Elsevier

NeuroToxicology

Volume 68, September 2018, Pages 81-87
NeuroToxicology

Full length article
Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance

https://doi.org/10.1016/j.neuro.2018.07.012Get rights and content

Highlights

  • Late gestational TSE exposure increased errors in the initial training on the radial-arm maze in female offspring.

  • In attentional testing, males exposed to TSE during gestation showed hypervigilance during low-motivating conditions.

  • Gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window.

  • Long-lasting behavioral effects were seen at TSE levels modeling secondhand smoke.

Abstract

Tobacco exposure during development leads to neurobehavioral dysfunction in children, even when exposure is limited to secondhand smoke. We have previously shown in rats that developmental exposure to tobacco smoke extract (TSE), at levels mimicking secondhand smoke, starting preconception and extending throughout gestation, evoked subsequent locomotor hyperactivity and cognitive impairment. These effects were greater than those caused by equivalent exposures to nicotine alone, implying that other agents in tobacco smoke contributed to the adverse behavioral effects. In the present study, we examined the critical developmental windows of vulnerability for these effects, restricting TSE administration (0.2 mg/kg/day nicotine equivalent, or DMSO vehicle, delivered by subcutaneously-implanted pumps) to three distinct 10 day periods: the 10 days preceding mating, the first 10 days of gestation (early gestation), or the second 10 days of gestation (late gestation). The principal behavioral effects revealed a critical developmental window of vulnerability, as well as sex selectivity. Late gestational TSE exposure significantly increased errors in the initial training on the radial-arm maze in female offspring, whereas no effects were seen in males exposed during late gestation, or with either sex in the other exposure windows. In attentional testing with the visual signal detection test, male offspring exposed to TSE during early or late gestation showed hypervigilance during low-motivating conditions. These results demonstrate that gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window in which exposure occurs. The fact that effects were seen at TSE levels modeling secondhand smoke, emphasizes the need for decreasing involuntary tobacco smoke exposure, particularly during pregnancy.

Introduction

Active maternal smoking during pregnancy is a clear contributor to increased risk of neurodevelopmental disorders (Pauly and Slotkin, 2008; Gaysina et al., 2013). Indeed, even lower-level exposures associated with secondhand tobacco smoke can cause persistent neurobehavioral effects (DiFranza et al., 2004; Yolton et al., 2005; Herrmann et al., 2008). These include increased externalizing behavior (Liu et al., 2013), emotional dysfunction (Bandiera et al., 2011) and impaired neuromotor development (Evlampidou et al., 2015; Yeramaneni et al., 2015). In previous studies, we showed that tobacco smoke extract (TSE) administered to rat dams at levels simulating secondhand smoke exposure, commenced in the premating period and continued throughout gestation, leads to persistent anomalies of both synaptic and behavioral function (Slotkin et al., 2015; Hall et al., 2016). Importantly, the effects of TSE were greater than those elicited by equivalent exposures to nicotine alone, indicating that other components of tobacco smoke including polycyclic aromatic hydrocarbons such as benzo[a]pyrene or heavy metals such as cadmium contribute significantly to the adverse outcomes.

Subsequently, we developed models to explore the impact of TSE exposure during restricted periods during the reproductive cycle: for ten days before mating; ten days during early gestation or ten days during late gestation. Rats are born at an immature state relative to humans. The first and second halves of the rat gestational period correspond to the first two trimesters of human gestation. In a neurochemical study that was the companion of the current neurobehavioral study, we found that late gestational TSE exposure caused the most pronounced effects on synaptic development in cholinergic and serotonergic systems (Slotkin et al., 2016). More modest neural effects were seen with early gestational exposure. There were also some significant neurochemical anomalies evoked by exposure prior to mating, which may be due to a persistence of TSE chemical components well past the end of direct exposure, or alternatively, epigenetic changes in the ovum that ultimately affect brain development even when exposure terminates prior to brain formation. In the current study, we assessed the long-term behavioral effects of low-level TSE exposure during the same critical periods, focusing on tests of locomotor activity, emotional behaviors and cognitive function, and distinguishing between males and females.

Section snippets

Tobacco smoke extract

Tobacco Smoke Extract (TSE) was prepared by Arista Laboratories (Richmond, VA, USA) from Kentucky Reference cigarettes (KY3R4F) on a Rotary Smoke Machine under International Organization for Standardization (ISO) mechanical smoking conditions. The smoke condensate was collected on 92 mm filter pads, which were then extracted by shaking with undiluted dimethyl sulfoxide (DMSO) for 20 min, to obtain a solution extract of 20 mg of TSE per ml. Condensate aliquots were stored in amber vials at

Maternal, litter and growth effects

As described previously (Slotkin et al., 2016) in an article describing the neurochemical results of these exposures, these TSE treatment regimens had little or no effect on maternal weight gain, the proportion of dams giving birth, litter size or sex ratio. The particular littermates used for the behavioral studies displayed no statistically significant treatment effects on body weight, although over a larger cohort there was transiently decreased body weight of 3–5% for the early gestational

Discussion

Our principal finding is that the late gestational period represents a critical window in which TSE exposure elicits cognitive deficits, corresponding to the hierarchy of synaptic defects in acetylcholine and serotonin systems, which likewise show a progressive increase in sensitivity as gestation proceeds (Slotkin et al., 2016). In our earlier work, we showed that nicotine exposure throughout gestation, at levels mimicking secondhand smoke and paralleling our TSE exposure model, also evoked

Disclosure

TAS has received consultant income in the past three years from Pardieck Law (Seymour, IN, USA) and Walgreens Co. (Deerfield, IL, USA).

Acknowledgements

This work was supported by the National Institutes of Health (ES022831) and by the U.S. Environmental Protection Agency (83543701). EPA support does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

References (16)

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