Elsevier

Experimental Neurology

Volume 254, April 2014, Pages 145-152
Experimental Neurology

Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: Role of altered catecholamines and BDNF

https://doi.org/10.1016/j.expneurol.2014.01.016Get rights and content

Highlights

  • Prenatal cigarette exposure (CS) causes hyperactivity and aggressive behavior.

  • Behavioral alterations caused by prenatal CS mainly affect the male offspring.

  • Prenatal CS exposure reduced striatal and cortical dopamine and serotonin.

  • Prenatal CS exposure reduced BDNF mRNA and protein.

Abstract

Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4 h/d and 5 d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking < 1 pack of cigarettes per day (25 ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4 weeks of age and again at 4–6 months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident–intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects.

Introduction

Despite many public health programs promoting the risks of smoking while pregnant, only 25% of women who smoke quit smoking cigarettes during pregnancy. Several reports established that maternal smoking during pregnancy adversely affects pre- and post-natal growth and increases the risk of fetal mortality, pre-term birth, low birth weight, and altered cognitive development (Wigle et al., 2008). Importantly, the adverse effects of maternal smoking on neurodevelopment persist through at least the adolescent period and may extend into adulthood (Keyes et al., 2011).

Although a large number of epidemiological studies reporting increased neurobehavioral deficits following maternal smoking exist, recent reports questioned their validity. The most notable regards the association between maternal smoking and attention-deficit hyperactivity disorder (ADHD). Several groups linked maternal smoking to an increased risk of ADHD (Banerjee et al., 2007, Langley et al., 2005, Linnet et al., 2003). In one of the first studies to directly assess the relationship between maternal smoking and ADHD, Milberger et al. (1998) found a 2.7-fold increased risk for ADHD associated with maternal smoking, a finding that has been replicated by several groups in a variety of cohort studies (Leech et al., 1999, Linnet et al., 2005, Obel et al., 2009, Thapar et al., 2003, Weissman et al., 1999). Using a cross-sectional study design from the National Health and Nutrition Examination Survey, Braun and co-workers found that pre- but not post-natal exposure to tobacco smoke led to an increased risk of ADHD diagnosis and the authors calculated that maternal smoking led to 270,000 excess cases of ADHD (Braun et al., 2006). This finding was confirmed even when more stringent criteria were applied (Froehlich et al., 2009).

However, several recent papers concluded that there is no causal relationship between maternal smoking and behavioral dysfunction, or that the effect sizes in previous studies were over-estimated (Ball et al., 2010, Langley et al., 2012, Lindblad and Hjern, 2010, Obel et al., 2011, Thapar et al., 2009). Rather, these studies argued that the association between maternal smoking and these effects is likely the result of a variety of confounders including genetic factors, other environmental factors, and/or existing maternal psychopathology that were not satisfactorily adjusted for in the previous studies.

To address this controversy and to gain insight into the mechanism(s) responsible for potential neurobehavioral effects of maternal smoking, we employed a pregnant mouse model of maternal smoking. Data demonstrate that in utero exposure to cigarette smoke (CS; at a concentration reflective of smoking < 1 pack of cigarettes per day) produces behavioral alterations in the offspring (specifically, the males) that are similar to those observed in epidemiological studies of maternal smoking, including hyperactivity and increased aggression. Mechanistically, these behavioral deficits are associated with decreased monoamine levels and brain-derived neurotrophic factor mRNA and protein. These data provide mechanistic support for the reported link between in utero CS exposure and behavioral deficits in the epidemiological literature.

Section snippets

Animals

B6C3F1 male and female mice were purchased from Jackson Laboratory (Bar Harbor, ME). These mice were chosen based on previous experiments characterizing developmental outcomes of CS exposure (Ng et al., 2006). Mice were housed in pairs (females) or individually (males) in polycarbonate cages (with corncob bedding) in temperature-controlled (20 °C–23 °C) and humidity-controlled (~ 55% RH) rooms. Food (purified AIN-98) and tap water were available ad libitum. The light/dark cycle was maintained on 12

General health of dams and reproductive outcomes

Out of 10 dams bred for each condition, 8/10 control dams and 10/10 CS-exposed dams gave birth. Dam weight gain measured on gestational days (GD) 11, 15, and 19 did not differ significantly between the control and CS exposure group (p = 0.14; Table 1). Although there were fewer pups born to CS-exposed dams compared to control, this did not quite reach statistical significance (p = 0.08; Table 1). This finding was likely influenced by two litters born to CS-exposed dams that consisted of only two

Discussion

Although maternal smoking has been associated with increased risk of behavioral dysfunction, for almost 20 years, recent reports have questioned whether there is a true causal association. This study sought to use a novel animal model of in utero exposure to cigarette smoke (CS), at a concentration reflective of smoking < 1 pack of cigarettes per day, to determine whether behavioral alterations were observed similar to that reported in the epidemiological studies. The data reveal that behavioral

Conclusion

Using a novel animal model, we demonstrate for the first time that the offspring of mice exposed to CS during gestation exhibit neurobehavioral deficits including hyperactivity and increased aggression, that is similar to those observed in epidemiological studies of maternal smoking. Importantly, we identified that some of these effects mimic those observed in other studies using prenatal exposure to nicotine. However, there were notable differences, including the effects on aggressive behavior

Financial disclosure

This research was supported in part by grants from the National Institutes of Environmental Health Sciences [P30ES000260 (JTZ), P30ES005022 (JRR), T32ES007148 (CY), R01ES015991 (JRR)] and a grant from the Institute for Science and Health (JTZ).

Acknowledgments

The authors thank Dr. Chen Zhang for excellent technical assistance.

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    1

    JTZ and JRR contributed equally as senior authors.

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