Neurodevelopmental disorders encompass a group of clinical conditions that appear in early developmental stages, marked by difficulty in personal, social, academic, or occupational areas, as identified by the American Psychiatric Association in 2022. Among these disorders, Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are the most common [1]. Although not officially classified under neurodevelopmental disorders by the DSM-5-TR, a growing body of evidence points to the neurodevelopmental roots of schizophrenia, corresponding conceptually with this group [2,3]. High prevalence of comorbidities is a shared characteristic of all neurodevelopmental disorders [4,5]. The diverse clinical presentations and complex pathophysiologies of neurodevelopmental conditions pose significant hurdles for early diagnosis and treatment [6]. Over 200 high-risk genes have been identified, influencing critical biological processes like synaptic function, transcriptional regulation, and epigenetic mechanisms [7]. Environmental factors are also critical in the emergence and progression of neurodevelopmental disorders, acting through oxidative stress, neuroinflammation, and epigenetic modifications, which ultimately result in structural and functional changes in the brain [8,9,10]. The interplay between genes and environment underscores why individuals with genetic predispositions are more susceptible to environmental hazards. Hence, the concept of the exposome—the collected environmental exposures throughout a person’s life and their impact on brain health—has gained significance [11,12]. Toxic heavy metals are well documented for their ability to disrupt enzymatic functions, modify cell signaling, induce neuroinflammation, and foster oxidative stress, linking them to neurodevelopmental disorders [13,14]. The study of the glymphatic system is a comparatively new frontier in scientific inquiry, having been proposed only in 2012 and experiencing notable advancements starting around 2015 [15]. The glymphatic system has become a focal point as a major pathway connecting environmental impacts to neurodevelopmental consequences. It manages waste removal via cerebrospinal fluid (CSF) directed from the subarachnoid space into the brain’s interstitium through astrocytic aquaporin-4 channels along perivascular spaces. The CSF moves into perivenous spaces and meningeal lymphatic routes, eventually reaching cervical lymph nodes, predominantly during sleep, which enhances glymphatic clearance [16,17]. A dysfunctional glymphatic system can compromise protein clearance, lead to the build-up of misfolded proteins, and alter neuroinflammatory responses [18,19]. This suggests it may act as a unifying mechanism between toxic exposures and susceptibility to neurodevelopmental disorders. This mini-review aims to synthesize empirical evidence on the interconnections between environmental toxins, glymphatic system dysfunction, and neurodevelopmental disorders, examining shared biological processes and evaluating potential intervention strategies.

The link between the glymphatic system and neurodevelopmental disorders like ASD, ADHD, and SCZ is gaining significant focus [20,21]. Specifically, in autism spectrum disorder (ASD), studies have shown consistent changes in perivascular spaces (PVS). Enlargement of these spaces can be observed as early as 24 months, correlating with a higher likelihood of ASD diagnosis and more severe symptoms such as verbal dysfunction and sleep issues [22,23]. Furthermore, increased volumes of extra-axial cerebrospinal fluid in children aged 6 to 24 months indicate a potential relationship between PVS dilation and impaired glymphatic function early in life [24,25]. Sex differences in ASD are noted, with boys showing greater PVS volume in the white matter than girls, which is linked to insomnia [26]. Advanced imaging approaches such as diffusion tensor imaging along the perivascular space (DTI-ALPS) support the notion of glymphatic dysfunction in ASD, showing lower values than in healthy individuals [23]. The DTI-ALPS index tends to increase with age, suggesting a decline in glymphatic function over time [27]. Comparing individuals with ASD to those with ADHD using both DTI-ALPS and diffusion kurtosis imaging (DKI-ALPS) has revealed a reduced index in ASD, which correlates with higher severity and worse developmental outcomes [22,23]. The DKI-ALPS is more sensitive for detecting alterations in the glymphatic system [28]. ADHD findings show increased PVS volume and changes in CSF diffusivity in children compared to their non-ADHD peers [29]. Furthermore, reduced DTI-ALPS values are linked to inattention symptoms and, in adults, correlate with poor visual memory performance [21]. This highlights persistent glymphatic issues in ADHD across the lifespan, potentially tied to cognitive deficits. Schizophrenia (SCZ) follows a similar pattern, with reduced DTI-ALPS values linked to cognitive difficulties, particularly in visuospatial, attention, and orientation domains [30]. A study has shown a connection among DTI-ALPS, cognitive performance, and gut microbiota composition, pointing to a potential gut-brain axis in this context [31]. Markers like PVS changes and extra-axial CSF can serve as early indicators in ASD, ADHD, and SCZ, aiding earlier diagnosis [29,32]. Recent findings support the idea that childhood PVS enlargement indicates impaired CSF circulation with potential consequences for neurodevelopment and long-term cognitive outcomes [24]. These findings collectively highlight the role of sleep-dependent glymphatic dynamics as a potential mechanism linking inflammation, BBB integrity, and solute clearance in neurodevelopmental disorders.

