Memory under siege: the cognitive costs of smoking and vaping

Abstract

Memory function is critically essential across all life stages, yet it is increasingly compromised by exposure to airborne pollutants due to human behaviours. This review examines the adverse impacts of tobacco smoke and e-cigarette vapour on memory function, emphasising the risks to younger populations. Both pollutants are potent oxidants that induce oxidative stress and inflammatory responses in the brain, leading to synaptic injury and neuronal apoptosis. These processes compromise neuronal integrity and function, potentially resulting in early-onset dementia. Additionally, third-hand exposure to tobacco smoke and e-cigarette vapour, through re-exposure to toxic chemicals on surfaces or clothing, poses significant risks, especially to toddlers. Epigenetic mechanisms, including DNA methylation and histone modification, further exacerbate these effects by altering gene expression critical for brain development and function. This review highlights the necessity for further research to develop risk-reduction strategies to protect cognitive health from these pollutants.

1. Overview

Competent memory function is essential across all stages of life. Many things affect memory, and importantly, a contemporary issue is the inhalation of airborne pollutants (Crous-Bou et al., 2020; De Luca et al., 2023; Durazzo et al., 2014; Jeong et al., 2023; Vanbrabant et al., 2024; Younan et al., 2020). Whilst exposure to some pollutants, such as tobacco smoking, is reducing globally, e-cigarette vaping exposures caused direct, second-hand, and even third-hand effects, which are increasing due to the rising rate of global usage (Chan et al., 2020; Li et al., 2018). These different sources of inhaled toxins have been shown to affect memory functions, and remarkably have very similar mechanisms of action (Crous-Bou et al., 2020; De Luca et al., 2023; Durazzo et al., 2014; Jeong et al., 2023; Vanbrabant et al., 2024; Younan et al., 2020). Upon inhalation, they can induce inflammation and oxidative stress in the lung, which enter the systemic circulation delivering pro-inflammatory cytokines and chemokines, as well as free radicals which are able to cross the blood-brain barrier (BBB) to act on the brain (Chan et al., 2020; Dobric et al., 2022b; Li et al., 2018). We speculate that whilst the induction of oxidative stress and inflammation in the lungs is similar, as are the neuro-pathological effects on memory and related brain regions, they each potentially could have specific mechanisms of action due to their different compositions, and exposure levels (Alasmari et al., 2022b; De Luca et al., 2023; Pisinger and Døssing, 2014; Ponzoni et al., 2015; Zelikoff et al., 2017). This narrative review aims to summarise the adverse impacts of these two major human activity-derived inhalable environmental pollutants on memory function, highlighting the risks in younger populations and identifying knowledge gaps to help researchers generate new experimental hypotheses, and highlights the somewhat hidden dangers of vaping in comparison to the well-recognised effects of cigarette smoking.

2. Introduction

In today's rapidly evolving global landscape, memory is not merely a faculty of the mind but the cornerstone of innovation, education, and professional competency (Gerver et al., 2023; Solaman et al., 2024). As societies advance, the cognitive demands on our younger populations, e.g., students in school, trainees acquiring new skills, and the emergent workforce, are intensifying at an unprecedented pace (Nau et al., 2024). The ability to acquire, retain, and apply new knowledge effectively is not just an educational goal but a fundamental prerequisite for societal progress and economic competitiveness (Nau et al., 2024). However, recent research demonstrates a troubling trend: the increasing incidence of memory-related cognitive functional decline is no longer restricted to older people but also affects young people (Hendriks et al., 2021). This rise is not only a health concern but a looming socioeconomic crisis that could stifle innovation and reduce the efficiency of our workforce (Kilty et al., 2023).

Dementia used to be associated with abnormal ageing and characterised by a gradual decline in memory, mood, and behavioural control (Brito et al., 2023). This is because dementia often occurs in two neurodegenerative diseases which occur in older people. For example, 60–70 % of dementia patients have Alzheimer's disease (AD) (Leng and Edison, 2021), whereas Parkinson's disease (PD) related dementia only contributes to 3–4 % of total dementia cases, although ∼40 % of PD patients develop dementia (Aarsland and Kurz, 2010). In addition, in patients with AD, memory loss, especially short term memory loss, is common in the early stage and other cognitive dysfunctions, such as those that affect thinking and reasoning, develop later (Leng and Edison, 2021). For patients with PD, dementia occurs later in the disease after motor dysfunction, including attention difficulties and hallucinations (Aarsland and Kurz, 2010). This may be due to differences in regional brain pathologies, i.e. amyloid-beta plaques in the hippocampus and cortical regions in AD versus alpha-synuclein aggregation in the basal ganglia and substantia nigra in PD (Outeiro et al., 2019; Shankar and Walsh, 2009). Neurodegenerative disease related dementia is relatively easier to recognise due to being a progressive comorbidity of the primary diagnosis. Even normal ageing is linked to the loss of neurons and synaptic connections, and is more prominent in the cortical regions (Morrison and Baxter, 2012). However, in recent years, young-age onset dementia has become more common (He et al., 2025). A recent cohort study using data from the UK Biobank suggested 15 factors that are associated with an increased risk of memory decline at a younger age. Among them, only one is genetically determined (2 apolipoprotein ε4 allele), while all the others are modifiable or treatable (e.g. alcohol use disorder, social isolation, vitamin D deficiency, diabetes, heart disease, and depression) (Hendriks et al., 2024). However, environmental pollutants generated by human activities are also a risk, as identified in this populational database. For example, the hazard risk of early-onset dementia for individuals who are currently smoking tobacco products is 1.73 (95 % CI: 1.35–2.20), and for those exposed to fine particles within polluted air is 1.25 (95 % CI: 1.16–1.36) (Hendriks et al., 2024).

3. Memory formation

Memory involves encoding, consolidating, storing, and retrieving information (Bisaz et al., 2014). Whenever the brain acquires new information or forms new memories, neuroplasticity, or brain plasticity, allows structural and functional changes (Sale et al., 2014), which modify the strength of connections between neurons and neurogenesis predominantly in the hippocampus (Bisaz et al., 2014; Roy et al., 2017). The formation and storage of episodic and semantic declarative memories rely on sensory inputs from the hippocampus, with help from the adjacent entorhinal cortex and perirhinal cortices (Deng et al., 2010; Neves et al., 2008) (Fig. 1). Hippocampal Cornu Ammon area 2 (CA2) is involved in storing social memory and spatial coding (Tzakis and Holahan, 2019), and regulates the network processing within the hippocampus, creating a balance between excitatory and inhibitory processes necessary for proper network function and preventing potential disruptions in hippocampal network activity (Boehringer et al., 2017; Tzakis and Holahan, 2019).

Fig. 1.

