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Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity

Award Number: R15ES030541
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: 05/16/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity - Project Summary. This is a renewal application of an initial award to explore genetic susceptibility to benzo[a]pyrene (BaP)-induced developmental neurotoxicity. BaP is a model polycyclic aromatic hydrocarbon found in traffic-related air pollution (TRAP), wildfire and cigarette smoke and grilled foods. Human studies have linked prenatal and early life exposure to PAHs with adverse effects on cognition and behavior persisting from early childhood to adolescence. Extensive animal studies have strongly implicated aryl hydrocarbon receptor (AHR) agonists including PAHs in developmental neurotoxicity. Our initial studies used mice with genetic differences in the AHR and two metabolic enzymes regulated by the AHR: CYP1A1 and CYP1A2. All three genes of interest vary in the human population and have been linked to adverse effects following exposure to TRAP. Data from our initial studies strongly supported our hypothesis that the AHR pathway plays a key role in mediating BaP developmental neurotoxicity. Both Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice had greater impairments in tests of learning and memory compared with wild type mice exposed to the same dose of BaP during gestation and lactation. Interestingly, we also found differences in behavior based on genotype alone in the knockout lines. This novel finding suggests both genes have a normal role in brain development or function. Both humans and mice have three members of the CYP1 family, so our future work will probe the significance of CYP1B1 and further explore mechanisms of neurotoxicity in the Cyp1a1 and Cyp1a2 knockouts. Aim 1: Determine the role of CYP1B1 in BaP neurotoxicity by comparing Cyp1b1(+/+) wild type and Cyp1b1(-/-) knockout mice using validated tests of learning & memory, behavior, and motor function, quantification of neurotransmitters and gene expression in brain regions governing those functions. Our initial studies uncovered increased susceptibility to developmental BaP exposure in mice lacking CYP1A1 and CYP1A2. These studies will allow us to complete the characterization of the entire CYP1 family in our mouse model. Aim 2: Identify changes in the gut microbiome and downstream metabolites associated with neuroprotection v neuroinflammation. During our initial studies, we were able to do an exploratory analysis of the gut microbiome in BaP-treated and control Cyp1a1(+/+) wild type and Cyp1a1(-/-) knockout dams and pups. We found significant differences in beta diversity in BaP-exposed knockouts. Using a targeted metabolomics approach, we also found striking differences in the tryptophan-kynurenine pathway in BaP treated Cyp1a2(-/-) knockout mice. These data and recent studies identifying links between AHR activation and dysregulation of the TRP-KYN pathway suggest a potential mechanism of neurotoxicity. As an AREA-R15 application, this will strengthen the research environment at Northern Kentucky University, a predominantly undergraduate institution in the Greater Cincinnati area serving a large percentage of diverse and disadvantaged students and support an Early Stage Investigator who can train these students in the use of bioinformatics techniques.


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 = $0 )
2026	2023	NORTHERN KENTUCKY UNIVERSITY	NUNN DR	NEWPORT	KY	41099	CAMPBELL	USA	Environmental Health	000	2	7/7/2026	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $400,151 )
2023	2023	NORTHERN KENTUCKY UNIVERSITY	NUNN DR	NEWPORT	KY	41099	CAMPBELL	USA	Environmental Health	000	2	8/15/2023	COMPETING CONTINUATION	$420,000
2023	2019	NORTHERN KENTUCKY UNIVERSITY	NUNN DR	NEWPORT	KY	41099	CAMPBELL	USA	Environmental Health	001	1	9/24/2023	NEW	-$19,849
														Subtotal = $400,151

Issue Date FY: 2019 ( Subtotal = $397,500 )
2019	2019	NORTHERN KENTUCKY UNIVERSITY	NUNN DR	NEWPORT	KY	41099	CAMPBELL	USA	Environmental Health	000	1	5/9/2019	NEW	$397,500
														Subtotal = $397,500

Grand Total All Awards = $797,651

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Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity

Award Number: R15ES030541

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: 05/16/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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