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

34 Citations (Scopus)

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 Cprlox/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 Cprlox/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 Cprlox/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)
Article numberkfq304
Pages (from-to)716-731
Number of pages16
JournalToxicological Sciences
Volume118
Issue number2
DOIs
StatePublished - Dec 2010
Externally publishedYes

Fingerprint

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

Keywords

  • Autism spectrum disorders
  • Behavioral neurotoxicity
  • Benzo(a)pyrene
  • Gene × environment interaction
  • In utero exposures
  • Novel object discrimination behavioral task
  • Polycyclic aromatic hydrocarbon
  • Susceptibility-exposure paradigm

ASJC Scopus subject areas

  • Toxicology

Cite this

Sheng, L., Ding, X., Ferguson, M., Mccallister, M., Rhoades, R., Maguire, M., ... Hood, D. B. (2010). Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicological Sciences, 118(2), 716-731. [kfq304]. https://doi.org/10.1093/toxsci/kfq303

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, Vol. 118, No. 2, kfq304, 12.2010, p. 716-731.

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, vol. 118, no. 2, kfq304, pp. 716-731. https://doi.org/10.1093/toxsci/kfq303
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. 2010 ; Vol. 118, No. 2. pp. 716-731.
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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 Cprlox/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 Cprlox/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 Cprlox/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.",
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