Diagram of memory formation network. Memory formation begins in the entorhinal cortex (EC) area, which processes initial inputs and transmits them to the hippocampus. Neurons in layer 2 of the EC project to the dentate gyrus (DG) and Cornu Ammonis (CA) 2 region, while neurons in layer 3 of the EC affect the subiculum (SUB) and CA1 region. In addition, the perforant fibres from the EC connect to granule cells, which in turn link to pyramidal cells in the CA3 region. This pathway continues to the CA1 region. The CA1 region then projects back to the EC, completing the loop and facilitating continuous information processing necessary for memory consolidation.

There are three categories of memory: working memory, short-term memory, and long-term memory. Short-term memory and working memory are often used interchangeably in the literature, yet they represent conceptually distinct constructs with different neurobiological processes involving different brain regions (Jonides et al., 2008). Short-term memory is the transient storage of limited information over brief intervals, a function associated with medial temporal lobe structures such as the hippocampus and surrounding cortical regions (Jonides et al., 2008; Vallar, 2001). This process is largely passive, serving as a temporary buffer for information that may subsequently be consolidated into long-term memory. It depends on pre-existing neural networks and post-translational modifications (Bisaz et al., 2014; Kandel, 2001) by increased release of presynaptic glutamate and changes in post-synaptic glutamatergic receptor activity (Lüscher and Malenka, 2012). In contrast, working memory extends beyond mere storage by incorporating active manipulation and updating of information to support goal-directed behaviours (Jonides et al., 2008). Working memory stores short-term information from our surroundings (Chai et al., 2018; Cowan, 2008), resulting in either short-term plasticity lasting over minutes or long-term plasticity lasting from hours up to a lifetime (Deperrois and Graupner, 2020; Jonides et al., 2008). This capacity depends heavily on the prefrontal cortex, which exerts top-down control over distributed neural networks, including parietal and subcortical circuits, to sustain and flexibly operate on information in real time (Funahashi, 2017; Lara and Wallis, 2015). Thus, while short-term memory enables the maintenance of information, working memory reflects the integration of storage with executive processes, providing the neural substrate for higher-order cognition such as reasoning, decision-making, and language comprehension. On the other hand, long-term memories involve structural and functional alterations in neural networks, which require new gene expression, de novo gene transcription, new protein translation, and synaptic growth at presynaptic and post-synaptic terminals (Asok et al., 2019; Bisaz et al., 2014; Kandel, 2001; Shuster et al., 1985).

Synapses convert electrical signals into chemical signals released from the presynaptic terminals, which bind to the receptors on the post-synaptic terminal and are subsequently converted back into electrical signals (Qi et al., 2022). Synaptogenesis forms synapses between neurons in response to new environmental stimuli (Batool et al., 2019; Qi et al., 2022), which facilitates the interactions between neurons (Qi et al., 2022). Approximately 5–10 % of new synapses are formed each day in response to various external stimuli (Li et al., 2017). Synaptic plasticity is important in enabling environmental adaptability and learning. However, exposure to factors, such as substance use (e.g. nicotine), can have significant influences on brain plasticity, leading to cognitive disorders (Appelbaum et al., 2023), which will be discussed later.

4. Effects of inhaled environmental pollutants on memory function

4.1. Tobacco cigarette smoke

4.1.1. Direct and second-hand exposure

Tobacco and tobacco smoke are composed of over 9500 chemical compounds, with 83 recognised as carcinogens (Li and Hecht, 2022). While less than half of these compounds are naturally present in the tobacco leaf, the rest are formed during tobacco combustion (Li and Hecht, 2022). The chemicals produced in tobacco combustion include carbon monoxide, hydrogen cyanide, benzene, formaldehyde, nicotine, phenol, and polycyclic aromatic hydrocarbons (Omare et al., 2022). Exposure to tobacco smoke has consistently been shown to exert neurotoxic effects across the lifespan, with the most significant adverse effects associated with early life exposure, especially during the in-utero period (Dwyer et al., 2009; Zeid et al., 2018). Furthermore, children with in-utero exposure to tobacco smoke due to maternal smoking or during early childhood due to second-hand smoking demonstrate lower IQ scores, impaired memory function assessed by various methods (eg. McCarthy Scales of Children's Abilities, Big-Little Stroop task; Preschool Go/No-Go; Computerised Shape School; Snack Delay; Goody Shelf), and reduced language skills (Micalizzi and Knopik, 2018). They also have an increased risk (HR = 1.7, 95 % CI 1.1–2.8) of developing neuropsychiatric conditions, such as attention deficit hyperactive disorder (ADHD), depression, and anxiety later in life (Huizink and Mulder, 2006; Sarala et al., 2022), in addition to the affective problems mentioned earlier (El Marroun et al., 2014). In adults, tobacco smoking can severely impair hippocampus-dependent functions, such as spatial navigation and new memory formation, assessed by Morris Water Maze in animal models (Bannerman et al., 2014; Cunningham and Sanderson, 2008; De Luca et al., 2023). One study showed the risk of cognitive impairment rises with the amount of smoking measured in pack-years (Muhammad et al., 2024). Interestingly, no dose-response correlation was found between second-hand smoking and cognitive impairment assessed by Mini-Mental State Examination (He et al., 2020). Also, the younger the smoking starts, the worse the cognitive outcome is, as assessed by a battery of instruments (e.g. Montreal Cognitive Assessment, The Contextual Memory Test and The Digit Span Task for memory function) (Nadar et al., 2021). Animal studies showed that mice exposed to chronic tobacco smoke for 24 weeks resulted in neurocognitive defects, particularly short term and working memory retention assessed by Novel Objective Recognition test, novel object place test and spontaneous alternation in the Y-maze task, with a reduction in presynaptic density and number of dendritic spines in the hippocampus (De Luca et al., 2022, 2023; Dobric et al., 2022a), which is the key structure for memory consolidation.

As nicotine is the addictive substance in tobacco smoke and is readily absorbed through the lungs and acts on nicotinic receptors in the brain, research on mechanisms of tobacco smoking often uses pure nicotine as a surrogate (England et al., 2015). For example, nicotine administration at a dose of 1.5 mg/kg in rodents has been suggested to be equivalent to the amount of nicotine obtained from smoking 20 cigarettes/day in humans (Ernst et al., 2001). In humans, tobacco-derived nicotine triggers feelings of stimulation and enjoyment while diminishing feelings of stress and anxiety; these effects can also occur during second-hand smoking (Morel et al., 2018; Ng et al., 2024; Patton et al., 1998). Smokers often turn to nicotine to regulate their arousal levels and manage their mood on a day-to-day basis (Morel et al., 2018; Ng et al., 2024; Patton et al., 1998). While nicotine is typically not categorised as a dangerous drug, it can lead to more dependence than cocaine (i.e. is more addictive), and prolonged tobacco use frequently leads to difficulties in withdrawal (Laviolette and van der Kooy, 2004; Nutt et al., 2007).