The primary categories of hazardous substances include heavy metals, pesticides, hydrocarbons, solvents, radioactive elements, and improperly disposed pharmaceuticals and cosmetics [33]. Approximately 7 million deaths yearly are linked to global environmental pollution, as reported by Rentschler and Leonova [34]. The detrimental impact of conventional toxicants like pesticides is well-documented in scientific research, posing significant risk factors for developing malignant tumors [35,36]. Studies confirm that agricultural workers exposed to chemicals like glyphosate and atrazine exhibit increased cancer incidences. Moreover, communities near farming areas demonstrate similar health concerns. Research findings highlight notable links between pesticide exposure and enhanced risks of non-Hodgkin’s lymphoma, leukemia, and bladder cancer [37,38].

Understanding how the glymphatic system functions at the intersection of neurodevelopmental disorders and environmental toxin exposure opens the door to developing new therapeutic approaches. Dysfunction of the glymphatic system, often tied to oxidative stress, neuroinflammation, and BBB impairment, as noted by various studies [18,75], suggests that targeting this system could yield significant therapeutic benefits. Evidence suggests that physical activity-based interventions can positively influence glymphatic function. In APP/PS1 transgenic mice, swimming exercise increased astrocytic aquaporin-4 expression and promoted its polarization at the ends of perivascular astrocytes, thereby decreasing Aβ plaque formation [76]. Similarly, another study using an animal model found that voluntary circular exercise promoted glymphatic clearance of Aβ, increased astrocytic aquaporin-4 polarization, and improved cognitive deficits and anxiety-related behaviors [77]. Although these models are linked to neurodegenerative diseases, a connection between Aβ deposition and toxicant exposure in neurodevelopmental disorders is plausible, as these conditions share similar pathophysiological features [27].

Recent studies highlight certain drugs with potential effects on the glymphatic system. Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has been shown to lower pro-inflammatory cytokines and prevent neuronal apoptosis [78]. In a related animal study, dexmedetomidine increased CSF flow and reduced the risk of accumulation of metabolic waste products [79]. Similarly, when administered in an intracerebral hemorrhage model, simvastatin restored the glymphatic system’s integrity through the VEGF-C/VEGFR3/PI3K-Akt pathway [80]. Another study in the same model showed that melatonin had a neuroprotective effect, enhancing glymphatic transport recovery and preventing BBB impairment [81].

The negative impact of toxic substances on the brain can be mitigated with specific antioxidant, anti-inflammatory, and chelating agents that reduce toxin burdens and safeguard neurovascular integrity. Experimental findings have demonstrated that combining deferiprone with N-acetylcysteine entirely reversed brain dysfunction caused by iron overload by restoring the BBB, mitochondrial function, and synaptic plasticity [82]. Moreover, advances in nanotechnology, such as the use of liposomes, exosomes, and dendrimers for the delivery of anti-inflammatory agents to the brain, offer promise [83]. These nanocarriers aim to reduce neuroinflammation, offering an innovative approach to mitigating the effects of environmental toxicants on the CNS.

