Adverse Benzo[a]pyrene Effects on Neurodifferentiation Are Altered by Other Neurotoxicant Coexposures: Interactions with Dexamethasone, Chlorpyrifos, or Nicotine in PC12 Cells

Background: Polycyclic aromatic hydrocarbons are suspected developmental neurotoxicants, but human exposures typically occur in combination with other neurotoxic contaminants. Objective and Methods: We explored the effects of benzo[a]pyrene (BaP) on neurodifferentiation in PC12 cells, in combination with a glucocorticoid (dexamethasone, used in preterm labor), an organophosphate pesticide (chlorpyrifos), or nicotine. Results: In cells treated with BaP alone, the transition from cell division to neurodifferentiation was suppressed, resulting in increased cell numbers at the expense of cell growth, neurite formation, and development of dopaminergic and cholinergic phenotypes. Dexamethasone enhanced the effect of BaP on cell numbers and altered the impact on neurotransmitter phenotypes. Whereas BaP alone shifted differentiation away from the cholinergic phenotype and toward the dopaminergic phenotype, the addition of dexamethasone along with BaP did the opposite. Chlorpyrifos coexposure augmented BaP inhibition of cell growth and enhanced the BaP-induced shift in phenotype toward a higher proportion of dopaminergic cells. Nicotine had no effect on BaP-induced changes in cell number or growth, but it synergistically enhanced the BaP suppression of differentiation into both dopaminergic and cholinergic phenotypes equally. Conclusion: Our results indicate that, although BaP can act directly as a developmental neurotoxicant, its impact is greatly modified by coexposure to other commonly encountered neurotoxicants from prenatal drug therapy, pesticides, or tobacco. Accordingly, neurodevelopmental effects attributable to polycyclic aromatic hydrocarbons may be quite different depending on which other agents are present and on their concentrations relative to each other.