Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos.
Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a beta-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.
Meyer
Armando
A
Centro de Estudos da Saúde do Trabalhador e Ecologia Humana (AM), Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Seidler
Frederic J
FJ
Aldridge
Justin E
JE
Slotkin
Theodore A
TA
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity; D013726:Terbutaline / Q000008:administration & dosage / Q000633:toxicity*; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000633:toxicity*
D000318:Adrenergic beta-Agonists; D007306:Insecticides; D011943:Receptors, Adrenergic, beta; D013723:Teratogens; D015149:Tocolytic Agents; D000262:Adenylyl Cyclases; D004390:Chlorpyrifos; D007545:Isoproterenol; D013726:Terbutaline