Mechanistic research (summarised in Table 1) first focused on the nicotinic acetylcholine receptors (nAChRs) which are ligand gated ion channels formed from five protein subunits, namely α and β subunits, located on both presynaptic and postsynaptic sites (Shen and Yakel, 2009). They are abundant in the brain. nAChRs are activated naturally through acetylcholine, a neurotransmitter derived from choline (Sanders and Zeisel, 2007). Nicotine, an exogenous agonist for most nAChR subtypes, can directly activate nAChRs at the binding sites for acetylcholine (Posadas et al., 2013). In the excitatory and inhibitory hippocampal circuitry, nicotine binds and activates nAChRs to release various neurotransmitters (eg. glutamate, GABA, dopamine, norepinephrine, and serotonin) in different brain regions, including the hippocampus (Dwyer et al., 2009; Fabian-Fine et al., 2001; Ji et al., 2001; Zeid et al., 2018). Most neurotransmitter release is regulated by presynaptic nAChRs, however, they can also be directly released from the neurons (Wonnacott, 1997). The action of nicotine at nAChRs can also regulate systemic levels of stress hormones, contributing to mood regulation (Wang et al., 2024b). However, nicotine has been shown to have a neuroprotective ability, due to the effect of nicotine enhancing neuronal resistance to apoptosis and suppressing inflammatory response and oxidative stress (Checkoway et al., 2002; Dong et al., 2020; Nicholatos et al., 2018). Not surprisingly, low doses of nicotine have been found to enhance performance in tasks related to attention and memory functions assessed by the Stroop interference test and 3-back letter task, respectively, opposite to observations in animal modelling (Ernst et al., 2001; Grundey et al., 2015; Squire et al., 2007). This study provides evidence to suggest that nicotine-free tobacco smoke is responsible for impaired memory function. This may be because the latter often adopts high doses of pure nicotine, as mentioned above that can induce neurotoxicity and impair memory function (Ernst et al., 2001).

Table 1.

Summary of the key impacts of tobacco smoke and e-cigarette vapour on memory and the brain mechanism of action.

Pollutant	Model	Neuropathology	Mechanisms of action	Citation
Tobacco cigarette smoke	7-week-old male BALB/c mice, 8 weeks	Impaired spatial working memory; ↑ microglial number in the DG and activation in CA1; impaired synaptic plasticity.	Pulmonary inflammation spill over to the system; ↑total protein carbonylation in the hippocampus; ↑ hippocampal Mmp12 expression; oxidative stress (↑ Nox1, ↓ iNos and Gpx1 expression)	De Luca et al. (2022)
Tobacco cigarette smoke	7-week-old male BALB/c mice, 24 weeks	Impaired short term and working memory, ↓ microglial and astrocyte number but ↑ microglial activation, ↓ presynaptic density, synaptogenesis, and number of dendritic spines in the hippocampus; impaired BBB integrity	Pulmonary inflammation spills over to the system; hippocampal inflammation	Dobric et al. (2022a)
Tobacco cigarette smoke	3-month-old male mice, 14 days of exposure	Impaired spatial learning abilities	Damage to the olfactory system, increased TNFα protein in the cortex	Prasedya et al. (2020)
Tobacco cigarette smoking	Human foetal brains (5–12 weeks of gestation) after abortion, from smoking women	Not measured	Abolished age-related increase in binding of nAChR subtype α4 in both pons and cerebellum; age-related ↑ in the pons in the expression of both 4 and 7 mRNA in the cerebellum; age-related ↓ in α4 mRNA expression and increase in the α7 mRNA in the medulla	Falk et al. (2005)
Tobacco cigarette smoking	9–11 years old children of smoking women, mixed sex	smaller total brain volume, cerebral grey matter volume, cerebral white matter volume, and surface area and less gyrification; no change in children exposed to maternal smoking only in the first trimester.	Neonatal DNA methylation in cord blood associated with maternal smoking is unrelated to brain morphology at 9–11 years	Zou et al. (2022b)
Nicotine	23-day old (pre-adolescent), 38-day old (adolescent) and 53-day old (adult) mice C57BL/6J, acute and 12 days nicotine injection	Enhanced contextual fear learning memory at all three ages with acute injection; only pre-adolescent mice showed enhanced fear learning with prolonged treatment	↑ cortical nAChRs binding at 23-day and 53-day old; ↑ hippocampal nAChRs binding at 53-day old after 24h of nicotine withdrawal; ↑ cortical and ↓ hippocampal cAMP response element-binding protein at 23-day old only after 24h of nicotine withdrawal	Portugal et al. (2012)
Nicotine	Maternal exposure to nicotine in C57BL/6 mice	Impaired Spatial working memory in adult male offspring only	Not addressed	Zhang et al. (2018)
Nicotine	Maternal exposure to nicotine in C57BL/6 mice	Increased anxiety-like behaviours at postnatal day 20 (weaning).	↓ NeuroD1 in CA1 and CA3 RNA sequencing of the hippocampus: ↑132 mRNAs, ↓163 mRNAs; ↑ BDNF, IL-4 and IL-1β; ↓ CXCL-10, CCL-12, and JNB.	Zhou et al. (2021)
		↑ neurite length and synapse in CA1
		↑ gliosis in CA1 and CA3; ↑ microglia number in CA1; hippocampal microglia polarisation towards an anti-inflammatory M2 phenotype.
Nicotine	Maternal exposure to nicotine in Sprague Dawley rats	Not measured	Increased whole-brain nicotine binding, and abnormal cellular development, reflected by changes in ornithine decarboxylase (ODC) activity and deoxyribonucleic acid (DNA)	Navarro et al. (1989)
E-cigarette	3-month old male mice, 14 days of exposure	Impaired spatial learning abilities, necrosis and cytoplasm vacuolisation in the cortex	damage to the olfactory system, increased TNFα protein in the cortex	Prasedya et al. (2020)
E-cigarette	5–8 weeks old male and female C57BL/6J mice	Improved long term memory	↑ hippocampal levels of vesicular glutamate transporter 1, cytokines (IFNβ-1 and MCP-5), and ↓ vesicular GABA transporter	Alasmari et al. (2022a)
E-cigarette	7-week old male Balb/c mice	Impaired short-term memory function, reduced microglia numbers in several hippocampal sub-regions, independent of nicotine	↑ tau phosphorylation, Glycogen Synthase Kinase-3 (GSK), and p-protein kinase B (Akt) and the ratio between p-Akt/Akt, ↓ total Akt.	Chen et al. (2021) Chaaya et al. (2023)
E-cigarette	Third hand exposure in 4-week old male Balb/c mice for 4 weeks	Impaired short-term memory by third-hand exposure to nicotine-free vapour; increased anxiety-like behaviours by exposure to nicotine-containing vapour.	↑ TNFα and NOX4 by third-hand exposure to nicotine-free vapour	Oliver et al. (2025)
		Reduced neuron numbers in the cortex and increased microglia numbers in the hippocampal CA1 by third-hand exposure to both types of vapour.
E-cigarette	Maternal exposure in CD1 mice	Smaller brain size during the suckling period, impaired learning and memory function in adolescent and adulthood in both male and female offspring; reduced astrocyte number; impaired hippocampal BBB integrity	↓ glucose transporter (GLUT-1) and water channel protein (AQP4)	Archie et al. (2023)
E-cigarette	Maternal exposure in Balb/c mice	impaired short-term memory independent of nicotine	↑ DNA methylation by prenatal exposure to nicotine-free e-vapour; differentially changed DNA methyltransferases (Dnmt3a, Dnmt3b) and ↓ histone-lysine demethylases (kdm5c), histone acetyltransferases Atf2, and Histone Phosphorylation (Aurka, Aurkb, Aurkc) by prenatal exposure to nicotine and nicotine-free e-vapour	Nguyen et al. (2018)
E-cigarette	Maternal exposure in C57BL/6 mice	Not measured	RNA sequencing: alterations in gene expressions in the prefrontal cortex, predicting decreases in memory, cognition, learning and neurotransmission, such as Ngfr, Chat, Bdnf, Gdnf, Gal, Tbr1, and Adra1d	Lauterstein et al. (2016)

