Research reportAn assessment of the long-term developmental and behavioral teratogenicity of prenatal nicotine exposure
Introduction
It has been estimated that greater than 25% of women in the United States smoked cigarettes at some time during their pregnancy [5], [17]. While tobacco smoke has a number of chemical constituents, numerous studies have implicated nicotine as the main psychoactive ingredient of tobacco use, as well as a strong growth and neurobehavioral teratogen [19], [42], [57]. Nicotine readily crosses the placental barrier and has been found in the amniotic fluid and umbilical cord of neonates [44]. Previous studies have shown that the use of tobacco products during pregnancy adversely affects prenatal and postnatal growth, and increases the risk of fetal mortality and morbidity [19], [22], [61], [62], [66], [74], [75]. Furthermore, nicotine is associated with motor, sensory, and cognitive deficits in infants and toddlers, suggesting a pervasive toxicological effect of tobacco use on early neurodevelopment [19], [31], [42], [57], [69]. While many of these deficits have been shown to exist through at least 1 year of age, the degree to which these children return to normal levels of intellectual functioning is not consistently reported in longitudinal studies to date and remains controversial. However, studies have suggested that the behavioral and cognitive deficits associated with in utero exposure to tobacco may continue into late childhood and adolescence, with offspring of smokers displaying higher rates of attentional deficits leading to an increased risk for attention-deficit/hyperactivity and conduct disorders [23], [25], [84], impaired learning and memory capabilities, and reduced IQs [17], [47], [53], [55], [58], [83]. Heterogeneity would be expected when the exposure to the neurobehavioral teratogen during development is widely separated from the time of the behavioral testing, and may relate to numerous factors, including the degree of exposure, gender, biological predisposition, and differences in postnatal nurturing and care.
While animal models of in utero exposure to nicotine have also demonstrated physical, behavioral, neurochemical, and cognitive abnormalities in offspring [42], [57], [69], as seen in human populations, these studies also show a large degree of heterogeneity in the various measured outcomes. While some animal studies have reported varying degrees of cognitive impairments associated with prenatal nicotine exposure, such measures vary significantly as a function of nicotine dose, schedule, route and time of administration, species, and strain, as well as the stringency of the learning and memory task employed [7], [29], [62]. This is particularly important since prenatal drug exposure may induce disorders on the cellular and subcellular level that may not be readily evident at birth, but form the basis for functional deficits (“functional teratogenicity”) which appear gradually during development and maturation as subtle neurodevelopmental and psychobehavioral deviations [6]. Therefore, the use of animal models are critical for corroborating human studies and for gaining an insight to the possible severity of prenatal nicotine exposure, the stability of these effects throughout the life-span of the animal, and perhaps most importantly, the underlying causes of these abnormalities.
The present studies were undertaken to systematically assess the developmental, behavioral, and cognitive function as a result of prenatal nicotine exposure at different stages of ontogenesis. Of particular interest is the indication that prenatal exposure to tobacco in humans may have different outcomes in females and males [84], so that a detailed examination of the gender-specific vulnerability to the effects of in utero nicotine exposure was undertaken. In addition, little is known about the rearing effects of nicotine withdraw and its possible interaction with neonatal development and behavior of the offspring. Therefore, a cross-fostering procedure was included to allow this assessment. These studies provide important information about growth, exploratory activity, anxiety “state” and cognitive ability of both genders following fetal nicotine exposure, and form the basis for future studies on the underlying causes of these deficits.
Section snippets
Subjects and nicotine administration
Female Sprague–Dawley rats (approximately 3 months of age) were obtained on day 2 of pregnancy (Zivic-Miller Laboratories, Pittsburgh, PA). All animal studies were performed in accordance with the Principles of Laboratory Animal Care (NIH publication 85-23, 1985). Animals were housed in a pathogen free USDA approved facility at Auburn University and maintained on a 12/12 h light/dark cycle (lights on at 06:00 h). Pregnant rats were implanted on day 3 of pregnancy with 28-day osmotic minipumps
Mortality and body weight in rats exposed prenatally to nicotine
No differences were seen in the body weights of nicotine-treated dams during gestation or lactation as compared to the saline-treated control animals, indicating that the nicotine dose used in these studies did not adversely affect overall dietary consumption in the nicotine-treated mothers [13]. There were no observable birth defects, still born pups, postnatal deaths, or cases of maternal cannibalism in any of the experimental groups. Body weights of offspring exposed prenatally to nicotine
Physical development
Prenatal nicotine exposure throughout pregnancy produced offspring that differed markedly from their saline-treated controls in the rate of physical maturation, locomotion, and adaptation to a new environment, anxiety level, and cognitive behavior. The deviations from normal development extended from birth through early adulthood, the last time point examined in these studies. Prenatal nicotine exposure induced significant reductions in female postnatal body weight of the offspring during
Acknowledgements
This work was supported in part by USPHS Grant AA11164, a NARSAD Young Investigator Award, and The Office of the Vice-President for Research, Auburn University Biogrants Program.
References (88)
- et al.
Prenatal nicotine exposure modifies behavior of mice through early development
Pharmacol. Biochem. Behav.
(1998) - et al.
Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters
Pharmacol. Biochem. Behav.
(2001) - et al.
Nicotine- or epinephrine-induced uteroplacental vasoconstriction and fetal growth in the rat
Toxicology
(1994) - et al.
