The """"""""macrocosm"""""""" of our society that is exposed to chemicals, such as polycyclic aromatic hydrocarbons (PAH's) and polychlorinated biphenyls (PCB's), represents a significant public health problem. Developmental neurotoxicity seems to be achieving a leading role and may even displace cancer as the basis for assessing the human risks posed by exposure to these types of environmental mixtures. Very little is known with regard to the effects of these mixtures on brain developmental gene expression. The temporal and spatial regulation of gene expression is a critical component of neuro-biological development and as such, may be a mediator of PAH/PCB neurotoxicity. Data obtained from our laboratory on the temporal and spatial regulation of gene expression in the brain indicate that subsequent to PAH aerosol exposure (1) Sp1 DNA-binding is developmentally regulated and expressed very highly in actively developing brain regions, and (2) a consequence of the transplacental deposition of desorbed PAH to the fetus is in utero neurotoxicity. Because the molecular level mechanism of PAH and PCB toxicity is mediated by the aryl hydrocarbon receptor, these data support the concept that PAH's and PCB's can alter developmental gene expression through interference with transcription factors. The primary objective of this proposal is to study the synergistic mechanism by which mixed transplacental exposures [PAH (aerosol)/PCB (gavage)] influence developmental gene expression; and to correlate genotypic """"""""immediate early"""""""" alterations with phenotypic neuronal """"""""late responses"""""""". This objective will be addressed within the context of a central hypothesis which states that synergistic alterations in developmental gene expression the brain occur as a result of mixed transplacental exposures [PAH (aerosol)/PCB(gavage] to ultimately result in altered cognitive function. The results from these studies will contribute to an understanding of the neuro-biological mechanisms by which constituents of mixed exposures mediate adverse acute neurological health effects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Meharry Medical College
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Charlton, Clivel G (2014) Methylation reactions at dopaminergic nerve endings, serving as biological off-switches in managing dopaminergic functions. Neural Regen Res 9:1110-1
Dhanushkodi, Nisha R; Mohankumar, Vidyarani; Raju, Ramaswamy (2012) Sindbis virus induced phosphorylation of IRF3 in human embryonic kidney cells is not dependent on mTOR. Innate Immun 18:325-32
Li, Zhu; Chadalapaka, Gayathri; Ramesh, Aramandla et al. (2012) PAH particles perturb prenatal processes and phenotypes: protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following in utero exposure to inhaled benzo(a)pyrene. Toxicol Sci 125:233-47
Jules, G E; Pratap, S; Ramesh, A et al. (2012) In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life. Toxicology 295:56-67
King, Jennifer M; Muthian, Gladson; Mackey, Veronica et al. (2011) L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease. Life Sci 89:638-43
Kawai, Yumiko; Garduño, Lakisha; Theodore, Melanie et al. (2011) Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 286:7629-40
Dhanushkodi, Nisha R; Mohankumar, Vidyarani; Pokkali, Supriya et al. (2011) Lipopolysaccharide inhibits Sindbis virus-induced IP-10 release in human peripheral blood mononuclear cells. Viral Immunol 24:237-43
Halder, Sunil K; Goodwin, J Shawn; Al-Hendy, Ayman (2011) 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 96:E754-62
Mittal, Mukul K; Singh, Kshipra; Misra, Smita et al. (2011) SLUG-induced elevation of D1 cyclin in breast cancer cells through the inhibition of its ubiquitination. J Biol Chem 286:469-79
Ansah, Twum A; Ferguson, Marcus C; Nayyar, Tultul (2011) The 5-HT(2A) Receptor Antagonist M100907 Produces Antiparkinsonian Effects and Decreases Striatal Glutamate. Front Syst Neurosci 5:48

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