Prenatal nicotine alters maturation of breathing and neural circuits regulating respiratory control
Introduction
Maternal smoking during pregnancy induces a high incidence of ventilatory abnormalities in infants (apnea, delayed arousal responses, altered hypoxic ventilatory drive, or bronchopulmonary disease) with increased risk of Sudden Infant Death Syndrome (Mitchell and Milerad, 2006). Although the effects of prenatal nicotine on ventilation have been extensively studied in animals (Huang et al., 2004, Bamford et al., 1996, Bamford and Carroll, 1999, Simakajornboon et al., 2004), results remain conflicting, due to divergent experimental designs (species, nicotine administration route, time of pregnancy, duration and dose of nicotine administration, postnatal age) and types of ventilatory analysis (baseline data, apnea incidence, ventilatory response to hypoxia or hyperoxia). Most studies assessed changes in overall minute ventilation rather than in the two components: respiratory frequency and tidal volume. In addition, the cellular mechanisms underlying the control of ventilation after prenatal nicotine exposure remain partially elucidated.
The neural circuits regulating breathing belong to the chemoafferent pathway (Bianchi et al., 1995). In rats, the afferent chemosensory fibers arising from the carotid bodies project onto discrete areas of the medulla oblongata: mainly the caudal part of the nucleus tractus solitarius and, to a lesser extent, the ventrolateral medulla (Finley and Katz, 1992). The nucleus tractus solitarius and the ventrolateral medulla contain clusters of noradrenergic and adrenergic neurons: A2C2 and A1C1, respectively. The A2C2 cell group displays a functional subdivision: the caudal part (A2C2c) is influenced by peripheral chemosensory input and the rostral part (A2C2r) by barosensory input (Soulier et al., 1992). The A2 and A1 cell groups are involved in respiration through their connections to the adjacent dorsal and ventral respiratory groups. In addition, the A5 cell group, located in the ventrolateral pons and projecting onto the medulla oblongata and spinal cord, controls sympathetic output and respiratory events (Guyenet et al., 1993). The locus coeruleus (A6), the major noradrenergic cell group in the brain, belonging to the pontine tegmentum, with extensive descending projections onto the medulla oblongata and spinal cord, is involved in arousal and cardiorespiratory regulation and is part of the chemoreflex pathway (Guyenet et al., 1993, Hilaire et al., 2004). Catecholamines are the main neurotransmitters involved in chemoafferent pathway control. Firstly, dopamine is the most abundant neurotransmitter at the chemosensory synapse of the carotid body (Finley et al., 1992). Secondly, the central integration sites located in the nucleus tractus solitarius and the ventrolateral medulla are respectively associated with the A2C2 and the A1C1 catecholaminergic clusters (Finley and Katz, 1992). Thirdly, there is growing evidence that brainstem catecholaminergic neurons participate in the control of breathing. Mice invalidated for genes such as BDNF, mash, ret or rnx exhibited catecholaminergic impairment of carotid body, petrosal ganglion or brainstem noradrenergic system, systematically accompanied by ventilatory deficiency (Hilaire, 2006).
Maturation of these neural circuits develops within the first postnatal weeks and is dependent on the perinatal environment (White et al., 1994, Gauda et al., 2004, Donnelly, 2005, Wong-Riley and Liu, 2005). Prenatal nicotine reduces the brainstem noradrenaline level and/or utilization rate until weaning (Navarro et al., 1988), and induces cell damage, cell loss and synaptic dysfunction in the developing brain (Slotkin, 1998, Slotkin, 2004, Slotkin et al., 2007). It also enhances the expression of protein kinase C which plays an important role in both excitatory and inhibitory respiratory neurons (Bandla et al., 1999), thus possibly contributing to altered ventilation (Simakajornboon et al., 2004). In rat carotid bodies, perinatal exposure to nicotine upregulates tyrosine hydroxylase (TH) mRNA (Holgert et al., 1995, Gauda et al., 2001) and depresses breathing by attenuating the carotid body drive (Holgert et al., 1995).
Catecholamines are major components regulating ventilation at the peripheral and central levels (Finley and Katz, 1992, Bianchi et al., 1995), yet no studies have concomitantly investigated the effects of prenatal nicotine exposure on the development of breathing and catecholamine metabolism within the chemoafferent pathway. We therefore tested the hypothesis that prenatal nicotine exposure might cause abnormal breathing pattern development and that the impaired respiratory function might result in part from impaired development of the neural network regulating breathing.
