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Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals

Award Number: R01ES030364
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The environmental obesogen hypothesis posits that lipophilic persistent organic pollutants (POPs) accumulate in adipose tissue (AT) and can disrupt metabolic systems. However, the underlying molecular mechanisms of these toxicants on AT function remain poorly understood. As the most studied POP, dichlorodiphenyl- dichloroethylene (DDE), a persistent metabolite of the insecticide dichlorodiphenyl-trichloroethane (DDT), provides a model for assessing the metabolic health impact of lipophilic POPs. Almost all U.S. children and adolescents have detectable DDE blood levels. Despite abundant evidence from experimental studies showing that DDE disrupts metabolic homeostasis, mechanisms underlying metabolic disruption by DDE in humans are unclear. We therefore propose a novel study design for investigating mechanisms of DDE metabolic effects in humans, based on a remarkable archive of clinical data and visceral AT samples from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and an in vitro human adipocyte experimental model. We hypothesize that the large metabolic changes after bariatric surgery provide a “natural experiment” that will magnify effects of the prototypical obesogen DDE, and that DDE in visceral AT will attenuate the reduction in body mass index and insulin resistance after bariatric surgery in a concentration-dependent manner (Aim 1). Although we know that high doses of DDE impair thermogenesis and insulin signaling in animal models, we still do not know whether these mechanisms underlie metabolic disruption by DDE in humans. We will assess effects of DDE on these pathways in a human primary adipocyte cell line, an experimental model that will be free from the potential for uncontrolled confounding in human observational studies and that may also identify new pathways (Aim 2). We will then test these pathways in metabolome and transcriptome profiles of human AT from Teen-LABS study participants, using a hierarchical modeling approach (Aim 3). Finally, we will integrate results from the DDE omics analyses in human AT and in the adipocyte cell line, using a novel latent variable modeling framework, to identify subgroups of adolescents who have less weight loss and less improvement in insulin resistance after bariatric surgery, based on their DDE exposure and multi-omics profile in AT (Aim 4). The proposed research will be the first human study to examine mechanisms of DDE toxicity to AT in humans, using adipose tissue-specific exposure and omic measures, and clinically relevant metabolic outcomes such as BMI and insulin resistance. A strong interdisciplinary team of investigators brings expertise in environmental epidemiology, bariatric surgery, toxicology, omics, and biostatistics. Our study, integrating in vitro and human observational approaches, has the potential to establish a new paradigm for the study of lipophilic obesogenic chemicals and to advance our understanding of environmental contributions to obesity and type 2 diabetes.


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: 2024 ( Subtotal = $626,692 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Environmental Health	000	5	12/8/2023	NON-COMPETING CONTINUATION	$626,692
														Subtotal = $626,692

Issue Date FY: 2023 ( Subtotal = $642,905 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Environmental Health	000	4	11/23/2022	NON-COMPETING CONTINUATION	$642,905
														Subtotal = $642,905

Issue Date FY: 2022 ( Subtotal = $643,019 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Environmental Health	000	3	1/13/2022	NON-COMPETING CONTINUATION	$643,019
														Subtotal = $643,019

Issue Date FY: 2021 ( Subtotal = $638,117 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Environmental Health	000	2	11/19/2020	NON-COMPETING CONTINUATION	$638,117
														Subtotal = $638,117

Issue Date FY: 2020 ( Subtotal = $678,924 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Environmental Health	000	1	1/23/2020	NEW	$678,924
														Subtotal = $678,924

Grand Total All Awards = $3,229,657

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Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals

Award Number: R01ES030364

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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