Prenatal Polycyclic Aromatic Hydrocarbon Exposure Leads to Behavioral Deficits and Downregulation of Receptor Tyrosine Kinase, MET
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Mice prenatally exposed to the PAH benzo(a)pyrene display blunted MET gene expression and behavioral deficits in a novelty test.
“Mice prenatally exposed to the PAH benzo(a)pyrene display blunted MET gene expression and behavioral deficits in a novelty test [253].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [253]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Role of Quinones in Toxicology
Bolton, J. L., Trush, M. A., Penning, T. M., Dryhurst, G., & Monks, T. J. (2000) · Chemical Research in Toxicology · doi:10.1021/tx9902082 · Cited by 1,703 · see citing works
Autism spectrum disorders: developmental disconnection syndromes
Geschwind, D. H., & Levitt, P. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.009 · Cited by 1,411 · see citing works
Self-citationNebert, D. W., Roe, A. L., Dieter, M. Z., Solis, W. A., Yang, Y., & Dalton, T. P. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00310-x · Cited by 997 · see citing works
Identifying autism loci and genes by tracing recent shared ancestry
Morrow, E. M., Yoo, S.-Y., Flavell, S. W., Kim, T.-K., Lin, Y., Hill, R. S., Mukaddes, N. M., Balkhy, S., Gascon, G., Hashmi, A., et al. (2008) · Science · doi:10.1126/science.1157657 · Cited by 737 · see citing works
Neuropathological findings in autism
Palmen, S. J. M. C. (2004) · Brain · doi:10.1093/brain/awh287 · Cited by 527 · see citing works
Geschwind, D. H. (2009) · Annual Review of Medicine · doi:10.1146/annurev.med.60.053107.121225 · Cited by 512 · see citing works
Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome
Flück, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonça, B. B., Fujieda, K., & Miller, W. L. (2004) · Nature Genetics · doi:10.1038/ng1300 · Cited by 509 · cited 3× · see citing works
“are known to occur at appreciable frequencies in human patients (Arlt et al., 2004; Fluck et al., 2004; Fukami et al., 2005, 2006; Huang et al., 2005).”
BackgroundInfluentialPerera, F. P., Rauh, V., Whyatt, R. M., Tsai, W., Tang, D. L., Díaz, D., Hoepner, L., Barr, D. B., Tu, Y.-H., Camann, D., et al. (2006) · Environmental Health Perspectives · doi:10.1289/ehp.9084 · Cited by 489 · see citing works
Prenatal Airborne Polycyclic Aromatic Hydrocarbon Exposure and Child IQ at Age 5 Years
Perera, F. P., Li, Z., Whyatt, R., Hoepner, L., Wang, S., Camann, D., & Rauh, V. (2009) · Pediatrics · doi:10.1542/peds.2008-3506 · Cited by 420 · see citing works
Structural and functional maturation of the developing primate brain
Levitt, P. R. (2003) · The Journal of Pediatrics · doi:10.1067/s0022-3476(03)00400-1 · Cited by 409 · see citing works
Self-citationA genetic variant that disrupts <i>MET</i> transcription is associated with autism
Campbell, D. B., Sutcliffe, J. S., Ebert, P. J., Militerni, R., Bravaccio, C., Trillo, S., Elia, M., Schneider, C., Melmed, R., Sacco, R., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605296103 · Cited by 401 · see citing works
Self-citationArlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)16503-3 · Cited by 345 · see citing works
Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Vliet, G. V., Sack, J., Flück, C. E., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/429417 · Cited by 336 · see citing works
Powell, E. M., Campbell, D. B., Stanwood, G. D., Davis, C., Noebels, J. L., & Levitt, P. R. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00622.2003 · Cited by 333 · see citing works
Self-citationPowell, E. M., Mars, W. M., & Levitt, P. (2001) · Neuron · doi:10.1016/s0896-6273(01)00264-1 · Cited by 321 · see citing works
Self-citationLevitt, P., & Campbell, D. B. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37934 · Cited by 234 · see citing works
Self-citationLiver-specific Deletion of the NADPH-Cytochrome P450 Reductase Gene
Gu, J., Weng, Y., Zhang, Q.-Y., Cui, H., Behr, M., Wu, L., Yang, W., Zhang, L., & Ding, X. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303125200 · Cited by 214 · see citing works
Self-citationDisruption of cerebral cortex MET signaling in autism spectrum disorder
Campbell, D. B., D'Oronzio, R., Garbett, K., Ebert, P. J., Mirnics, K., Levitt, P., & Persico, A. M. (2007) · Annals of Neurology · doi:10.1002/ana.21180 · Cited by 193 · see citing works
