Developmental exposure to terbutaline and chlorpyrifos, separately or sequentially, elicits presynaptic serotonergic hyperactivity in juvenile and adolescent rats.
Developmental exposure to unrelated neurotoxicants can nevertheless converge on common final targets so as to exacerbate damage or functional deficits. We examined the effects of developmental exposure to terbutaline, a beta2-adrenergic receptor agonist used to arrest preterm labor, and chlorpyrifos, 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 chlorpyrifos (5 mg/kg) on PN11-14, with assessments conducted in juvenile and adolescent stages (PN21, PN30 and PN45), comparing each agent alone as well as sequential administration of both. By itself, terbutaline produced persistent 5HT presynaptic hyperactivity as evidenced by increased 5HT turnover in brain regions containing 5HT terminal zones; this effect was similar to that seen in earlier studies with chlorpyrifos administration during the same early postnatal period. Later administration of chlorpyrifos (PN11-14) produced a transient increase in 5HT turnover during the juvenile stage, and the sequential exposure paradigm, terbutaline followed by chlorpyrifos, showed a corresponding increase in effect over either agent alone. In combination with our earlier work on 5HT receptors, these results indicate that terbutaline is a developmental neurotoxicant that targets the 5HT system, findings that lend a mechanistic underpinning to clinical indications of elevated childhood psychiatric disorders in the offspring of women treated with beta-agonist tocolytics. Equally importantly, the interaction between terbutaline and chlorpyrifos suggests that tocolytic therapy may alter the subsequent susceptibility to common environmental toxicants.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic J
FJ
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects*; D002648:Child; D004390:Chlorpyrifos / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013726:Terbutaline / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D007306:Insecticides; D015149:Tocolytic Agents; D012701:Serotonin; D004390:Chlorpyrifos; D013726:Terbutaline