title: 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.
authors.affiliation: Department of Neuroscience and Pharmacology, Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville, Tennessee 37208, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Sheng
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Marcus
authors.initials: M
authors.lastname: Ferguson
authors.forename: Monique
authors.initials: M
authors.lastname: McCallister
authors.forename: Raina
authors.initials: R
authors.lastname: Rhoades
authors.forename: Mark
authors.initials: M
authors.lastname: Maguire
authors.forename: Aramandla
authors.initials: A
authors.lastname: Ramesh
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: Daniel
authors.initials: D
authors.lastname: Campbell
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
authors.forename: Darryl B
authors.initials: DB
authors.lastname: Hood
mesh_terms: D000284:Administration, Oral; D000393:Air Pollutants / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001321:Autistic Disorder; D001522:Behavior, Animal / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D019859:Proto-Oncogene Proteins c-met