Elsevier

Brain Research Bulletin

Volume 59, Issue 4, 15 January 2003, Pages 319-329
Brain Research Bulletin

Developmental toxicity of terbutaline: Critical periods for sex-selective effects on macromolecules and DNA synthesis in rat brain, heart, and liver

https://doi.org/10.1016/S0361-9230(02)00925-5Get rights and content

Abstract

β-Adrenoceptors (βARs) control cell replication/differentiation, and during development, signaling is not subject to desensitization. We examined the effects of terbutaline, a β2AR agonist used as a tocolytic, on development in rat brain regions and peripheral tissues with high βAR 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 βAR 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 β-agonist tocolytics.

Section snippets

INTRODUCTION

In the U.S., preterm labor occurs in up to 20% of all pregnancies, with preterm delivery, a leading cause of neonatal morbidity and mortality, in about half the cases [10]. Terbutaline and other β2-adrenoceptor (β2AR) agonists are commonly used as tocolytics, and although terbutaline is considered generally safe, it is important to note that preterm labor is not on FDA’s list of approved uses. In addition to blocking uterine contractions, terbutaline penetrates the placenta to activate fetal β

Animals and Treatments

All experiments were carried out in accordance with the declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health. Timed-pregnant rats (Zivic Laboratories, Pittsburgh, PA) were housed in breeding cages, with a 12 h/12 h light/dark cycle and free access to food and water. For studies of prenatal treatment, dams were given daily subcutaneous injections of 10 mg/kg of terbutaline hemisulfate (Sigma Chemical

Ontogenetic Profiles of Macromolecules and DNA Synthesis

The relative growth rates of the different brain regions and tissues in control rats mirrored the specific postnatal “growth spurt” [52]. Between PN6 and PN15, during which time the animals nearly doubled their body weights, the cerebellum increased 3.5-fold in weight, as compared to only a 60% increase in the brainstem, the earliest-developing brain region, and an 80% increase in the forebrain, which has a maturational profile intermediate between those of the brainstem and cerebellum (Fig. 1

DISCUSSION

Unlike the adult, βARs in the fetus and neonate are resistant to agonist-induced desensitization and, after prolonged exposure to receptor stimulants, actually increase their ability to generate cyclic AMP, primarily by inducing adenylyl cyclase activity 2., 3., 65., 72., 83.. In turn, the close involvement of cyclic AMP in the switch from cell replication to differentiation 12., 15., 24., 27., 66., 67., 68., 78., suggested to us that tocolytic drugs, such as terbutaline, might have an adverse

Acknowledgements

This research was supported by USPHS HD09713.

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