In our examination, we attempt to outline how the glymphatic system’s operation and structure might be associated with neurodevelopmental disorders such as ASD, SCZ, and ADHD, particularly considering the influence of environmental toxicants in these processes. Nevertheless, to date, only a limited number of investigations have thoroughly explored this potential relationship. Even with the noteworthy escalation in research publications in recent years, this domain is still in its developmental stages, necessitating further original studies to solidify its translational potential [15]. Furthermore, the complexity and multifactorial nature of neurodevelopmental disorders remain an enigma, further complicating efforts to elucidate their relationship to environmental toxicant exposure and glymphatic system function.

Current studies underscore the crucial role of the glymphatic system in clearing the brain of metabolites generated by neuroinflammatory and oxidative stress responses. Based on this understanding, we propose a broader investigational scope beyond traditional mechanisms, emphasizing the potential modulation of glymphatic system efficacy in neurodevelopmental disorders by extensive environmental exposure spanning progenitors’ lifetimes, and during gestation, as well as the exacerbation of symptoms in patients with these disorders.

Various environmental toxicants have been linked to unfavorable neurodevelopment, including fine particulate matter (PM_2.5), other air pollutants like ozone (O₃) and nitrogen dioxide (NO₂), metals (such as lead with mixed findings for mercury), PFAS, pesticides (like glyphosate), heavy metals (including methylmercury and lead), and nanoplastics. Preclinical findings suggest potential mechanistic pathways by which these pollutants interfere with the BBB, disrupt astrocytic aquaporin-4 polarization at astrocytic end feet, impair the exchange of cerebrospinal fluid and interstitial fluid, and heighten neuroinflammation—culminating in glymphatic dysfunction.

Overall, this body of research suggests that various environmental toxicants can significantly influence brain physiology and development, presenting notable links with both neurodevelopmental disorders and the glymphatic system. Although no research has directly examined the effects of toxicants on the glymphatic system in the context of neurodevelopmental disorders, a hypothesis holds that early-life exposure to toxicants may elevate the risk of glymphatic dysfunction and subsequent neurodevelopmental issues.

Early-life environmental exposures disrupt crucial axes, such as the BBB and astrocytic aquaporin-4, thereby hindering the glymphatic system’s clearance of solutes like amyloid-beta, tau, and inflammatory mediators. This can skew neurodevelopmental trajectories, elevating the risk of heightened conditions in patients with neurodevelopmental disorders. To rigorously examine this proposition, future research must blend exposome evaluations with glymphatic system-specific neuroimaging (e.g., DTI-/DKI-ALPS), cerebrospinal fluid biomarkers, and tangible sleep metrics. Studies should be designed to differentiate by disorder subtypes and developmental stages.

Noteworthy evidence gaps persist, including the lack of focused studies testing toxicant impacts on the glymphatic system in neurodevelopmental disorder populations, limited longitudinal study designs spanning sensitive periods, insufficient attention to sex differences and exposure mixtures, and the absence of glymphatic system endpoints amenable to translation. The intersection of the glymphatic system, toxicants, and neurodevelopment represents an exciting yet underexplored field. Addressing these gaps could enhance our understanding of disease mechanisms, fostering novel prevention and therapeutic strategies and providing pathways for new approaches.

In summary, research corroborates substantial links between environmental toxicants and several neurodevelopmental disorders. This connection underscores the critical importance of minimizing exposure, especially during early developmental stages. Consistent with this perspective, dysregulation of the glymphatic system may provide a mechanistic connection between environmental toxicant exposure and the onset or progression of neurodevelopmental disorders. By integrating strategies targeting the glymphatic system with preventive actions and toxicant protection, a promising approach for treating and managing neurodevelopmental disorders can be developed.