title: In vitro models reveal differences in the developmental neurotoxicity of an environmental polycylic aromatic hydrocarbon mixture compared to benzo[a]pyrene: Neuronotypic PC12 Cells and embryonic neural stem cells.
abstract: In addition to their carcinogenic activity, polycyclic aromatic hydrocarbons (PAHs) are suspected to be developmental neurotoxicants. We evaluated the effects of PAHs with two in vitro models that assess distinct "decision nodes" in neurodifferentiation: neuronotypic PC12 cells, which characterize the transition from cell replication to neurodifferentiation, neurite outgrowth and neurotransmitter specification; and embryonic neural stem cells (NSCs), which evaluate the origination of neurons and glia from precursors. We compared an environmentally-derived PAH mixture from a Superfund contamination site (Elizabeth River Sediment Extract, ERSE) to those of a single PAH, benzo[a]pyrene (BaP). In PC12 cells, BaP impaired the transition from cell replication to neurodifferentiation, resulting in higher numbers of cells, but with reduced cell size and deficits in all indices of neuronal features (neurite formation, development of dopamine and acetylcholine phenotypes). ERSE was far less effective, causing only modest changes in cell numbers and size and no impairment of neurite formation or neurotransmitter specification; in fact, ERSE evoked a slight increase in emergence of the acetylcholine phenotype. In the NSC model, this relationship was entirely reversed, with far greater sensitivity to ERSE than to BaP. Furthermore, ERSE, but not BaP, enhanced NSC differentiation into neurons, whereas both ERSE and BaP suppressed the glial phenotype. Our studies provide a cause-and-effect relationship for the observed association of developmental PAH exposure to behavioral deficits. Further, PAH sensitivity occurs over developmental stages corresponding to rudimentary brain formation through terminal neurodifferentiation, suggesting that vulnerability likely extends throughout fetal brain development and into early childhood.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address: t.slotkin@duke.edu.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Skavicus
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Card
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC, 27708, USA.
authors.forename: Richard T Di
authors.initials: RT
authors.lastname: Giulio
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D004785:Environmental Pollutants / Q000633:toxicity*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D051381:Rats
chemical_list: D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; D001564:Benzo(a)pyrene
keywords: Benzo[a]pyrene; Neural stem cells; Neurodifferentiation; PC12 cells; Polycyclic aromatic hydrocarbons