Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats.
It is increasingly clear that environmental toxicants target specific human subpopulations. In the current study, we examined the effects of prior developmental exposure to a beta(2)-adrenoceptor agonist used to arrest preterm labor, terbutaline, on the subsequent effects of exposure to the organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14. Although neither treatment affected growth or viability, each elicited alterations in indices of brain cell differentiation and cholinergic innervation in the immediate posttreatment period (PN15), persisting into adulthood (PN60). Biomarkers of brain cell number (DNA concentration and content), cell size (protein/DNA ratio) and neuritic projections (membrane/total protein) were affected by either agent alone, with patterns consistent with neuronal and neuritic damage accompanied by reactive gliosis. The combined exposure augmented these effects by both additive and synergistic mechanisms. Similarly, choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was affected only by combined exposure to both terbutaline and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and m(2)-muscarinic acetylcholine receptor binding] showed impairment after exposure to either terbutaline or CPF but the effects were more severe when the treatments were combined. These findings suggest that terbutaline, like CPF, is a developmental neurotoxicant, and that its use in the therapy of preterm labor may create a subpopulation that is sensitized to the adverse neural effects of a subsequent exposure to organophosphate insecticides.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Melissa C
MC
Rhodes
Frederic J
FJ
Seidler
Dan
D
Qiao
Charlotte A
CA
Tate
Mandy M
MM
Cousins
Theodore A
TA
Slotkin
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004390:Chlorpyrifos / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000188:drug therapy; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013726:Terbutaline / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology*
D004785:Environmental Pollutants; D008565:Membrane Proteins; D043585:Receptor, Muscarinic M2; D015149:Tocolytic Agents; D004247:DNA; D000110:Acetylcholinesterase; D004390:Chlorpyrifos; D013726:Terbutaline