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Establishing Drosophila melanogaster as a model for determining gene-environment interactions that confer risk of autism using bisphenols and the autism risk gene, fragile x mental retardation 1

Award Number: SC2GM132005
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY There is an urgent need for an efficient system to identify environmental factors that confer risk of autism spectrum disorder (ASD). Evidence indicates that ASD can arise from complex gene-environment interactions during critical periods of neurodevelopment. Genomic studies have identified hundreds of genes linked to ASD, many of which have well-characterized neurodevelopmental functions. However, the identification of non-heritable etiologic factors is lagging. The effort is complicated by the fact that candidate environmental factors must also be examined in combination with ASD-associated genetic variants to adequately assess adverse effects. We propose using Drosophila melanogaster as a model organism for the identification of environmental ASD-risk factors; the combination of rapid generation time, genetic tractability, and simple assays for investigating neurodevelopmental phenotypes makes Drosophila an ideal candidate. Moreover, many ASD-associated genes are functionally conserved in Drosophila, including the most common monogenic cause of ASD: fragile x mental retardation 1 (FMR1). This study will determine if developmental exposure to chemicals commonly used in the production of plastics—bisphenol-A (BPA), bisphenol-F (BPF), and bisphenol-S (BPS)—interfere with neurodevelopment in wild-type and fmr1 mutant Drosophila. BPA has established endocrine-disrupting capabilities, and recent studies indicate that BPA may also disrupt neurodevelopment. BPA-free plastics typically contain BPA-analogues, such as BPF or BPS, that have been linked to endocrine-disruption, but their role in neural development is largely unknown. Because of the ubiquity of plastics in our environment and ability of bisphenols to cross the placental and fetal blood-brain barriers, it is critical to determine the potential neurodevelopmental impacts of these pervasive environmental chemicals. In Aim 1, two courtship paradigms (including an associative learning paradigm) of Drosophila behavioral analysis will be used to delineate the relative neurodevelopmental impacts of BPA, BPF, and BPS on wild-type and fmr1 Drosophila. In Aim, 2 in vivo immunohistochemical methods will be used to determine if BPA, BPF, and BPS affect three neuronal phenotypes relevant to ASD and linked to fmr1 function—neural stem cell proliferation, axon outgrowth, and synapse formation. This study is significant because it will determine if bisphenols molecularly converge with fmr1 to affect specific ASD-associated phenotypes. More broadly, this project will help establish Drosophila as a model for the investigation of gene-environment interactions, which would provide a low-cost alternative to vertebrate models and accelerate the pace of in vivo toxicological assessment. This project closely aligns with the mission of the National Institute of Mental Health to identify etiologies of and preventative measures for mental illness; characterization of gene-environment interactions that confer risk of ASD is critical for establishing preventative measures and to better define the complex biological underpinnings of this increasingly prevalent disorder.


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 = $0 )
2025	2021	UNIVERSITY ENTERPRISES, INC.	6000 J ST STE 3700	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	3	11/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY ENTERPRISES INC	6000 J ST	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	3	6/2/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $142,000 )
2021	2021	UNIVERSITY ENTERPRISES, INC.	6000 J ST	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	3	5/20/2021	NON-COMPETING CONTINUATION	$142,000
														Subtotal = $142,000

Issue Date FY: 2020 ( Subtotal = $142,000 )
2020	2020	UNIVERSITY ENTERPRISES, INC.	6000 J ST	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	2	5/19/2020	NON-COMPETING CONTINUATION	$142,000
														Subtotal = $142,000

Issue Date FY: 2019 ( Subtotal = $142,000 )
2019	2019	UNIVERSITY ENTERPRISES, INC.	6000 J ST	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	1	6/10/2019	NEW	$142,000
														Subtotal = $142,000

Grand Total All Awards = $426,000

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Establishing Drosophila melanogaster as a model for determining gene-environment interactions that confer risk of autism using bisphenols and the autism risk gene, fragile x mental retardation 1

Award Number: SC2GM132005

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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