A selective genetic analysis of the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus)
Behav. Brain Res.
(1999) - et al.
Preweaning experience as a modifier of prenatal drug effects in rats and mice—a review
Neurotoxicol. Teratol.
(2000) - et al.
Rats and mice share common ethologically relevant parameters of exploratory behavior
Behav. Brain Res.
(2001) - et al.
Behavioral and neural consequences of prenatal exposure to nicotine
J. Am. Acad. Child Adolesc. Psychiatry
(2001) - et al.
Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors
Physiol. Behav.
(1999) - et al.
Effects of training, early handling, and perinatal flumazenil on shuttle box acquisition in Roman low-avoidance rats: toward overcoming a genetic deficit
Neurosci. Biobehav. Rev.
(1995) Factors controlling measures of anxiety and responses to novelty in the mouse
Behav. Brain Res.
(2001)
Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats
Eur. J. Pharmacol.
Individual response profiles of male Wistar rats in animal models for anxiety and depression
Behav. Brain Res.
Gender differences in brain and behavior: hormonal and neural bases
Biochem. Behav.
Prenatal nicotine exposure and cognitive performance in rats
Neurotoxicol. Teratol.
Prenatal adverse effects of nicotine on the developing brain
Prog. Brain Res.
Prenatal administration of nicotine results in dopaminergic alterations in the neocortex
Neurotoxicol. Teratol.
Nicotine exposure during pregnancy is a factor which influences serotonin transporter density in the rat brain
Eur. J. Pharmacol.
Nicotine administration to rats: methodological considerations
Life Sci.
Pre- and postnatal development of high-affinity []nicotine binding sites in rat brain regions: an autoradiographic study
Brain Res. Dev. Brain Res.
Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth
Brain Res. Bull.
Effects of cross-fostering on emotional and learning behavior of different strains of rats
Life Sci.
Novelty seeking in periadolescent mice: sex differences and influence of intrauterine position
Physiol. Behav.
Behavioral effects of prenatally administered smokeless tobacco on rat offspring
Neurotoxicol. Teratol.
Hyperactivity in the offspring of nicotine-treated rats: role of the mesolimbic and nigrostriatal dopaminergic pathways
Pharmacol. Biochem. Behav.
Effects of prenatal nicotine exposure on the morphogenesis of somatosensory cortex
Neurotoxicol. Teratol.
Sex differences in aversive and appetitive conditioning in two strains of rats
Physiol. Behav.
The behaviour of infants whose mothers smoke in pregnancy
Early Hum. Dev.
A new device for monitoring early motor development: prenatal nicotine-induced changes
Pharmacol. Biochem. Behav.
In search of a mechanism for receptor-mediated neurobehavioral teratogenesis by nicotine: catecholamine release by nicotine in immature rat brain regions
Brain Res. Dev. Brain Res.
Prenatal nicotine sex-dependently alters agonist-induced locomotion and stereotypy
Neurotoxicol. Teratol.
Effects of prenatal nicotine exposure on neuronal development: selective actions on central and peripheral catecholaminergic pathways
Brain Res. Bull.
The effects of prenatal nicotine on radial-arm maze performance in rats
Pharmacol. Biochem. Behav.
Hyperactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors
Pharmacol. Biochem. Behav.
Can nootropic drugs be effective against the impact of ethanol teratogenicity on cognitive performance?
Eur. Neuropsychopharmacol.
The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?
Neurosci. Biobehav. Rev.
Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood
J. Am. Acad. Child Adolesc. Psychiatry
Presynaptic nicotinic ACh receptors
Trends Neurosci.
Alterations in hippocampal cholinergic receptors and hippocampal behaviors after early exposure to nicotine
Brain Res. Bull.
Procedural considerations in evaluating prenatal effects of alcohol in animals
Neurobehav. Toxicol. Teratol.
Nicotine-induced changes in the cerebral circulation in ovine fetuses
Am. J. Perinatol.
Objectively measured tobacco exposure during pregnancy: neonatal effects and relation to maternal smoking
Br. J. Obstet. Gynaecol.
Perinatalni farmakoterapie a riziko funkcne teratogennich defektu
Ceskoslovenska Fysiologie
Effects of prenatal exposure to cigarette smoke and nicotine on pregnancy, offspring development and avoidance behavior in rats
Neurobehav. Toxicol. Teratol.
Landmark stability: further studies pointing to a role in spatial learning
Q. J. Exp. Psychol. B
Cited by (160)
Maternal nicotine exposure promotes hippocampal CeRNA-mediated excitotoxicity and social barriers in adolescent offspring mice
2024, Ecotoxicology and Environmental SafetyMitigation of nicotine-induced developmental effects by 24-epibrassinolide in zebrafish
2023, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyDistinct sex-dependent effects of maternal preconception nicotine and enrichment on the early development of rat offspring brain and behavior
2022, Neurotoxicology and TeratologyCigarette and E-cigarettes smoking and reproductive and developmental toxicity
2022, Reproductive and Developmental ToxicologyReview of rodent models of attention deficit hyperactivity disorder
2022, Neuroscience and Biobehavioral ReviewsDevelopmental nicotine exposure impairs memory and reduces acetylcholine levels in the hippocampus of mice
2021, Brain Research Bulletin
- 1
Co-corresponding author.