title: Is fipronil safer than chlorpyrifos? Comparative developmental neurotoxicity modeled in PC12 cells.
abstract: Fipronil, a GABA(A) receptor antagonist, is replacing many insecticide uses formerly fulfilled by organophosphates like chlorpyrifos. Few studies have addressed the potential for fipronil to produce developmental neurotoxicity. We compared the neurotoxicity of fipronil and chlorpyrifos in undifferentiated and differentiating neuronotypic PC12 cells, evaluating indices of cell replication, cell number, differentiation, and viability for short- and long-term exposures. Fipronil inhibited DNA and protein synthesis in undifferentiated PC12 cells and evoked oxidative stress to a greater extent than did chlorpyrifos, resulting in reduced cell numbers even though cell viability was maintained. In differentiating cells, fipronil displayed an even lower threshold for disruption of development, reducing cell numbers without impairing cell growth, and promoting emergence of neurotransmitter phenotypes; superimposed on this effect, the phenotypic balance was shifted in favor of dopamine as opposed to acetylcholine. Differentiation also enhanced the susceptibility to fipronil-induced oxidative stress, although antioxidant administration failed to provide protection from cell loss. At low concentrations maintained for prolonged periods, fipronil had a biphasic effect on cell numbers, increasing them slightly at low concentrations, implying interference with apoptosis, while nevertheless reducing cell numbers at higher concentrations. Our results suggest that fipronil is inherently a more potent disruptor of neuronal cell development than is chlorpyrifos. The neurodevelopmental effects are not predicated on GABA(A) antagonist properties, since PC12 cells lack the GABA(A) receptor. If fipronil is intended to provide greater safety than chlorpyrifos, then this will have to entail advantages from factors that are yet unexamined: exposure, persistence, pharmacokinetics.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. tll18@duke.edu
authors.forename: T Leon
authors.initials: TL
authors.lastname: Lassiter
authors.forename: Emiko A
authors.initials: EA
authors.lastname: MacKillop
authors.forename: Ian T
authors.initials: IT
authors.lastname: Ryde
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D058787:GABA-A Receptor Antagonists; D007306:Insecticides / Q000633:toxicity*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D014176:Protein Biosynthesis / Q000187:drug effects; D011720:Pyrazoles / Q000633:toxicity*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D058787:GABA-A Receptor Antagonists; D007306:Insecticides; D011720:Pyrazoles; D004247:DNA; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D004390:Chlorpyrifos; C082360:fipronil