Cognitive and Behavioral Impairments Evoked by Low-Level Exposure to Tobacco Smoke Components: Comparison with Nicotine Alone

Abstract

Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE effects to those of an equivalent dose of Nic alone, and to a 10-fold higher Nic dose. Gestational exposure to TSE and Nic significantly disrupted cognitive and behavioral function in behavioral tests given during adolescence and adulthood (postnatal weeks 4-40), producing hyperactivity, working memory deficits, and impairments in emotional processing, even at the low exposure levels corresponding to second-hand smoke. Although TSE effects were highly correlated with those of Nic, the effects of TSE were much larger than could be attributed to just the Nic in the mixture. Indeed, TSE effects more closely resembled those of the 10-fold higher Nic levels, but still exceeded their magnitude. In combination with our earlier findings, this study thus completes the chain of causation to prove that second-hand smoke exposure causes neurodevelopmental deficits, originating in disruption of neurodifferentiation, leading to miswiring of neuronal circuits, and as shown here, culminating in behavioral dysfunction. As low level exposure to Nic alone produced neurobehavioral teratology, 'harm reduction' Nic products do not abolish the potential for neurodevelopmental damage.

Is There a Critical Period for the Developmental Neurotoxicity of Low-Level Tobacco Smoke Exposure?

“…We found that low TSE levels, comparable to secondhand smoke exposure (i.e. producing plasma nicotine levels one-tenth of those in typical smokers), nevertheless engendered synaptic dysfunction in acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT) systems, culminating in impaired cognitive and emotional behaviors (Hall et al, 2016;Slotkin et al, 2015). TSE exposure had greater effects than did comparable treatment with nicotine alone and indeed, TSE was similar to a 10-fold higher nicotine level; that is, TSE simulating secondhand exposure elicited outcomes like nicotine at active smoking levels.…”

“…Recently, we developed a tobacco smoke administration model in pregnant rats that ensures reliable dosing and avoids the stress of inhalation exposure (Hall et al, 2016;Slotkin et al, 2015). We paralleled the standard technique for nicotine delivery in pregnant rats, namely subcutaneously-implanted pumps (Slotkin, 2008) that deliver standardized tobacco smoke extract (TSE).…”

Neurobehavioral effects of choninergic drugs in prenatal period

“…С курением во время беременности связаны проблемы в обуче-нии, поведении, общих когнитивных функциях, а так-же изменения, касающиеся функционирования слу-ховой зоны мозга у детей [41, 82,123], вследствие воздействия никотина повышается риск развития множественных пороков развития у плода [104]. Пассивное курение, как низкодозовое воздействие никотина, также приводит к нейроповеденческим, когнитивным нарушениям и увеличению риска ре-спираторного дистресс-синдрома у новорожденных [33, 69,82,212].…”

“…Точно так же Shacka et al [160] предположили, что централь-ный контроль моторной функции у самцов может быть более уязвимым для пренатального никотина, так как пренатально леченные самцы на 14-й день гестации не показывали гиперактивности после стимуляции никотином. Действие никотина во вре-мя беременности значительно нарушает структуры субпопуляций нейронов ДА в ВТО и другие структу-ры мезолимбической системы, что может вызвать тяжелые эффекты на нейронных сетях, вовлеченных в процессы привыкания и подкрепления, целена-правленного поведения и спонтанной и вызванной гиперреактивности у молодых крыс [67,82,99].…”

“…Большинство факторов внешней среды, воз-действующих на развивающийся мозг в этот период, нарушают нормальный онтогенез нейромедиатор-ных систем мозга, изменения активности которых могут коррелировать с поведенческими дефицита-ми во взрослом состоянии [2-9, 17, 18, 20, 82,156,168,197].…”