Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylyl cyclase signaling cascade.
Developmental neurotoxicity caused by chlorpyrifos exposure is generally thought to target cholinesterase but chlorpyrifos may also act on cellular intermediates, such as adenylyl cyclase, that serve global functions in the coordination of cell development. In the current study, neonatal rats were exposed to apparently subtoxic doses of chlorpyrifos (no weight loss, no mortality) either on Postnatal Days 1-4 or on Postnatal Days 11-14, and the effects on components of the adenylyl cyclase cascade were evaluated in brain regions that are enriched (forebrain) or sparse (cerebellum) in cholinergic innervation, as well as in a nonneural tissue (heart). In all three, chlorpyrifos evoked deficits in multiple components of the adenylyl cyclase cascade: expression and activity of adenylyl cyclase itself, functioning of G-proteins that link neurotransmitter and hormone receptors to cyclase activity, and expression of neurotransmitter receptors that act through this cascade. Disruption of signaling function was not restricted to transduction of cholinergic signals but rather extended to adrenergic signals as well. In most cases, the adverse effects were not evident during the immediate period of chlorpyrifos administration, but appeared after a delay of several days. These results suggest that chlorpyrifos can affect cell development by altering the activity and reactivity of the adenylyl cyclase signaling cascade, a major control point for trophic regulation of cell differentiation. The effects are not restricted to cholinergic targets, nor even to the central nervous system. Hence, disruption of cell development by chlorpyrifos is likely to be more widespread than previously thought.
Song
X
X
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Seidler
F J
FJ
Saleh
J L
JL
Zhang
J
J
Padilla
S
S
Slotkin
T A
TA
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004390:Chlorpyrifos / Q000378:metabolism / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D011247:Pregnancy; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011863:Radioimmunoassay; D011897:Random Allocation; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D004390:Chlorpyrifos