In the present study, nicotine was delivered in pellet form throughout gestation from embryonic day 5 (E5) until birth; functional sequelae on resting ventilation and ventilatory response to acute hypoxic challenge were analyzed at postnatal days 7 (P7), 11 (P11) and 21 (P21). To determine whether nicotine-induced developmental abnormalities in ventilation were associated with changes in the postnatal maturation of ventilatory control, in vivo TH activity was analyzed at P7, P11 and P21 in the peripheral and central catecholaminergic structures of the chemoafferent pathway: i.e., carotid bodies, A2C2 caudal (A2C2c) and rostral (A2C2r) part, A1C1, A5 and A6 brainstem cell groups.
Section snippets
Animals
Male and female Sprague–Dawley rats (IFFA Credo, France) were mated at night, and the morning on which sperm-positive smears were obtained was defined as embryonic day 0 (E0). Pregnant rats (300–320 g) were then housed in an air-conditioned room at 26 ± 1 °C with a 12-h light–dark cycle and free access to food and water. They were randomly assigned to two groups: nicotine and control.
The nicotine group received the following treatment: pregnant dams were operated on at E5, so as not to disturb
Maternal plasma nicotine and cotinine concentrations
The release of nicotine from the pellet was monitored by measuring plasma nicotine and cotinine levels over the 3-week time course. Following an initial peak on the day of pellet implantation (E5), plasma concentrations of nicotine and cotinine stabilized (Fig. 2).
Viability and growth
Pregnant rats were exposed to nicotine 5 days after impregnation to avoid disturbing embryo implantation. Nevertheless, 7% of the nicotine-treated dams resorbed their fetuses. Administration of prenatal nicotine significantly reduced
Discussion
Although the ventilatory effects of prenatal nicotine exposure have been widely investigated and nicotine-induced changes in central respiratory control mechanisms have been proposed (Slotkin et al., 1995, Slotkin et al., 1997), no study previously examined developmental change in the catecholaminergic neural circuits controlling respiration. The originality and relevance of the present study lie in the in vivo assessment of the chemoafferent pathway and the longitudinal evaluation of both
Acknowledgements
This work was supported by the Centre National de la Recherche Scientifique, the Université Claude Bernard, and the Fédération “Naitre et Vivre” (France). David Perrin held a fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche, Julie Peyronnet held grants from the Karolinska Institute, Sweden, and Aurélien Boussouar held grants from the Agence de l’Environnement et de la Maîtrise de l’Energie.
References (70)
- et al.
Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates
Semin. Perinatol.
(2004) - et al.
Neurotransmitters in carotid body development
Respir. Physiol. Neurobiol.
(2005) - et al.
Developmental pattern of M1 and M2 gene expression and receptor levels in cat carotid body, petrosal and superior cervical ganglion
Neuroscience
(2006) - et al.
Developmental profile of cholinergic and purinergic traits and receptors in peripheral chemoreflex pathway in cats
Neuroscience
(2007) - et al.
Carbachol effect on carotid body dopamine in vitro release in response to hypoxia in adult and pup rabbit
Neurosci. Res.
(2001) - et al.
Effect of nicotine exposure on postnatal ventilatory responses to hypoxia and hypercapnia
Respir. Physiol.
(1996) - et al.
Dynamic ventilatory responses in rats: normal development and effects of prenatal nicotine exposure
Respir. Physiol.
(1999) - et al.
Control of breathing in experimental anemia
Respir. Physiol.
(1970) Development of carotid body/petrosal ganglion response to hypoxia
Respir. Physiol. Neurobiol.
(2005)- et al.
The central organization of carotid body afferent projections to the brainstem of the rat
Brain Res.
(1992)
Transmitter diversity in carotid body afferent neurons: dopaminergic and peptidergic phenotypes
Neuroscience
Oxygen and carotid body chemotransduction: the cholinergic hypothesis—a brief history and new evaluation
Respir. Physiol.
Developmental expression of tyrosine hydroxylase, D2-dopamine receptor and substance P genes in the carotid body of the rat
Neuroscience
Peripheral arterial chemoreceptors and Sudden Infant Death Syndrome
Respir. Physiol. Neurobiol.
Maturation of peripheral arterial chemoreceptors in relation to neonatal apnoea
Semin. Neonatal.