Self-citationGenetic advances in autism: heterogeneity and convergence on shared pathways
Bill, B. R., & Geschwind, D. H. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.04.004 · Cited by 164 · see citing works
Fukami, M., Horikawa, R., Nagai, T., Tanaka, T., Naiki, Y., Sato, N., Okuyama, T., Nakai, H., Soneda, S., Tachibana, K., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0810 · Cited by 155 · see citing works
Ramesh, A., Inyang, F., Hood, D. B., et al. (2001) · Experimental and Toxicologic Pathology · doi:10.1078/0940-2993-00192 · Cited by 154 · see citing works
Self-citationCampbell, D. B., Li, C., Sutcliffe, J. S., Persico, A. M., & Levitt, P. (2008) · Autism Research · doi:10.1002/aur.27 · Cited by 154 · see citing works
Self-citationEnvironmental contaminant–mixture effects on CNS development, plasticity, and behavior
Wormley, D. D., Ramesh, A., & Hood, D. B. (2004) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2004.01.016 · Cited by 152 · see citing works
Self-citationWortham, M., Czerwiński, M., He, L., et al. (2007) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.016436 · Cited by 150 · see citing works
Campbell, D. B., Buie, T. M., Winter, H., Bauman, M., Sutcliffe, J. S., Perrin, J. M., & Levitt, P. (2009) · Pediatrics · doi:10.1542/peds.2008-0819 · Cited by 145 · see citing works
Self-citationLioy, P. L., Waldman, J. M., Greenberg, A., et al. (1988) · Archives of Environmental Health An International Journal · doi:10.1080/00039896.1988.10545954 · Cited by 142 · see citing works
Automation of the novel object recognition task for use in adolescent rats
Silvers, J. M., Harrod, S. B., Mactutus, C. F., & Booze, R. M. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.06.032 · Cited by 118 · see citing works
Brown, L. A., Khousbouei, H., Goodwin, J. S., Irvin-Wilson, C. V., Ramesh, A., Sheng, L., McCallister, M. M., Jiang, G. C. T., Aschner, M., & Hood, D. B. (2007) · NeuroToxicology · doi:10.1016/j.neuro.2007.05.005 · Cited by 110 · see citing works
Self-citationPrenatal exposure to benzo(a)pyrene impairs later-life cortical neuronal function
McCallister, M., Maguire, M. J., Ramesh, A., et al. (2008) · NeuroToxicology · doi:10.1016/j.neuro.2008.07.008 · Cited by 100 · see citing works
Self-citationHGF regulates the development of cortical pyramidal dendrites
Gutiérrez, H., Dolcet, X., Tolcos, M., & Davies, A. (2004) · Development · doi:10.1242/dev.01209 · Cited by 91 · see citing works
MET and autism susceptibility: family and case-control studies
Sousa, I., Clark, T., Toma, C., Kobayashi, K., Choma, M., Holt, R., Sykes, N. H., Lamb, J., Bailey, A., Battaglia, A., et al. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.215 · Cited by 90 · see citing works
Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function
Li, Z., Dong, T., Pröschel, C., & Noble, M. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050035 · Cited by 90 · see citing works
Judson, M. C., Bergman, M. Y., Campbell, D. B., Eagleson, K. L., & Levitt, P. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.21969 · Cited by 80 · see citing works
Self-citationFukami, M., Hasegawa, T., Horikawa, R., Ohashi, T., Nishimura, G., Homma, K., & Ogata, T. (2006) · Pediatric Research · doi:10.1203/01.pdr.0000195825.31504.28 · Cited by 79 · see citing works
Conditional knockout of the mouse NADPH‐cytochrome p450 reductase gene
Wu, L., Gu, J., Weng, Y., Kluetzman, K., Swiatek, P. J., Behr, M. J., Zhang, Q., Zhuo, X., Xie, Q., & Ding, X. (2003) · genesis · doi:10.1002/gene.10214 · Cited by 68 · see citing works
Self-citationKerzee, J. K., & Ramos, K. S. (2000) · Molecular Pharmacology · doi:10.1124/mol.58.1.152 · Cited by 68 · see citing works
Hood, T. (2000) · Inhalation Toxicology · doi:10.1080/089583700402897 · Cited by 66 · see citing works
Jackson, P. B., Boccuto, L., Skinner, C., Collins, J. S., Neri, G., Gurrieri, F., & Schwartz, C. E. (2009) · Autism Research · doi:10.1002/aur.87 · Cited by 65 · cited 1× · see citing works
“The focus on understanding the impact of exposure to a common environmental pollutant on MET is based in part on our initial discovery (Campbell et al., 2006), which was subsequently replicated (Campbell et al., 2009; Jackson et al., 2009; Judson et al., 2009), of MET as an ASD risk gene.”
