Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET.

Liu Sheng, Xinxin Ding, Marcus Ferguson, Monique McCallister, Raina Rhoades, Mark Maguire, Aramandla Ramesh, Michael Aschner, Daniel Campbell, Pat Levitt, Darryl B. Hood

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)625-634
Number of pages10
JournalToxicological sciences : an official journal of the Society of Toxicology
Volume118
Issue number2
StatePublished - Dec 2010
Externally publishedYes

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Proto-Oncogene Proteins c-met
Benzo(a)pyrene
Polycyclic Aromatic Hydrocarbons
Down-Regulation
Genes
Autistic Disorder
Metabolites
Gene Components
Gene-Environment Interaction
Receptor Protein-Tyrosine Kinases
Child Development
Neurodegenerative Diseases
Synapses
Dams
Assays
Body Weight
Learning
RNA
Data storage equipment

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. / Sheng, Liu; Ding, Xinxin; Ferguson, Marcus; McCallister, Monique; Rhoades, Raina; Maguire, Mark; Ramesh, Aramandla; Aschner, Michael; Campbell, Daniel; Levitt, Pat; Hood, Darryl B.

In: Toxicological sciences : an official journal of the Society of Toxicology, Vol. 118, No. 2, 12.2010, p. 625-634.

Research output: Contribution to journalArticle

Sheng, L, Ding, X, Ferguson, M, McCallister, M, Rhoades, R, Maguire, M, Ramesh, A, Aschner, M, Campbell, D, Levitt, P & Hood, DB 2010, 'Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET.', Toxicological sciences : an official journal of the Society of Toxicology, vol. 118, no. 2, pp. 625-634.
Sheng, Liu ; Ding, Xinxin ; Ferguson, Marcus ; McCallister, Monique ; Rhoades, Raina ; Maguire, Mark ; Ramesh, Aramandla ; Aschner, Michael ; Campbell, Daniel ; Levitt, Pat ; Hood, Darryl B. / Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. In: Toxicological sciences : an official journal of the Society of Toxicology. 2010 ; Vol. 118, No. 2. pp. 625-634.
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