Developmental neurotoxicity of perfluorinated chemicals modeled in vitro.
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.


OBJECTIVE
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 approximately 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.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slotkin@duke.edu
MacKillop
Emiko A
EA
Melnick
Ronald L
RL
Thayer
Kristina A
KA
Seidler
Frederic J
FJ
D017738:Alkanesulfonic Acids / Q000633:toxicity; D000818:Animals; D002210:Caprylates / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005466:Fluorocarbons / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D013449:Sulfonamides / Q000633:toxicity
D017738:Alkanesulfonic Acids; D002210:Caprylates; D005466:Fluorocarbons; D013449:Sulfonamides; C063900:perfluorooctanesulfonamide; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid; C108042:perfluorobutane