Developmental toxicity of terbutaline: critical periods for sex-selective effects on macromolecules and DNA synthesis in rat brain, heart, and liver.
beta-Adrenoceptors (betaARs) control cell replication/differentiation, and during development, signaling is not subject to desensitization. We examined the effects of terbutaline, a beta(2)AR agonist used as a tocolytic, on development in rat brain regions and peripheral tissues with high betaAR concentrations. Prenatal terbutaline (gestational days 17-20) decreased cell numbers (DNA content) in the fetal brain and liver. Early postnatal exposure (PN2-5) reduced DNA synthesis in early-developing brain regions of females, with sensitization of the effect upon repeated terbutaline administration; after multiple terbutaline injections, DNA content was reduced in male cerebellum. The cerebellum was targeted later (PN11-14), exhibiting decreased DNA synthesis in both sexes; in contrast, cardiac DNA synthesis decreased after one injection but increased after the fourth daily injection. Our results suggest that excessive betaAR stimulation by terbutaline alters cell development in brain regions and peripheral tissues, with the net effect depending on sex and the timing of exposure. These effects may contribute to neuropsychiatric, cognitive, cardiovascular, and metabolic abnormalities reported in the offspring of women treated with beta-agonist tocolytics.
Garofolo
Melissa C
MC
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Seidler
Frederic J
FJ
Cousins
Mandy M
MM
Tate
Charlotte A
CA
Qiao
Dan
D
Slotkin
Theodore A
TA
D000318:Adrenergic beta-Agonists / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D002452:Cell Count; D004247:DNA / Q000032:analysis* / Q000187:drug effects; D005260:Female; D005333:Fetus; D006321:Heart / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011506:Proteins / Q000032:analysis / Q000187:drug effects; D051381:Rats; D012737:Sex Factors; D013726:Terbutaline / Q000633:toxicity*; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D011506:Proteins; D004247:DNA; D013726:Terbutaline