Research report
An assessment of the long-term developmental and behavioral teratogenicity of prenatal nicotine exposure

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Abstract

Maternal tobacco use during pregnancy adversely affects prenatal and postnatal growth and increases the risk of developmental and behavioral deficits in children and adolescents. In the present study, the effects of prenatal nicotine exposure (infused at 6 mg/kg/day) and maternal withdraw during neonatal development, was examined in Sprague–Dawley rats on an array of behavioral tasks during different stages of ontogenesis. Offspring of both genders were monitored for exploratory, locomotor, and novelty-seeking activity, anxiety, and learning and memory in an active-avoidance task. Nicotine-exposed animals showed growth retardation, hyperactivity, and poor adaptation in a new environment, increased level of anxiety during the early adolescent period, and robust cognitive deficits in early adulthood. In addition, the deficits were generally more severe in the female nicotine-exposed offspring. Cross-fostering also revealed that while maternal behavior and nicotine withdraw did not affect postnatal somatic growth retardation or cognitive ability of the offspring; measures of exploration and adaptation in a new environment were impacted during the post-weanling and early adolescence period. Nicotine-exposed offspring, and the saline-treated offspring cross-fostered to nicotine-exposed mothers, showed higher measures of anxiety in the elevated plus-maze and decreased novelty-seeking behavior on the hole-board apparatus. These studies demonstrated that prenatal nicotine exposure produced significant long-term developmental and behavioral teratogenic effects. The study design provides a model system for studying the mechanism(s) responsible for the decline in central nervous system function following prenatal nicotine exposure, as well as that of other neurological and behavioral teratogens during pregnancy.

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.

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