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The interaction of perinatal organophosphate flame retardant exposure and adult chronic stress on cognitive processing

Award Number: K99ES033256
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/02/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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The interaction of perinatal organophosphate flame retardant exposure and adult chronic stress on cognitive processing - Project Summary Abstract Mental disorders, including major depressive disorder, schizophrenia, and others, all share a central feature – cognitive impairment which results in individuals confronted with difficulty in memory, concentration, and decision-making. Emerging evidence points to two key factors contributing to cognitive decline beyond the underlying disease pathology - exposure to 1) environmental chemicals such as endocrine disrupting compounds (EDCs) during development and 2) chronic stress in adulthood. The interaction of chemical exposure and stress are unknown; but together may exacerbate cognitive impairment. First, EDCs exert their toxicity by disrupting nuclear receptor signaling during sensitive brain developmental periods. Numerous EDC studies have detected cognitive impairments in humans and animals. One group of understudied EDCs are organophosphate flame retardants (OPFRs) acting on nuclear and steroid receptors linked with cognition. The association between perinatal OPFR exposure and cognitive processing has not been explored. We previously identified an association between perinatal OPFR exposure on neonatal and juvenile hypothalamic gene expression and adult locomotor activity and approach/avoidance behaviors. Second, mental disorders share a common feature: exposure to stress, which contributes to cognitive dysfunction by exacerbating symptoms. A common paradigm to recapitulate chronic stressors in rodents is to apply mild stress for 6 weeks, known as chronic variable mild stress (CVMS). Using CVMS, the neural circuits underlying maladaptive effects of stress include corticotropin releasing factor (CRF) neurons. CRF is co-released with norepinephrine (NE), acetylcholine (ACh), and dopamine (DA), which control key brain regions (hippocampus, prefrontal cortex), and all are involved in cognition and mood. Based on our prior work and the literature, I hypothesize that perinatal OPFR exposure can disrupt cognition, alone or when combined with adult chronic stress exposure. My central hypothesis is that EDCs such as OPFRs influence the developing cognitive and stress neurocircuitry potentially inducing long-lasting functional deficits in cognitive processing and sensitize adults to exposure to chronic stress in mice. In Aim 1 (K99 phase), I will first determine if perinatal OPFR exposure disrupts adult cognition on the behavioral level and through alterations in ACh synaptic transmission using electrophysiology. In Aim 2 (K99), I will examine the effects of OPFR exposure on regional concentrations of NE and DA and CRF and associated gene expression in adults, and the role of hippocampal CRF neurons using optogenetics. Lastly, in Aim 3 (R00), I will combine my prior expertise in spine density analysis and immunohistochemistry, and new training in electrophysiology, high-performance liquid chromatography, and optogenetics to determine if the combination of perinatal OPFR exposure and adult CVMS alters cognition. The ultimate goal of my research program will be to determine the interactions of perinatal EDC exposure and adult chronic stressors on cognitive processing by influencing CRF and neurotransmitter signaling throughout the brain.


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	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Environmental Health	000	2	12/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Environmental Health	000	2	3/12/2025	NON-COMPETING CONTINUATION	$0
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Environmental Health	001	2	8/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $120,789 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Environmental Health	000	2	1/19/2024	NON-COMPETING CONTINUATION	$120,789
														Subtotal = $120,789

Issue Date FY: 2023 ( Subtotal = $120,789 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Environmental Health	000	1	2/1/2023	NEW	$120,789
														Subtotal = $120,789

Grand Total All Awards = $241,578

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The interaction of perinatal organophosphate flame retardant exposure and adult chronic stress on cognitive processing

Award Number: K99ES033256

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/02/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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