Alterations in serotonin transporter expression in brain regions of rats exposed neonatally to chlorpyrifos.
Chlorpyrifos (CPF), one of the most widely-used organophosphate pesticides, is a suspected neuroteratogen. We administered CPF to neonatal rats on postnatal days (PN) 1-4 (1 mg/kg) or PN11-14 (5 mg/kg), treatments devoid of overt toxicity. At the end of the treatment period (PN5 and 15, respectively) and 5-7 days later, we then examined the effects on paroxetine (PXT) binding to the presynaptic 5HT high-affinity transporter, a marker for serotonin (5HT) projections. In males, we found a persistent decrease in PXT binding across the two different treatment regimens, with deficits apparent in a brain region containing 5HT terminal fields (forebrain) as well as in a region containing 5HT cell bodies (brainstem). In contrast, females given the early treatment regimen (PN1-4) showed deficits in the brainstem but transient elevations in the forebrain; the later treatment regimen (PN11-14) had no significant effect on PXT binding in females. These data are consistent with earlier work showing brainstem cell injury resulting from neonatal CPF exposure, and indicate specific damage to 5HT neurons, with a consequent loss of transporter expression in both terminal fields and perikarya. In females, the damage may be temporarily offset by initial trophic effects in the terminal region, consequent to the cholinergic stimulation evoked by cholinesterase inhibition via the active metabolite, CPF oxon. The gender-selective effects on 5HT systems are likely to contribute to similar gender dimorphism in behavioral performance. Because the CPF effects involve 5HT, a neurotransmitter intimately involved in the control of mood, we suggest the need to evaluate behaviors that typify animal models of depression.
Raines
K W
KW
Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813 DUMC, Durham, NC 27710, USA.
Seidler
F J
FJ
Slotkin
T A
TA
D000818:Animals; D000831:Animals, Newborn; D001923:Brain Chemistry / Q000187:drug effects*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004390:Chlorpyrifos / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000378:metabolism / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium
D002352:Carrier Proteins; D004390:Chlorpyrifos; D002800:Cholinesterase Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; C493232:Slc6a4 protein, rat