Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions.
Developmental exposure to unrelated neurotoxicants can nevertheless produce similar neurobehavioral outcomes. We examined the effects of developmental exposure to terbutaline, a tocolytic beta2-adrenoceptor agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and CPF (5 mg/kg) on PN11-14, with assessments conducted on PN45, comparing each agent alone as well as sequential administration of both. Although neither treatment affected growth or viability, each elicited similar alterations in factors that are critical to the function of the 5HT synapse: 5HT1A receptors, 5HT2 receptors, and the presynaptic 5HT transporter (5HTT). Either agent elicited global increases in 5HT receptors and the 5HTT in brain regions possessing 5HT cell bodies (midbrain, brainstem) as well as in the hippocampus, which contains 5HT projections. For both terbutaline and CPF, males were affected more than females, although there were some regional disparities in the sex selectivity between the two agents. Both altered 5HT receptor-mediated cell signaling, suppressing stimulatory effects on adenylyl cyclase and enhancing inhibitory effects. When animals were exposed sequentially to both agents, the outcomes were no more than additive and, for many effects, less than additive, suggesting convergence of the two agents on a common set of developmental mechanisms. Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens.
Aldridge
Justin E
JE
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Meyer
Armando
A
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044263:Receptors, Serotonin, 5-HT1 / Q000187:drug effects* / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D012737:Sex Factors; D013723:Teratogens / Q000633:toxicity; D013726:Terbutaline / Q000008:administration & dosage / Q000633:toxicity*; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000633:toxicity*
D000067956:Adenylyl Cyclase Inhibitors; D007306:Insecticides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044263:Receptors, Serotonin, 5-HT1; D044348:Receptors, Serotonin, 5-HT2; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013723:Teratogens; D015149:Tocolytic Agents; D012701:Serotonin; D000262:Adenylyl Cyclases; D004390:Chlorpyrifos; D013726:Terbutaline