Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET

Abstract

Gene by environment interactions (G × E) are thought to underlie neurodevelopmental disorder, etiology, neurodegenerative disorders, including the multiple forms of autism spectrum disorder. However, there is limited biological information, indicating an interaction between specific genes and environmental components. The present study focuses on a major component of airborne pollutants, polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene [B(a)P], which negatively impacts cognitive development in children who have been exposed in utero. In our study, prenatal exposure of Cpr(lox/lox) timed-pregnant dams to B(a)P (0, 150, 300, and 600 μg/kg body weight via oral gavage) on embryonic day (E14-E17) consistent with our susceptibility-exposure paradigm was combined with the analysis of a replicated autism risk gene, the receptor tyrosine kinase, Met. The results demonstrate a dose-dependent increase in B(a)P metabolite generation in B(a)P-exposed Cpr(lox/lox) offspring. Additionally, a sustained persistence of hydroxy metabolites during the onset of synapse formation was noted, corresponding to the peak of Met expression. Prenatal B(a)P exposure also downregulated Met RNA and protein levels and dysregulated normal temporal patterns of expression during synaptogenesis. Consistent with these data, transcriptional cell-based assays demonstrated that B(a)P exposure directly reduces human MET promoter activity. Furthermore, a functional readout of in utero B(a)P exposure showed a robust reduction in novel object discrimination in B(a)P-exposed Cpr(lox/lox) offspring. These results confirm the notion that common pollutants, such as the PAH B(a)P, can have a direct negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes.

Effects of Prenatal Exposure to Air Pollutants (Polycyclic Aromatic Hydrocarbons) on the Development of Brain White Matter, Cognition, and Behavior in Later Childhood

“…35,36 Animal studies of PAH-induced neurotoxicity have focused primarily on brain gray matter, but our findings suggest that they should investigate PAH effects on white matter as well.…”

Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment

“…Exposed rats exhibit reductions in evoked potential in cortex [73] and decreased LTP in dentate gyrus of the hippocampus relative to control rats [20]. Impaired learning and memory (adverse outcome): Several studies have shown impaired learning and memory in rodents exposed to BaP in utero and during adulthood [12,[50][51][52]77,103]. Table 9 provides a summary of the evidence for the proposed KEs in rats and mice.…”

Autism Spectrum Disorder

“…1 In previous independent studies, we have identified (1) increased autism spectrum disorder risk among children exposed to high levels of local near-roadway traffic-related air pollution and regional particulate matter near the time of birth 2,3 ; (2) increased autism spectrum disorder risk among children with the C allele of the MET gene promoter variant rs1858830, 4,5 which is associated with decreased expression of MET protein in brain 6 and immune system 7 ; and (3) decreased MET protein expression in brain and altered behavior in offspring of mouse dams exposed during pregnancy to the polycyclic aromatic hydrocarbon benzo(a)pyrene (a component of traffic-related air pollution and particulate matter). 8 Based on these independent autism spectrum disorder associations and the biological link between benzo(a)pyrene and MET , we hypothesized that a gene-environment interaction contributes to autism spectrum disorder risk.…”