BackgroundTyndall, S. J., & Walikonis, R. S. (2006) · Cell Cycle · doi:10.4161/cc.5.14.2918 · Cited by 58 · see citing works
Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling
Conroy, J., Fang, C., Gu, J., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2497 · Cited by 56 · see citing works
Wu, R., Zhao, J., Zhai, J., Guo, X., & Guo, W. (2007) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e3180cac8db · Cited by 55 · see citing works
Campbell, D. B., Warren, D. E., Sutcliffe, J. S., Lee, E. B., & Levitt, P. R. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30998 · Cited by 48 · see citing works
Self-citationFunctional Analysis of the Rat N-Methyl-D-aspartate Receptor 2A Promoter
Liu, A., Zhuang, Z.-Y., Hoffman, P. W., & Bai, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211165200 · Cited by 43 · see citing works
Gestational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure effects on sensory cortex function
Hood, D. B., Woods, L., Brown, L. A., Johnson, S., & Ebner, F. F. (2006) · NeuroToxicology · doi:10.1016/j.neuro.2006.05.022 · Cited by 36 · see citing works
Self-citationWang, S., Chanock, S. J., Tang, D. L., Li, Z., Edwards, S., Jedrychowski, W. A., & Perera, F. P. (2009) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2009.00550.x · Cited by 34 · see citing works
Gu, J., Chen, C.-S., Wei, Y., Fang, C., Xie, F., Kannan, K., Yang, W., Waxman, D. J., & Ding, X. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.118240 · Cited by 25 · see citing works
Self-citationHepatocyte growth factor promotes the number of PSD-95 clusters in young hippocampal neurons
Nakano, M., Takagi, N., Takagi, K., Funakoshi, H., Matsumoto, K., Nakamura, T., & Takeo, S. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.06.007 · Cited by 22 · see citing works
Akita, H., Takagi, N., Ishihara, N., Takagi, K., Murotomi, K., Funakoshi, H., Matsumoto, K., Nakamura, T., & Takeo, S. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.10.001 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene
Volk, H. E., Kerin, T., Lurmann, F., Hertz-Picciotto, I., McConnell, R., & Campbell, D. B. (2014) · Epidemiology · doi:10.1097/ede.0000000000000030 · Cited by 163 · see citing works
Self-citationStamou, M., Streifel, K. M., Goines, P. E., & Lein, P. J. (2013) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2012.12.001 · Cited by 128 · see citing works
- Authors
- Sheng, L., Ding, X., Ferguson, M., McCallister, M., Rhoades, R., Maguire, M., Ramesh, A., Aschner, M., Campbell, D., Levitt, P., & Hood, D. B.
- Affiliations
- New York State Department of Health (US)
- Meharry Medical College (US)
- Vanderbilt University (US)
- University of Southern California (US)
- ORCID
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-01
- Volume
- 118
- Issue
- 2
- Pages
- 625-634
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC2984527
- OpenAlex
- W2121068123
- Cited by
- 63
- References
- 48
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 9 · 2014: 5 · 2013: 5 · 2012: 8
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (G12RRO3032)
- National Institute of Mental Health (T32MH065782)
- National Cancer Institute (R01CA142845)
- National Institute of General Medical Sciences (S06GM08037, S06GM008037)
- National Institute of Neurological Disorders and Stroke (U54NS041071)
- National Institute of Environmental Health Sciences (R56ES017448, S11ES014156, R01ES007462)
- National Center for Research Resources (G12RR003032)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- polycyclic aromatic hydrocarbons, benzo[a]pyrene, prenatal exposure, MET receptor tyrosine kinase, autism risk genes, gene-environment interaction, synaptogenesis, novel object discrimination, learning and memory impairment, dose-dependent toxicity, behavioral development
- MeSH terms
- Administration, Oral, Air Pollutants, Animals, Autistic Disorder, Behavior, Animal, Cells, Cultured, Cerebral Cortex, Cognition, Discrimination Learning, Disease Models, Animal, Embryo, Mammalian, Exploratory Behavior, Female, Humans, Male, Mice, Transgenic, Polycyclic Aromatic Hydrocarbons, Pregnancy, RNA, Messenger, Down-Regulation, Gene Expression, Maternal Exposure, Proto-Oncogene Proteins c-met, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