During cigarette smoking, any anti-inflammatory and neuroprotective effects of nicotine are insufficient to counteract the adverse effects of the other chemicals in tobacco cigarette smoke (Checkoway et al., 2002; Dong et al., 2020; Nicholatos et al., 2018). Burning tobacco releases reactive oxygen species (ROS) that evade cigarette filters and activate inflammatory pathways, e.g. NFκB pathway, in a variety of myeloid and lymphoid cells, both within the lungs and in the circulation (Dobric et al., 2022b; Qiu et al., 2017). Both acute and long-term tobacco smoke inhalations have been shown to result in systemic inflammation in both human and animal models (Dobric et al., 2022a, 2022b; Elisia et al., 2020; Van Der Vaart et al., 2004). This is partially due to the heavy metals, such as nickel, iron, chromium, and phenolic compounds produced during the combustion of tobacco, in addition to ROS, that can evade the cigarette filters and enter the circulation (Caliri et al., 2021). These chemicals can directly enter the brain to activate local immune cells and, subsequently, change neural integrity and cognitive function, especially prominent in individuals with long-term tobacco smoking induced chronic obstructive pulmonary disease (Dobric et al., 2022b; Li et al., 2021a). Moreover, extracellular ROS can induce cells to produce more intracellular ROS (Rahman and Adcock, 2006), which in the brain can overwhelm the antioxidant defences of glial cells and neurons, leading to oxidative stress. Both microglia and neurons are highly sensitive to such a detrimental microenvironment (Salim, 2017). Together with cytokines released by immune cells in the lung (e.g. TNF-α), oxidative stress activates microglia (Block et al., 2007), which provoke inflammatory signalling through MAPK and NF-kB to induce the release of downstream cytokines (e.g. TNF-α), and other neurotoxic mediators, such as nitric oxide and superoxide, further contributing to neuronal injury and impairing neuronal function (Colton and Gilbert, 1987; Moss and Bates, 2001; Sawada et al., 1989; Song et al., 2022).

In neurons, oxidative stress can lead to mitochondrial dysfunction, reducing the energy supply necessary for neuronal activity and synaptic transmission (Badshah et al., 2019; Muhammad et al., 2019), resulting in neuronal apoptosis (Leng and Edison, 2021; Rego and Oliveira, 2003). Neurons in the hippocampus are particularly vulnerable to such damage due to their high metabolic activity and relatively low levels of endogenous antioxidants (Rego and Oliveira, 2003), where oxidised cellular components, such as lipids, proteins, and DNA, can disrupt normal cellular functions, impairing synaptic function and plasticity, which are essential for memory formation and retrieval (Singh et al., 2019). This is supported by mouse studies where antioxidant supplements can significantly ameliorate the adverse effects of tobacco smoke exposure on brain health (De Luca et al., 2022; Sukjamnong et al., 2017). In addition, such protection of synaptic plasticity may be independent of microglial activity (De Luca et al., 2022).

All the above evidence indicates that tobacco smoke-induced oxidative stress is a key factor in neuronal damage and cognitive decline. Promoting the capacity of antioxidant defences may be a potential strategy to protect against tobacco smoke exposure-induced neurotoxicity.

4.1.2. Third-hand exposure to tobacco smoke

Third-hand smoke exposure can occur for at least 1 year after smoking has stopped, but it also occurs concurrently with first/second-hand smoking (Bahl et al., 2016; Díez-Izquierdo et al., 2018). Third-hand smoke exposure consists of exposure to residual contaminants that remain on surfaces and in dust and are re-emitted into the gas phase or react with oxidants and other compounds to yield secondary pollutants (Wu et al., 2022). Exposure can occur by inhalation, but also via the skin, or via ingestion (Matt et al., 2011). Infants and young children are more at risk of third-hand smoke exposure than adults due to their age-related behaviours, such as crawling on carpets and frequently putting things in their mouths (Díez-Izquierdo et al., 2018; Hang et al., 2017b). In particular, babies can be 100 times more likely to be affected by pollutants in house dust than adults; the young ingest more dust and are up to ten times more vulnerable to exposure (Díez-Izquierdo et al., 2018; Roberts et al., 2009). However, adults may still be affected by prolonged third-hand exposure (Hang et al., 2017a).

The study of third-hand tobacco smoke on memory impairment is very limited, as it is believed to have fewer health effects compared with direct smoking and second-hand inhalation (Arfaeinia et al., 2023; Roberts et al., 2017). Emerging evidence suggests that third-hand smoke may also have neurodevelopmental and cognitive consequences, particularly for infants and young children who are more susceptible to environmental contaminants (Díez-Izquierdo et al., 2018; Hang et al., 2017b; Martins-Green et al., 2014). A mouse study modelling childhood exposure to third-hand smoke demonstrated increased anxiety-like behaviours and hyperactivity; however, no mechanistic investigation was performed in this study (Martins-Green et al., 2014). In another study using mouse neural stem cells to model foetal brains, extracts from smoke exposed terry cloth induced cell fragmentation, loss of cytoplasm, vacuoles in the cytoplasm, and changes in morphology due to disruption of the actin microfilaments and depolymerisation of the microtubules, without investigating molecular mechanisms either (Bahl et al., 2016). In fact, most published research on the mechanisms of third-hand smoke exposure has primarily focused on its impact on the respiratory system, likely due to the predominance of lung researchers in areas such as childhood asthma (Arfaeinia et al., 2023; Díez-Izquierdo et al., 2018; Jung et al., 2012). In addition, the conclusion from human studies can be complicated by the difficulties in separating parental second/third-hand smoking during pregnancy and postnatal third-hand exposure (Díez-Izquierdo et al., 2018; Jung et al., 2012). Nevertheless, mice exposed to third-hand smoke also exhibited an elevation of pro-inflammatory cytokines in the lung (Martins-Green et al., 2014); while lung inflammation is known to “spill over” into the systemic circulation and affect multiple organ systems, including the brain (Dobric et al., 2022b). In human respiratory epithelial cells, in vitro exposure to third-hand smoke for 3 h resulted in changes in mitochondrial activity, which led to an adaptive activation of survival mechanisms, such as ATP synthesis and increased oxidative phosphorylation (Pozuelos et al., 2019). However, the increase in ATP production also resulted in increased ROS as a by-product, thereafter, exaggerating existing oxidative stress, which is hypothesised to “spill over” into the circulation to reach the brain (Dobric et al., 2022b; Pozuelos et al., 2019).

