title: Oxidative stress from diverse developmental neurotoxicants: antioxidants protect against lipid peroxidation without preventing cell loss.
abstract: Oxidative stress has been hypothesized to provide a mechanism by which apparently unrelated chemicals can nevertheless produce similar developmental neurotoxic outcomes. We used differentiating PC12 cells to compare the effects of agents from four different classes and then to evaluate antioxidant amelioration: fipronil, perfluorooctanesulfonamide (PFOSA), dieldrin and chlorpyrifos. The rank order for lipid peroxidation corresponded to the ability to evoke cell loss: fipronil>PFOSA>dieldrin>chlorpyrifos. The same sequence was found for an index of cell enlargement (protein/DNA ratio) but the effects on neurite outgrowth (membrane/total protein) diverged, with fipronil producing a decrease and PFOSA an increase. Cotreatment with antioxidants reduced (ascorbate) or eliminated (Vitamin E) lipid peroxidation caused by each of the agents but failed to protect against cell loss, with the sole exception of chlorpyrifos, for which we earlier showed partial protection by Vitamin E; addition of higher NGF concentrations protected neither against oxidative stress nor cell loss. Despite the failure to prevent cell loss, ascorbate protected the cells from the effects of PFOSA on neuritic outgrowth; NGF, and to a lesser extent, ascorbate, offset the effects of fipronil on both cell enlargement and neuritogenesis. At the same time, the ameliorant treatments also worsened some of the other toxicant effects. Our results point out the problems in concluding that, just because a neurotoxicant produces oxidative stress, antioxidant therapy will be effective in preventing damage. Instead, additional mechanisms for each agent may provide alternative routes to neurotoxicity, or may be additive or synergistic with oxidative stress.
authors.affiliation: Department of Pharmacology & Cancer Biology Duke University Medical Center Durham, North Carolina 27710, USA. t.slotkin@duke.edu
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D017738:Alkanesulfonic Acids / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects; D004390:Chlorpyrifos / Q000037:antagonists & inhibitors / Q000633:toxicity; D004026:Dieldrin / Q000037:antagonists & inhibitors / Q000633:toxicity; D005466:Fluorocarbons / Q000037:antagonists & inhibitors / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology / Q000627:therapeutic use; D009420:Nervous System / Q000187:drug effects* / Q000254:growth & development; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D017738:Alkanesulfonic Acids; D000975:Antioxidants; D005466:Fluorocarbons; D009414:Nerve Growth Factors; D009498:Neurotoxins; D011720:Pyrazoles; D014810:Vitamin E; C076994:perfluorooctane sulfonic acid; D004026:Dieldrin; D004390:Chlorpyrifos; D001205:Ascorbic Acid; C082360:fipronil