Chlorpyrifos induces oxidative stress in oligodendrocyte progenitor cells.
There are increasing concerns regarding the relative safety of chlorpyrifos (CPF) to various facets of the environment. Although published works suggest that CPF is relatively safe in adult animals, recent evidence indicates that juveniles, both animals and humans, may be more sensitive to CPF toxicity than adults. In young animals, CPF is neurotoxic and mechanistically interferes with cellular replication and cellular differentiation, which culminates in the alteration of synaptic neurotransmission in neurons. However, the effects of CPF on glial cells are not fully elucidated. Here we report that chlorpyrifos is toxic to oligodendrocyte progenitors. In addition, CPF produced dose-dependent increases in 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCF-DA) and dihydroethidium (DHE) fluorescence intensities relative to the vehicle control. Moreover, CPF toxicity is associated with nuclear condensation and elevation of caspase 3/7 activity and Heme oxygenase-1 mRNA expression. Pan-caspase inhibitor QVDOPh and cholinergic receptor antagonists' atropine and mecamylamine failed to protect oligodendrocyte progenitors from CPF-induced injury. Finally, glutathione (GSH) depletion enhanced CPF-induced toxicity whereas nitric oxide synthetase inhibitor L-NAME partially protected progenitors and the non-specific antioxidant vitamin E (alpha-tocopherol) completely spared cells from injury. Collectively, this data suggests that CPF induced toxicity is independent of cholinergic stimulation and is most likely caused by the induction of oxidative stress.
Saulsbury
Marilyn D
MD
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA 23668, United States. marilyn.saulsbury@hamptonu.edu
Heyliger
Simone O
SO
Wang
Kaiyu
K
Johnson
Deadre J
DJ
D000818:Animals; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053179:Caspase 7 / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004996:Ethidium / Q000031:analogs & derivatives / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D005453:Fluorescence; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000235:genetics; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism
C110400:2',7'-dichlorodihydrofluorescein diacetate; D005452:Fluoresceins; D007306:Insecticides; D012333:RNA, Messenger; C067883:dihydroethidium; D051547:Heme Oxygenase-1; D053148:Caspase 3; D053179:Caspase 7; D004996:Ethidium; D004390:Chlorpyrifos