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Developmental flame retardant exposure, gut microbiome, and obesity

Award Number: R01ES030197
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: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Developmental flame retardant exposure, gut microbiome, and obesity - PROJECT SUMMARY Obesity and type-II diabetes are a pandemic, causing grave social and economic burdens in the United States. Epidemiological and animal studies showed that the flame retardants polybrominated diphenyl ethers (PBDEs) and a most widely used current PBDE-alternative – tetrabromobisphenol A (TBBPA) are linked to obesity and diabetes. However, mechanisms governing early life exposure to flame retardants and obesity/diabetes remains unknown; no studies have compared the effect of PBDEs vs. TBBPA, and little is known regarding how early life flame retardant plus additional risk factors (e.g. dietary factors) later in life modulate obesity. The liver- and intestine-enriched pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are novel regulators for obesity. Intestinal inflammation, as triggered by dysbiosis of the gut microbiota, is an early mediator of obesity and type-II diabetes. In the previous grant cycle, we have demonstrated that: 1) early life exposure to the PBDEs and TBBPA produces a pro-inflammatory/pro-obese microbial signature later in life; 2) PXR and CAR are necessary in maintaining the basal healthy gut flora to prevent the blooming of pro-inflammatory microbes; 3) the presence of gut microbiome promotes immunotolerance in the liver, whereas early life exposure to PBDEs produced gut dysbiosis associated with enhanced immune cell hepatic mobilization, reduced PXR/CAR signaling, and predicted liver injuries in adulthood; Early life exposure to an industrial PBDE mixture persistently disrupted the microbial tryptophan metabolism. We also showed that the microbial tryptophan metabolite indole-3- propionic acid (IPA) mimicry FKK6 compound protected against intestinal inflammation associated with increased anti-inflammatory short-chain fatty acids (SCFAs) and the SCFA-producing microbes. Building on our findings, the objective of the renewal is to determine how the host nuclear receptors, gut microbiome, and early life flame retardant exposure interact to modulate the adult onset of obesity and type-II diabetes. Our central hypothesis is: early life flame retardant exposures upset the physiological functions of PXR/CAR, leading to pro- inflammation and pro-obesity microbial metabolites and elevated AhR signaling, which augmented obesity following a 2nd hit (e.g. a high fat diet [HFD]) later in life; whereas the microbial mimicry is a novel remediation strategy. We will test this hypothesis in 3 Aims: Aim 1 will determine to what extent PXR and CAR modulate the inflammation- and obesity-related host and microbial signatures following early life exposure to PBDEs and TBBPA. Aim 2 will determine how early life flame retardant exposure and PXR/CAR interact to modulate the high fat diet-induced obesity later in life. Aim 3 will determine how gut microbiome mechanistically contributes to the divergent roles of PXR and CAR in obesity following the “two-hit” exposure paradigm. The overall impact of this research is that we will determine how TBBPA vs. PBDE exposure in early life, especially in the combination of a high-risk obesogenic adult diet, results in adult obesity. This perspective will be shown through the lens of the important host nuclear receptors, which are well-established mediators of endocrine response.


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 = $499,625 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	002	7	2/14/2025	NON-COMPETING CONTINUATION	$499,625
2025	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	001	6	2/12/2025	COMPETING CONTINUATION	$321,161
2025	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	5	2/12/2025	NON-COMPETING CONTINUATION	-$321,161
														Subtotal = $499,625

Issue Date FY: 2024 ( Subtotal = $679,987 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	001	6	4/2/2024	COMPETING CONTINUATION	$679,987
2024	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	5	3/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $679,987

Issue Date FY: 2023 ( Subtotal = $596,584 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	5	12/23/2022	NON-COMPETING CONTINUATION	$596,584
														Subtotal = $596,584

Issue Date FY: 2022 ( Subtotal = $606,172 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	4	12/15/2021	NON-COMPETING CONTINUATION	$606,172
														Subtotal = $606,172

Issue Date FY: 2021 ( Subtotal = $616,474 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	3	12/21/2020	NON-COMPETING CONTINUATION	$616,474
														Subtotal = $616,474

Issue Date FY: 2020 ( Subtotal = $626,238 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	2	12/17/2019	NON-COMPETING CONTINUATION	$626,238
														Subtotal = $626,238

Issue Date FY: 2019 ( Subtotal = $664,850 )
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	001	1	1/9/2019	NEW	$0
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Environmental Health	000	1	12/27/2018	NEW	$664,850
														Subtotal = $664,850

Grand Total All Awards = $4,289,930

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Developmental flame retardant exposure, gut microbiome, and obesity

Award Number: R01ES030197

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: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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