Exposure can occur through several sites in the body, including the digestive system (ingestion), and the respiratory system, however an inflammatory response in the lung may reflect both systemic inflammation and local inflammatory process (Martins-Green et al., 2014). Another study confirmed third-hand smoke exposure can lead to increased B-cell numbers and decreased myeloid cells in the blood, without significant sex differences (Hang et al., 2017a). In addition, recent research suggests that third-hand tobacco smoke exposure may have other adverse health effects due to cytotoxicity, genetic damage, and oxidative stress. This includes insulin resistance due to lipid peroxidation, protein nitrosylation, and DNA damage in skeletal muscle, DNA damage in human liver and lung cell lines, impaired wound healing processes due to impaired collagen deposition, altered inflammatory response, decreased angiogenesis and increased oxidative stress damage, increased lung cancer risk in mice due to DNA damage, increased endoplasmic reticulum stress and p53 signalling activation, as well as increased all cancer risks in children (1–6 years old) and non-smokers (Dhall et al., 2016; Hang et al., 2013, 2017b; Martins-Green et al., 2014; Ramírez et al., 2014), suggesting broader systemic effects. As such, these adverse responses in other organs may also occur in neurons in the brain (Martins-Green et al., 2014), where direct evidence is still sparse. These findings highlight the need to broaden research on organ changes beyond the respiratory system. However, it needs to be noted that the experimental protocols for third-hand exposure may require long term settings in comparison to direct smoking research, as the cytotoxins are expected to in lower concentrations (Díez-Izquierdo et al., 2018). In particular, future studies also need to directly investigate the long-term impact on brain health and cognitive outcomes due to childhood exposure to third-hand tobacco cigarette smoke.

4.1.3. Maternal smoking

The brain is constantly changing and re-wiring from the foetal period to adulthood, which is fundamental for behavioural adaptation to the external environment, including memory processing and learning (Kolb and Gibb, 2011). The developing brain reaches 90 % of the adult volume by age 6. However, throughout childhood and adolescence, structural modifications persist in grey and white matter, contributing to functional organisations that are reflected in behavioural changes (Stiles and Jernigan, 2010). When tobacco smoke exposure occurs during foetal brain development, the adverse effects can persist long after the removal of such stimuli after birth, resulting in lasting changes in hippocampal structure, function, and behaviours (Zeid et al., 2018).

At birth, babies from smoking mothers commonly have small birth weights and brain sizes (Blatt et al., 2015; Chan et al., 2016b; Froggatt et al., 2020; Harrod et al., 2014; Ko et al., 2014). The most well-understood relationship is the dose correlation between maternal tobacco use and in-utero underdevelopment or smaller birth weight (Ernst et al., 2001), which has been suggested to determine cognitive function later in life, especially in those with a birth weight <2000 g (Krishna et al., 2019; Upadhyay et al., 2019). Neuroimaging studies have revealed that prenatal exposure to tobacco is associated with smaller total brain volumes, particularly in regions critical for cognitive and behavioural functions, such as the prefrontal cortex and hippocampus (El Marroun et al., 2014, 2016; Zou et al., 2022a). Additionally, these children often exhibit behavioural problems, such as affective disorders during school (El Marroun et al., 2014). Such disorders are prominent if the mother smoked more than 10 cigarettes a day (Ernst et al., 2001). Maternal smoking is closely linked to verbal and visual memory dysfunction in 13–16 years old children (Fried et al., 2003). For example, reduced auditory acuity during infancy was found if the mother smoked >17 cigarettes a day (Ernst et al., 2001). It is generally believed that a dose-response correlation between in-utero smoke exposure and cognitive impairment after birth also occurs (Ernst et al., 2001). For example, children of smokers also have a higher frequency of ADHD, and the severity of the symptoms increases with the mother's smoking habit (Altink et al., 2009). Even children from smokers quitting during pregnancy can still display some levels of cognitive dysfunction (e.g. ADHD and learning disability (Li et al., 2024)), suggesting permanent epigenetic modification of germ cells (Huizink and Mulder, 2006; Sarala et al., 2022). As such, quitting smoking during pregnancy can only partially protect the cognitive function of young children (Sexton et al., 1990). However, some postnatal factors may not have been adjusted in such studies, for example, mothers resuming smoking after childbirth, resulting in second-hand smoking during childhood.

