Chlorpyrifos developmental neurotoxicity: interaction with glucocorticoids in PC12 cells.
Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on models relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuritogenesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent.
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Jennifer
J
Card
Frederic J
FJ
Seidler
D000818:Animals; D018929:Cell Culture Techniques; D004390:Chlorpyrifos / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D008954:Models, Biological; D055495:Neurogenesis / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats
D005938:Glucocorticoids; D007306:Insecticides; D004390:Chlorpyrifos