Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood.
The developmental neurotoxicity of chlorpyrifos (CPF) involves multiple mechanisms, thus rendering the immature brain susceptible to adverse effects over a wide window of vulnerability. Earlier work indicated that CPF exposure at the neural tube stage elicits apoptosis and disrupts mitotic patterns in the brain primordium but that rapid recovery ensues before birth. In the current study, we assessed whether defects in cholinergic synaptic activity emerge later in development. CPF was given to pregnant rats on gestational days 9-12, using regimens devoid of overt maternal or fetal toxicity. We then examined subsequent development of acetylcholine systems and compared the effects to those on general biomarkers of cell development. Choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was increased in the hippocampus and striatum in adolescence and adulthood. In contrast, hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, an index of nerve impulse activity, was markedly subnormal. Furthermore, m2-muscarinic cholinergic receptor binding was significantly reduced, instead of showing the expected compensatory upregulation for reduced neural input. CPF also elicited delayed-onset alterations in biomarkers of cell packing density, cell number, cell size and neuritic projections, involving brain regions both with and without reductions in indices of cholinergic activity. In combination with earlier results, the current findings indicate that the developing brain, and especially the hippocampus, is adversely affected by CPF regardless of whether exposure occurs early or late in brain development, and that defects emerge in adolescence or adulthood even in situations where normative values are initially restored in the immediate post-exposure period.
Qiao
Dan
D
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC Rm c162, LSRC Building Research Drive, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Abreu-Villaça
Yael
Y
Tate
Charlotte A
CA
Cousins
Mandy M
MM
Slotkin
Theodore A
TA
D000105:Acetyl Coenzyme A / Q000493:pharmacokinetics; D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development; D002452:Cell Count / Q000379:methods; D048429:Cell Size / Q000187:drug effects; D004390:Chlorpyrifos / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006426:Hemicholinium 3 / Q000493:pharmacokinetics; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; C065959:AFDX 384; D006426:Hemicholinium 3; D010890:Pirenzepine; D000105:Acetyl Coenzyme A; D004247:DNA; D002795:Choline O-Acetyltransferase; D004390:Chlorpyrifos; D000109:Acetylcholine