subtotal = $617,630 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	6	7/31/2018	COMPETING CONTINUATION	$617,630
														Subtotal = $617,630

Issue Date FY: 2017 ( Subtotal = $670,342 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	001	5	7/26/2017	NON-COMPETING CONTINUATION	$670,342
2017	2015	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Environmental Health	000	3	3/1/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,342

Issue Date FY: 2016 ( Subtotal = $670,342 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	4	7/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$670,342
														Subtotal = $670,342

Issue Date FY: 2015 ( Subtotal = $670,342 )
2015	2015	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	3	7/27/2015	NON-COMPETING CONTINUATION	$670,342
														Subtotal = $670,342

Issue Date FY: 2014 ( Subtotal = $663,637 )
2014	2014	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	2	7/29/2014	NON-COMPETING CONTINUATION	$663,637
														Subtotal = $663,637

Issue Date FY: 2013 ( Subtotal = $683,024 )
2013	2013	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Environmental Health	000	1	8/29/2013	NEW	$683,024
														Subtotal = $683,024

Grand Total All Awards = $8,267,534

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Chromatin contacts are germline-transmissable vehicles underlying epigenetic transgenerational inheritance

Award Number: R01ES023316

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: 09/01/2013

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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