Saturday, November 23, 2024
11/23/2024
Project Summary. Traffic-related air pollution (TRAP) is a mixture of particulates, gases and organic molecules, primarily polycyclic aromatic hydrocarbons (PAHs). Although the effects of TRAP on lung function and heart health are well known, there is emerging evidence that TRAP also harms the developing brain with effects on IQ and behavior persisting into school age. These studies are limited, because they can only identify correlations and not the specific causative factor. Extensive animal studies have strongly implicated aryl hydrocarbon receptor (AHR) agonists including PAHs in developmental neurotoxicity. Many of these studies focused on the prototypical PAH benzo[a]pyrene (BaP) and found deficits in learning and memory, behavior, and dopaminergic pathways. Those studies, however, did not take into account genetic variations that could affect BaP metabolism and its resultant effects on neurodevelopment and brain function. The studies proposed here will address the limitations of prior human and animal studies by using a mouse model with allelic differences in the AHR-CYP1 pathway previously shown to alter susceptibility to BaP carcinogenesis. All three genes of interest (AHR, CYP1A1 and CYP1A2) vary in the human population and have been linked to adverse effects following exposure to TRAP. Therefore, our studies will help identify those at highest risk of adverse effects. We will use mice with allelic differences at the Ahr, Cyp1a1 and Cyp1a2 loci to test the over-arching hypothesis that the AHR pathway mediates neurotoxicity. Aim 1: Determine how genetic differences in the AHR-CYP1 pathway alter the severity of developmental BaP neurotoxicity using validated tests of learning & memory, behavior, and motor function. Together, we will determine if BaP also affects motor function while testing the hypothesis that the loss of CYP1A1 increases the severity of developmental BaP neurotoxicity. Aim 2: Compare neurotransmitter levels in the cortex, cerebellum, striatum, and hippocampus in adult mice exposed to BaP during early brain development. Developmental neurotoxicants often act by permanently disrupting normal neuronal signaling. Using HPLC and UPLC to quantify neurotransmitters in multiple brain regions, we are likely to identify the critical pathways affected by developmental BaP exposure. This will be important in identifying the specific mechanism of neurotoxicity. Aim 3: Compare BaP metabolism in exposed dams and their offspring during late gestation and lactation. Our over-arching hypothesis is based on prior studies demonstrating differential metabolism of BaP in mice with variations in CYP1 genes. By including mice with variation in AHR affinity for BaP, we will be able to examine both gene-gene and gene-environment interactions and more closely model human genetic variation. 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.
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