It is obvious that the chemicals in cigarette smoke that women inhale can impact their children's cognitive development. However, the mechanistic understanding (summarised in Table 1) of how maternal smoking adversely affects offspring has also been drawn from research using pure nicotine due to the complex confounding variables in humans (Ernst et al., 2001). Nicotine can cause blood vessel constriction, which limits the blood supply to the placenta, affecting foetal access to oxygen and nutrients (Chan et al., 2020). The amount of carboxyhemoglobin can also be increased by cigarette smoke inhalation in the mother and foetal blood, which impairs the oxygen-carrying ability of the red blood cells (Chan et al., 2020). This can further exaggerate foetal hypoxia, resulting in small-sized brains and later memory impairments (Chan et al., 2020). Indeed, studies have shown that maternal smoking is associated with reduced growth of brain volumes, smaller cerebellar size and cortical grey matter, and thinner cortices at the ages of 6–8 years (El Marroun et al., 2014). A study showed that the reduction in global and regional brain volumes in children exposed to maternal smoking remained at 9–11 years of age (Zou et al., 2022a). In addition, nicotine is known to interfere with neurodevelopment as a neuronal teratogen that induces apoptotic cell death, decreases cell size in various brain regions, and disrupts synaptic plasticity, which may lead to a smaller brain volume of the foetus that persists in the long term (Jamshed et al., 2020; Zou et al., 2022a). For example, prenatal nicotine exposure is associated with increased neuron apoptosis and astrogliosis in the hippocampal CA1 region (Zeid et al., 2018). Additionally, neuron density is also reduced in hippocampal CA3, CA1, and DG regions (Zeid et al., 2018). Furthermore, apical dendritic spine complexity on pyramidal cells is significantly reduced in the CA3 region, while dendritic spine density is increased on basal and terminal pyramidal cell dendrites, DG basal granule dendrites, and CA1 basal pyramidal cell dendrites (Zeid et al., 2018). Prenatal nicotine exposure may also disrupt the function of non-neuronal cells (Thompson et al., 2009). Nicotine can alter and disrupt the function and integrity of the BBB (Brooks and Henderson, 2021; Eppolito et al., 2010; Lockman et al., 2005). It can also potentially impair the health of neural progenitor cells, which in turn can differentiate into unhealthy mature neurons resulting in abnormal brain function (Brooks and Henderson, 2021; Jiang et al., 2016). A study in mice showed that offspring from dams exposed to nicotine during gestation and lactation showed delayed somatic and neural development at weaning age with increased anxiety-like behaviour (Zhou et al., 2021). This was associated with increased neurite length in the CA1 region and post-synaptic proteins in the whole hippocampus but reduced mature excitatory neurons in the CA1 and CA3 regions, suggesting excessive pruning of neurites on top of impaired neurogenesis (Zhou et al., 2021). However, it also needs to be noted that breastfeeding is protective, thus, microglia had an anti-inflammatory phenotype in those offspring (Zhou et al., 2021). The observations at weaning may change as the offspring mature when such protections fade away. Furthermore, tobacco smoke exposure may have an adverse effect on bone growth, which may cause a reduction in skull capacity that originates in foetal life and persists in childhood, thus restricting brain development in the long term (Brand et al., 2020; Zou et al., 2022a).

In animal studies, the adverse in-utero effects have been reported mostly among the nicotine dose range of 1.3–6 mg/kg (Ernst et al., 2001). However, such heavy use of cigarettes in humans quite often results in difficulties in maintaining pregnancy, whereas in rodent studies, even higher nicotine doses, e.g. 4–6 mg/kg/day, have been reported (Ernst et al., 2001). Studies using pure nicotine rarely report any negative effects of low doses (e.g. 0.3 mg nicotine/kg, ∼4 cigarettes/day based on the above estimation), as occurs in light smokers (Ernst et al., 2001), perhaps suggesting that low doses of nicotine alone do not induce measurable adverse effects on foetal development. Other chemicals in combusted tobacco may also contribute to the negative effects on cognition (Li and Hecht, 2022; Omare et al., 2022), but these have not been studied due to the difficulty in obtaining nicotine-free tobacco. Nevertheless, studies have identified abnormalities in nAChRs in different brain regions that have been associated with the suppression of DNA synthesis and heightened apoptosis (Chan et al., 2020). nAChRs are present in the brain from early developmental stages and are involved in critical aspects of brain maturation during prenatal, early postnatal, and adolescence stages, including cell survival, proliferation, differentiation, and neurogenesis (Ren et al., 2022). Therefore, during these critical developmental periods, nAChRs are temporarily upregulated and induce neural structure changes by altering subunit composition when the brain experiences significant phases of differentiation and synaptogenesis (Dwyer et al., 2009). As a result, the brain is particularly susceptible to in-utero environmental pollutants at this stage of early development. Nicotine can easily cross the placental barrier, and is measurable in the amniotic fluid and umbilical cord blood (Ren et al., 2022). As such, maternal nicotine exposure results in increased nicotine binding to nAChRs in the foetal and neonatal brain (Ren et al., 2022), which can disrupt normal brain development and neural plasticity, as well as cognitive functions after birth (Thompson et al., 2009; Wells and Lotfipour, 2023).

The cholinergic system is an important regulator of prenatal and postnatal hippocampal circuitry, in addition to its role in mature neural functioning later in life (Dulawa and Janowsky, 2019; Madrid et al., 2021; Zeid et al., 2018). Decreased cholinergic functioning has been linked to cognitive decline and cognitive dysfunction associated with neurodegenerative disorders, including AD and PD (Zeid et al., 2018). A study in adolescent and adult rats suggested that enhanced cholinergic activity following prenatal exposure to nicotine resulted in long-lasting disruptions in the brain development trajectory caused by alterations to the cholinergic system, which likely explains the behavioural impairments observed in animals exposed prenatally to nicotine (Eppolito et al., 2010).

Tobacco smoke possesses strong oxidative capacity, which following maternal inhalation can reach multiple foetal organs, including the brain, to exert long-lasting postnatal impairment of memory function (Nguyen et al., 2015; Stangenberg et al., 2015; Sukjamnong et al., 2018). Mouse models of tobacco cigarette smoking in pregnancy result in foetal and postnatal underdevelopment in offspring, as well as some levels of organ dysfunction even without additional postnatal insult, which is consistent with the effects in humans (Chan et al., 2016b; Nguyen et al., 2015; Stangenberg et al., 2015; Sukjamnong et al., 2018). On the other hand, early-life underdevelopment and later organ dysfunction due to maternal tobacco smoke exposure can be mitigated by giving antioxidants to the mothers during gestation and lactation, suggesting the adverse impact of maternal smoking is also largely driven by oxidative stress, an effect similar to that due to direct tobacco smoke exposure (Chan et al., 2016b; Nguyen et al., 2015; Stangenberg et al., 2015; Sukjamnong et al., 2018). Even without direct exposure to cigarette smoke after birth, maternal smoking can result in a permanent increase in brain inflammatory markers in adult offspring (Chan et al., 2016b). Neuroinflammation caused by dysfunctional microglia is a key driver in the onset and progression of AD (Newcombe et al., 2018). Therefore, maternal smoking may increase the susceptibility of AD in offspring, in addition to memory dysfunction at younger ages (Miwa et al., 2011; Shen and Yakel, 2009; Wells and Lotfipour, 2023).

4.2. E-cigarette vapour

4.2.1. Direct and second-hand exposure

E-cigarettes have gained significant popularity among the younger populations due to a perceived safer alternative to smoking, the variety of sweet-like flavours, low cost, and effective social media campaigns (Li et al., 2018). E-cigarettes are battery-operated atomizers to heat up the e-liquids or e-fluids, which typically include propylene glycol and/or vegetable glycerin, nicotine (ranging from 0 mg/mL to 24 mg/mL or higher), and flavourings. These flavouring compounds are generally used as food additives (Li et al., 2018), but their safety after heating to 400 °C or when delivered to the lung is not certain. Furthermore, as there is a lack of standardisation of e-liquid components such as flavouring, whether internationally or nationally, it is very difficult to examine the toxicity of thousands of e-fluid combinations available on the market, and thus, only a few selected flavourings have been examined in the laboratory (Kosmider et al., 2016; Salam et al., 2020; Wang et al., 2024a; Ween et al., 2021). Research on the chemical composition of the aerosol (e-vapour), either using e-cigarette devices or simulation devices, suggests that on a puff-by-puff comparison, e-cigarettes produce fewer toxic compounds than tobacco cigarette smoke, although toxic carbonyl compounds, formaldehyde, acetaldehyde, benzaldehyde, acrolein, and heavy metals are present in e-vapour (Li et al., 2018). However, e-cigarette users can vape excessive amounts (price is not a limitation to usage) which on average has shown to be the equivalent to 163 cigarettes per day (assuming one puff is one cigarette) (Cho et al., 2025; Dautzenberg and Bricard, 2015).