Monoaminergic neurons, chemosensation and arousal
Respir. Physiol. Neurobiol.
Endogenous noradrenalin affects the maturation and function of the respiratory network: possible implication for SIDS
Auton. Neurosci.: Basic Clin.
Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents
Respir. Physiol. Neurobiol.
Influence of prenatal nicotine exposure on postnatal development of breathing pattern
Respir. Physiol. Neurobiol.
Prenatal nicotine exposure affects the development of the central serotonergic system as well as the dopaminergic system in rat offspring: involvement of route of drug administrations
Brain Res. Dev. Brain Res.
Chronic hypoxia affects peripheral and central vasoactive intestinal peptide-like immunoreactivity in the rat
Neurosci. Lett.
Time domains of the hypoxic ventilatory response
Respir. Physiol.
Upregulation of nicotinic receptors following continuous infusion of nicotine is brain-region-specific
Brain Res.
Role of acetylcholine in neurotransmission of the carotid body
Respir. Physiol. Neurobiol.
Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response
Respir. Physiol. Neurobiol.
Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates
Toxicol. Appl. Pharmacol.
Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for Sudden Infant Death Syndrome
Brain Res. Bull.
Ontogeny of the O2-sensitive pathway in medulla oblongata of postnatal rat
Respir. Physiol.
Neurochemical development of brainstem nuclei involved in the control of respiration
Respir. Physiol. Neurobiol.
Protein kinase C modulates ventilatory patterning in the developing rat
Am. J. Respir. Crit. Care Med.
Central control of breathing in mammals: neuronal circuitry, membrane properties, and neurotransmitters
Physiol. Rev.
Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase
Naunym-Schmied. Arch. Pharmacol.
β2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: a receptor basis for sleep-disordered breathing after nicotine exposure
Proc. Natl. Acad. Sci. U.S.A.
Perinatal exposure to nicotine causes deficits associated with a loss of nicotinic receptor function
Proc. Natl. Acad. Sci. U.S.A.
Developmental plasticity in respiratory control
J. Appl. Physiol.
Cited by (14)
Impact of tobacco smoke and nicotine exposure on lung development
2016, ChestCitation Excerpt :The mechanisms underlying this link between prenatal tobacco smoke exposure and SIDS have not been clearly elucidated. Rodent studies have indicated that nicotine exposure during prenatal life may alter central and peripheral respiratory chemoreception.46,47 A study in neonatal rats found that pups exposed to prenatal cigarette smoke had prolonged gasping following a hyperthermic or hypoxic exposure.48
Prenatal nicotine exposure increases hyperventilation in α4-knock-out mice during mild asphyxia
2015, Respiratory Physiology and NeurobiologyCitation Excerpt :Also possible is that prenatal nicotine exposure may have impaired the development of the hypoxic ventilatory response of the carotid body (Mahliere et al., 2008). In the absence of α4 such impairement may include abnormal adenosine release or altered release of inhibitory modulators such as dopamine and tyrosine hydroxylase (Mahliere et al., 2008; Meza et al., 2012). Potentially, the enhanced central chemoreflex may be compensating for poor carotid body function.
Perinatal nicotine/smoking exposure and carotid chemoreceptors during development
2013, Respiratory Physiology and NeurobiologyPrenatal nicotine exposure alters the response of the mouse in vitro respiratory rhythm to hypoxia
2012, Respiratory Physiology and NeurobiologyCitation Excerpt :There is also evidence that exposure to nicotine that is restricted to the prenatal period can affect the postnatal growth of rat pups. In a study in which rat pups exposed to nicotine prenatally were redistributed at birth to nursing females that had never been exposed to nicotine, thereby avoiding postnatal transfer of nicotine and cotinine (a metabolite of nicotine), exposure significantly reduced rat pup weight at P3 and enhanced it at P21 (Mahliere et al., 2008). In the present study, pre- and early postnatal nicotine exposure did not lead to a significant difference in irregularity of the baseline fictive respiratory rhythm in slices from nicotine-exposed mice compared to that of sham-operated mice.
The effects of strain and prenatal nicotine exposure on ethanol consumption by adolescent male and female rats
2010, Behavioural Brain ResearchRole of cholinergic-nicotinic receptors on hypoxic chemoreflex during postnatal development in rats
2009, Respiratory Physiology and Neurobiology