Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods.
During brain development, serotonin (5HT) provides essential neurotrophic signals. In the present study, we evaluated whether the developmental neurotoxicity of chlorpyrifos (CPF) involves effects on 5HT signaling, as a potential mechanism underlying noncholinergic neuroteratogenic events. We evaluated four different treatment windows ranging from the neural tube stage [gestational days (GD) 9-12] and the late gestational period (GD17-20) through postnatal phases of terminal neuronal differentiation and synaptogenesis [postnatal days (PN) 1-4, PN11-14]. Exposure to CPF on GD9-12 elicited initial suppression, immediately followed by rebound elevation, of 5HT1A and 5HT2 receptors as well as the 5HT transporter, all at doses below the threshold for cholinergic hyperstimulation and the resultant systemic toxicity. In contrast, with GD17-20 exposure, the initial effect was augmentation of all three components by low doses of CPF. Sensitivity of these effects declined substantially when exposure was shifted to the postnatal period. We also identified major alterations in 5HT-mediated responses, assessed for the adenylyl cyclase signaling cascade. Although GD9-12 exposure had only minor effects, treatment on GD17-20 elicited supersensitivity to both stimulatory and inhibitory responses mediated by 5HT. Our results indicate that CPF affects 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction during a discrete critical gestational window. These effects are likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Justin E
JE
Aldridge
Frederic J
FJ
Seidler
Armando
A
Meyer
Indira
I
Thillai
Theodore A
TA
Slotkin
D000262:Adenylyl Cyclases / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000502:physiology; D004390:Chlorpyrifos / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000502:physiology; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction
D002352:Carrier Proteins; D007306:Insecticides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D000262:Adenylyl Cyclases; D004390:Chlorpyrifos