Animal modelling together with human cohort studies can help to predict the effects of vaping on neurocognitive functioning, highlighting potential impacts on attention, memory, and learning (Alzoubi et al., 2021). Vaping may negatively impact the cognitive performance of young adults which can potentially lead to issues such as reduced learning abilities, poorer academic performance, and impaired memory and cognition (Tobore, 2019). Indeed, young e-cigarette users often complain about cognitive deficits, demonstrated by difficulties in concentrating, remembering, and decision-making (Xie et al., 2020a). Another major public health concern is that there is an increased prevalence of depression among young people who vape when compared to older groups (Sikström et al., 2023). Similar to tobacco cigarette smoking, starting vaping at a younger age leads to more severe impairments in memory and other executive functions (Xie et al., 2020a), while quitting e-cigarette vaping may also mitigate impaired cognitive function (Xie et al., 2020b).

In 3-month-old male mice, 14 days of e-cigarette vapour exposure caused a similar impairment in spatial learning abilities when compared to tobacco cigarette smoke, assessed by a maze apparatus (50 × 50 cm) with buried food (Prasedya et al., 2020), while long term exposure caused both short-term and long term memory impairment using novel objective recognition test with a test interval of 1 h to 1 day (Alasmari et al., 2022a; Chen et al., 2021). Nicotine-containing e-cigarette vapour exposure can increase hippocampal levels of vesicular glutamate transporter 1 (essential transporter of glutamate into synaptic cleft) and decrease vesicular GABA transporter (protein carrier to transport GABA into synapses), which may increase neuron excitability to cause ADHD (Alasmari et al., 2022a). The mechanistic research on e-cigarettes has been guided by decades of research on the physiological effects of tobacco cigarettes. These studies (summarised in Table 1) also suggested similar molecular pathways to those underlying tobacco smoking-induced memory and cognitive impairment mentioned in section 3.1, since nicotine has been once again used as a surrogate to model and study health issues related to vaping. As such, nicotine within e-cigarette vapour is still the suggested major chemical that impairs memory and cognitive function in users. However, nicotine-independent e-vapour can impair short-term memory function assessed by the novel objective recognition test, with reduced microglia numbers, in several hippocampal sub-regions due to long-term exposure, suggesting the toxicity to immune cells may be due to other elements in the e-vapour (Chaaya et al., 2023; Chen et al., 2021). Reduced microglia number may affect phagocytosis, which may lead to the accumulation of toxic chemicals in the brain that, in turn, impairs neural function (Gao et al., 2023), such as short-term memory dysfunction (Chen et al., 2021). However, research on nicotine-free e-vapour is scarce in any disease area; therefore, the information on its molecular mechanism is limited. In fact, nicotine-free e-cigarettes are being used by some adolescents (Tokle et al., 2022; Wiley and Seabrook, 2023), suggesting the need for more research to address this knowledge gap.

4.2.2. Third-hand exposure

Third-hand vaping takes place when exposure to e-cigarette vapour residues occurs. It is known that residues include nicotine and other chemicals (Burton, 2011). This is a currently understudied yet important public health topic. E-cigarette vapour contains numerous toxicants, including aldehydes, phenols, metals, and ROS (Chen et al., 2020; Emma et al., 2022; Tobore, 2019). Some of the residues can settle on surfaces like clothing, furniture and carpets and may remain for extended periods of time (Roberts et al., 2017). E-cigarette aerosols can also travel through ventilation systems and settle in adjacent premises (Li et al., 2021b). E-cigarette emissions are variable in chemical composition as both e-liquids and devices are highly variable (Díez-Izquierdo et al., 2018). A study investigated the chemical residues of third-hand vaping which were recoverable from a cotton towel (Chen et al., 2020). It found that while the original composition of e-vapour included formaldehyde, benzene, phenol, and benzaldehyde, only nicotine and propylene glycol were detected on the towel (Chen et al., 2020), which may be due to the sensitivity of detection or the short exposure time, while more chemicals have been identified in long term tobacco smoke residues, such as myosmine, bipyridine, N-formylnornicotine, nicotelline, and carcinogens (Díez-Izquierdo et al., 2018). However, propylene glycol is detrimental to the developing brain (Chen et al., 2020), which may affect brain function in younger children who are at high risk of exposure. Indeed, short-term third-hand exposure to e-cigarette vapour led to smaller brain weight in mice, however, only in the nicotine-free group (Chen et al., 2020). This also correlated to impaired short-term memory function during Novel Objective Recognition Test in mice exposed to third-hand nicotine-free e-cigarette vapour for 4 weeks (Oliver et al., 2025). This may again be due to the neuroprotective effect of nicotine, such as suppressing oxidative stress and inflammatory responses (Dong et al., 2020). However, mice exposed to third-hand nicotine e-cigarette vapour exhibited increased anxiety-like behaviour when placed on the elevated plus maze (Oliver et al., 2025). Interestingly, neuron density in the cortex was reduced while microglial number in the hippocampal CA1 region was increased by both exposures, yet the overall behavioural outcomes are different (Oliver et al., 2025). This may be driven by more nuanced activation of molecular pathways, such as those related to inflammation and oxidative stress (Oliver et al., 2025). Long term studies are needed to determine the exact molecular mechanisms underlying such adverse effects and whether more cognitive impairments will be developed. However, similar to third-hand tobacco smoking, the inflammatory response and oxidative stress may be systemic, given similar findings were observed in studies that investigated the effects of third-hand vaping on brain and lung health (Chen et al., 2020; Oliver et al., 2025; Thorpe et al., 2023). Such studies provide important insights into the risk factors that may affect other organ functions, such as the liver and kidneys. Such a significant knowledge gap requires more research to fully understand the risk of third-hand vaping. Furthermore, the impacts of third-hand residuals inhaled by pregnant mothers also need to be considered which may negatively impact brain development in growing foetuses and later cognitive function after birth, given the rising rate of e-cigarette use among young people globally and the known adverse effects on offspring's lung health (Donovan et al., 2024).

