| Developmental Neurotoxicity of Perfluorinated Chemicals Modeled in Vitro Theodore A. Slotkin,1 Emiko A. MacKillop,1 Ronald L. Melnick,2 Kristina A. Thayer,2 and Frederic J. Seidler1 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA; 2National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Abstract
Background: The widespread detection of perfluoroalkyl acids and their derivatives in wildlife and humans, and their entry into the immature brain, raise increasing concern about whether these agents might be developmental neurotoxicants. Objectives: We evaluated perfluorooctane sulfonate (PFOS) , perfluorooctanoic acid (PFOA) , perfluorooctane sulfonamide (PFOSA) , and perfluorobutane sulfonate (PFBS) in undifferentiated and differentiating PC12 cells, a neuronotypic line used to characterize neurotoxicity. Methods: We assessed inhibition of DNA synthesis, deficits in cell numbers and growth, oxidative stress, reduced cell viability, and shifts in differentiation toward or away from the dopamine (DA) and acetylcholine (ACh) neurotransmitter phenotypes. Results: In general, the rank order of adverse effects was PFOSA > PFOS > PFBS ≈ PFOA. However, superimposed on this scheme, the various agents differed in their underlying mechanisms and specific outcomes. Notably, PFOS promoted differentiation into the ACh phenotype at the expense of the DA phenotype, PFBS suppressed differentiation of both phenotypes, PFOSA enhanced differentiation of both, and PFOA had little or no effect on phenotypic specification. Conclusions: These findings indicate that all perfluorinated chemicals are not the same in their impact on neurodevelopment and that it is unlikely that there is one simple, shared mechanism by which they all produce their effects. Our results reinforce the potential for in vitro models to aid in the rapid and cost-effective screening for comparative effects among different chemicals in the same class and in relation to known developmental neurotoxicants. Key words: developmental neurotoxicity, PC12 cells, perfluorinated chemicals, perfluoroalkyl acids, perfluorobutane sulfonate, perfluorooctane sulfonamide, perfluorooctane sulfonate, perfluorooctanoate, perfluorooctanoic acid. Environ Health Perspect 116:716–722 (2008) . doi:10.1289/ehp.11253 available via http://dx.doi.org/ [Online 3 March 2008]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu This research was supported by the NIEHS (HHSN27320062006C) . We thank I. Ryde for technical assistance. T.A.S. and F.J.S. have served as expert witnesses on behalf of governmental entities, corporations, and/or individuals. The authors declare they have no competing financial interests. Received 10 January 2008 ; accepted 3 March 2008.
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