Developmental toxicity of terbutaline: Critical periods for sex-selective effects on macromolecules and DNA synthesis in rat brain, heart, and liver
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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2018, ToxicologyCitation Excerpt :However, the potential for neurobehavioral deficits resulting from terbutaline treatment are less well recognized. βARs, including the β2 subtype, are expressed prominently throughout the developing brain (Harden et al., 1977; Lorton et al., 1988) and control the balance between neural cell replication and apoptosis (Garofolo et al., 2003; Hodges-Savola et al., 1996; Slotkin et al., 1988; Zhu et al., 1998, 1999). In animal models, developmental exposure to terbutaline leads to glial activation (Rhodes et al., 2004; Zerrate et al., 2007), a hallmark of neurotoxicity (O'Callaghan, 1993), culminating in abnormalities of brain structure, impaired synaptic function and behavioral deficits (Aldridge et al., 2005; Meyer et al., 2005; Rhodes et al., 2004; Slotkin et al., 1989; Slotkin and Seidler, 2007; Zerrate et al., 2007).
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2014, Medical HypothesesCitation Excerpt :It was also noted that dexamethasone had a synergistic effect with isoproterenol. In terbutaline tocolysis, rat brain shows inhibition of DNA synthesis that is both time sensitive and region specific [129]. Staying with tocolysis for a moment, it is often the case in treating preterm labor with terbutaline that the drug becomes less effective at subduing uterine contractions after a couple days of therapy.
Terbutaline impairs the development of peripheral noradrenergic projections: Potential implications for autism spectrum disorders and pharmacotherapy of preterm labor
2013, Neurotoxicology and TeratologyCitation Excerpt :All procedures utilized tissues that were archived from earlier studies and maintained frozen at − 45 °C, so that no additional animals were actually used for this study. Details of animal husbandry, institutional approvals, maternal and litter characteristics, and growth curves, have all been presented in earlier work from the original animal cohorts (Garofolo et al., 2003; Kreider et al., 2004; Slotkin et al., 1996; Thai et al., 1996). Timed-pregnant Sprague–Dawley rats were housed individually and given free access to food and water.