4.2.3. Maternal vaping

The most adverse neurotoxic effects associated with exposure to e-cigarette vapour have been shown to occur in early life exposure (Froggatt et al., 2020). The use of nicotine-containing e-cigarettes has dramatically risen in pregnant and lactating women, with some people replacing traditional tobacco usage with e-cigarettes (Zeid et al., 2018). Maternal e-vaping has similar effects on increasing the risk of low birth weight (small for gestational age) in human cohort studies. However, newborns from e-cigarette-using mothers do not necessarily have a smaller head circumference, but with delayed motor maturity, abnormal reflex scores, and neuropathological brainstem outcomes affecting breathing function (Froggatt et al., 2020; Ussher et al., 2024). Thus, it is important to understand the impact of maternal e-vaping has on brain health and cognitive functional outcomes in the offspring (summarised in Table 1).

The BBB is formed by tight junctions and is important for maintaining the health of the central nervous system (Zhu et al., 2025). It has been shown that prenatal e-cigarette exposure in mice disrupted the BBB integrity and further caused impaired learning and memory function assessed by the Novel Object Recognition test and Morris Water Maze test in adolescent and adult offspring and may contribute to the development of anxiety and ADHD (Archie et al., 2023; Wells and Lotfipour, 2023). Proteins such as claudin-5 and occludin are essential in keeping the permeability of the BBB and tight junction stabilisation (Archie et al., 2023; Cummins, 2012). Claudin-5 forms tight junctions that prevent foreign bodies, such as bacteria, macrophages, and leukocytes, from entering the peripheral circulation of the brain (Greene et al., 2019). A study showed that male mice with prenatal e-cigarette exposure showed a decrease in occludin and claudin-5 expression, with reduced astrocyte numbers, increased inflammatory response in the hippocampus, and decreased learning and recognition memory evaluated by the Novel Object Recognition test and Morris Water Maze test at adolescence and adult age (Archie et al., 2023).

In mice, offspring from dams exposed to nicotine-containing e-vapour had significantly smaller birth weights compared with those from control dams and dams exposed to nicotine-free e-vapour (Chen et al., 2018). Such offspring can develop impaired short-term memory dysfunction assessed by the Novel Objective Recognition test when they grow older (Nguyen et al., 2018). Interestingly, using RNA sequencing analysis of gene expression in the prefrontal cortex, the predicted risk of developing a neurological disease or psychiatric disorder is sex- and nicotine-independent (Lauterstein et al., 2016). Specifically, maternal exposure to nicotine-free e-cigarettes can suppress gene regulating memory function in both male and female offspring (Lauterstein et al., 2016). For example, the downregulation of brain-derived neurotrophic factor (bdnf) in both male and female offspring may impair their neurodevelopment and synaptic plasticity, which are key to memory function (Lauterstein et al., 2016). Such gene changes may be related to increased DNA methylation and suppressed histone demethylation (Nguyen et al., 2018). Therefore, the message of quitting smoking during pregnancy should also include the cessation of e-cigarette use.

5. What research is needed

Despite advancements made in understanding the impacts of first- and second-hand smoking and vaping exposure, as well as maternal smoking or vaping as outlined above and summarised in Table 1 and Fig. 2, there remain several gaps in knowledge concerning the impacts of third-hand vaping and maternal third-hand vaping exposure. The underlying mechanisms need to be defined to enable the development of mitigation strategies. In addition, there are several key research questions regarding how airborne toxins reach and impact the brain that need to be answered in order to inform future public health interventions. First, it remains unclear whether all pollutants enter the brain via the same pathway, such as through the lungs, or if different pollutants use alternative routes, like ingestion or through the skin. This distinction is crucial; if certain pollutants enter through routes other than the lungs, relying solely on masks for protection may be insufficient. Additionally, understanding the interaction between systemic inflammation and toxins reaching the brain is critical. It is unknown whether systemic inflammation exacerbates the effects of these toxins on brain health or if these factors work independently to drive cognitive decline, such as memory loss and other dysfunctions. Last but not least is the need for investigation into possible biological sex differences; in particular, studies in which both biological sexes are studied also need to be analysed separately under the same conditions. A persistent sex bias exists in neuroscience research, where female animals are frequently underrepresented due to concerns over variability introduced by hormonal cycles (Beery and Zucker, 2011). Interestingly, female rodents seem to exhibit less viability than males in brain related parameters, or even a similar response to males (Alasmari et al., 2022a; Beery, 2018). Although maternal models enable the use of female offspring, male animals are often still preferred in experimental designs, partly because of the observations that males exhibit higher susceptibility to the detrimental effects of in-utero toxin exposures in both humans and animal models (Batstra et al., 2003; Chan et al., 2016a, 2016b; Chiu et al., 2013; Oliver et al., 2024). Even for studies where both sexes were included, they were often pooled and analysed as a single cohort (Zou et al., 2022b). This skewed representation can limit the generalisability of findings and overlooks the critical roles that sex differences may play in neurodevelopmental outcomes. Comprehensive research on these fronts is essential to develop effective prevention strategies and policies to safeguard brain health from environmental pollutants.

Fig. 2.

Maternal environmental pollutant exposure endangers offspring's memory function. Cartoon depicting the common mechanisms of detrimental changes to brain health and memory function of mothers and babies resulting from inhalation of airborne oxidants (tobacco cigarette smoke and e-cigarette vapour). Inhalation results in the production/release of inflammatory mediators, which can act directly on both the maternal and foetal brain.

6. Conclusion

Tobacco smoke and e-cigarette vapour have detrimental impacts on neurocognition and neurodevelopment, resulting in memory and other cognitive function decline mediated by oxidative stress and inflammatory responses in the brain. These pollutants affect individuals across all stages of life, with unborn foetuses, infants, and children being particularly vulnerable, whose exposures are often involuntary. Future studies need to focus on the impact of direct third-hand and maternal third-hand exposure to e-cigarette vapour, given the rising rate of global e-cigarette use along with potential postnatal effects.

CRediT authorship contribution statement

Brian G. Oliver: Writing – review & editing. Qi Wang: Writing – review & editing. Rochelle A. Yarak: Writing – review & editing. Tharathip Hikasem: Writing – review & editing. Catherine A. Gorrie: Writing – review & editing. Chenju Yi: Writing – review & editing, Conceptualization. Hui Chen: Writing – review & editing, Conceptualization.

Clinical trial number

Not applicable.

Ethics, consent to participate, and consent to publish declarations

Not applicable.

Funding

Rochelle Yarak was supported by an Australian Government Research Training Program (RTP) Scholarship. Chenju Yi was supported by grants from the National Natural Science Foundation of China (32170980), Guangdong Basic and Applied Basic Research Foundation (2022B1515020012), and Shenzhen Fundamental Research Program (RCJC20231211090018040 and ZDSYS20220606100801003); Qi Wang was supported by grants from the National Natural Science Foundation of China (32400809) and Shenzhen Fundamental Research Program (RCBS20221008093118042 and JCYJ20220530144816038).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.