Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure.
The commonly-used organophosphate insecticide, chlorpyrifos (CPF), impairs brain cell development, axonogenesis and synaptogenesis. In the current study, we administered CPF to neonatal rats on postnatal (PN) days 1-4 (1 mg/kg) or PN11-14 (5 mg/kg), treatments that were devoid of overt toxicity. We then examined two cholinergic synaptic markers, choline acetyltransferase activity (ChAT) and [3H]hemicholinium-3 binding (HC-3) in the hippocampus, midbrain, striatum, brainstem and cerebral cortex in the juvenile (PN30) and young adult (PN60). Across all brain regions, CPF exposure evoked significant reductions in both markers, with larger effects on HC-3 binding, which is responsive to neuronal impulse activity, than on ChAT, a constitutive marker. Superimposed on the deficits, there were gender-selective effects and distinct regional disparities in the critical exposure period for vulnerability. In the hippocampus, either the early or late treatment regimen evoked decreases in ChAT but the early regimen elicited a much larger decrease in HC-3; effects persisted into adulthood. In the midbrain, CPF administration on PN1-4 elicited deficits similar to those seen in the hippocampus; however, exposure on PN11-14 elicited changes preferentially in females. Gender selectivity was also apparent in the striatum, in this case reflecting deficits in females after CPF treatment on PN1-4. In contrast, the effects of CPF on the brainstem were relatively more robust in males; effects in the cerebral cortex were less notable than in other regions. These results indicate that neonatal CPF exposure produces widespread deficiencies in cholinergic synaptic function that persist into adulthood. The effects are likely to contribute to gender-selective alterations in behavioral performance that persist or emerge long after the termination of exposure and well after the restoration of cholinesterase activity.
Slotkin
T A
TA
Department of Pharmacology and Cancer Biology, Box 3813 DUMC, Duke University Medical Center, 27710, Durham, NC, USA. t.slotkin@duke.edu
Cousins
M M
MM
Tate
C A
CA
Seidler
F J
FJ
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D006426:Hemicholinium 3 / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008636:Mesencephalon / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D027981:Symporters; D014316:Tritium / Q000493:pharmacokinetics
D015415:Biomarkers; D002352:Carrier Proteins; D007306:Insecticides; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D027981:Symporters; D014316:Tritium; C075746:Slc6a8 protein, rat; D006426:Hemicholinium 3; D002795:Choline O-Acetyltransferase; D004390:Chlorpyrifos; D000109:Acetylcholine