Cerebral chemical stability, which underlies normal human thinking, learning, and behavior, is strictly regulated by brain barrier systems that separate the blood circulation from brain extracellular fluids. The blood-brain barrier (BBB), whose structural basis is capillary endothelial cells sealed by tight junctions, disconnects the blood from cerebral interstitial fluid. The BBB is central to the neurovascular unit which includes pericytes and astrocyte end-feet and allows regional coupling of blood supply with neuronal activity. The epithelial cells of choroid plexuses are also sealed by tight junctions, but separate blood from the ventricular cerebrospinal fluid (CSF), constituting the blood-CSF barrier. Much more than physical barriers, these cellular monolayers transport materials and produce endogenous proteins for the brain, eliminate cerebral metabolites, and regulate neuro-immune interactions. Understanding brain barrier properties is currently rapidly advancing, thanks to powerful technology innovations that facilitate in-depth barrier functional studies.
Progresses in brain barrier research during past decades have clearly linked these structures to the pathoetiology of brain diseases. For example, alteration of the integrity of the neurovascular unit is now known as an important determinant of the onset of epilepsy (Baruah et al., 2020). The interaction between BBB injury and cerebral amyloid angiopathy, which influences each other’s phenotype, could contribute to the pathogenesis in Alzheimer’s disease. Furthermore, alterations in BBB structure, changes in CSF biomarkers, and histopathology noted in autopsies indicative of impaired BBB, are consistently observed in neurodegenerative diseases including chronic traumatic encephalopathy, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis (Sweeney et al., 2018).
Because of their indispensable gatekeeper functions and their vulnerability inherent to direct exposure to circulating toxicants, the brain barriers are of paramount importance in toxicant-induced brain disorders. Yet, the interaction of environmental toxicants with brain barrier systems has only recently drawn attention. Two areas of discoveries have prompted recent enthusiasm in toxicological investigation of brain barriers.
The integrity of brain barrier systems is a recognized target of environmental toxicants. The efficacy of the barriers can be compromised by 2 categories of barrier toxicants. The directly acting barrier toxicants damage the barriers structure, allowing blood-borne toxicants to come into contact with neuronal structures. Exposure to lead, for example, damages the cerebral endothelial layer, resulting in extensive extravascular stains of lanthanum nitrate (a nonbarrier permeant tracer) in brain parenchyma (Wang et al., 2007). Bacterium-derived lipopeptides, short-chain fatty acids and indoles may compromise the integrity of the barriers, thus supporting a role for gut-originated microbiota in brain diseases such as Parkinson’s disease and autism spectrum disorders (Srikantha and Mohajeri, 2019). The indirectly acting barrier toxicants may not directly change the tight organization of barriers, but rather alter transport functions of barriers, inducing neurotoxicities through more subtle changes in cerebral homeostasis. Copper, for example, is removed from the CSF to blood by CTR1/ATP7B carriers in the blood-CSF barrier. Manganese exposure does not damage the choroidal epithelium, yet alters the intracellular trafficking of ATP7B in the blood-CSF barrier that leads to reduced copper clearance and dysfunction of copper homeostasis in brain regions (Fu et al., 2014).
Importantly, the efficacy of an enzymatic barrier in protecting brain from toxicants has also recently been recognized. Aside from the protection by tight junctions and efflux transporters, metabolic processes within barriers are capable of enzymatically inactivating toxicants in a liver-like manner. This is especially true for the blood-CSF barrier that displays high activities of conjugating enzymes, epoxide hydrolase and antioxidant enzymes. Glutathione S-transferases and glutathione peroxidases, for example, control the level of toxicants and peroxides in the central milieu during postnatal development, ie, at stages when the protective astrocytes are immature and detoxifying activities in liver remain low (Kratzer et al., 2018). Biotransformation at brain barriers thus contributes to define the neurotoxic potential of chemicals, for which the current efforts are being directed toward therapeutic strategies aiming at enhancing or restoring the neuroprotective capacity of brain interfaces toward toxicants.
These discoveries prompt (replace “support”) a reenergized brain barrier research in toxicological sciences; but there are 3 emerging areas, by our assessment, in which additional work will be of special added value.
First, brain barrier toxicological research can benefit from the rapid advancement in neuroimaging technologies. A limited number of studies show that dynamic contrast-enhanced magnetic resonance imaging, dynamic contrast-enhanced computed tomography and positron emission tomography can provide quantitative functional information on brain barriers, such as cerebrovascular reactivity, cerebral blood flow, integrity of both barriers, and intracellular metabolic processes (Hubert et al., 2019; Thrippleton et al., 2019). Applying these technologies in toxicological investigations, however, will require interdisciplinary efforts of toxicologists, imagers, BBB scientists, and pathologists within common research structures devoted to the understanding of brain disorders.
Second, incorporation of machine learning and artificial intelligence is needed to help predict the brain barriers injury caused by multiple factors. Big-data algorithms offer unique advantages not only for fast processing of existing data, but more importantly, by maximizing the chances of successful choices, for accurate prediction of disorder outcomes. Artificial intelligence can analyze 5 categories of “data,” ie, tabular, imaging, voice, text, and graphic data. Researchers have already started to train artificial intelligence models to enable unbiased quantifications of angioarchitecture of brain vasculature (Todorov et al., 2020) and to predict the BBB permeability for potential drugs used for treatment of brain diseases (Saxena et al., 2019). At present, fast accumulation in large quantities of data from in vivo, in vitro, and in silico studies has called for application of artificial intelligence to develop reliable models to detect and predict signs and degrees of brain barriers injuries caused by toxic exposure as well as the ensuing neurotoxicities.
Third, there is a clear lack of information relevant to neuroprotective properties of brain barriers and their sensitivity to toxicants across all developmental stages. The theme of the “early-life exposure leading to late-life disorders” is not new, but has not been extensively examined in the brain barriers field. The vulnerability and specific properties of developing brain barriers need to be better understood, together with the impact of toxicant-induced early brain barrier dysfunctions on the onset and progression of neurological impairment in the later life. Similarly, the brain barriers are significantly weakened in aged individuals, and thus, efforts are needed to understand pathophysiological changes of brain barriers in aging, the relationship of aged barriers with cerebral-vascular diseases, and the role of chemical exposure in the aging process of brain barriers.
As structures controlling the exchanges between the blood and brain extracellular fluids, the brain barrier systems form the first defense line against insults from blood-borne endo- and xenobiotics of environmental, gut-microbiota, and/or pathogen (virus) origins. Thus, it is imperative to establish the relationship between weakened brain barriers’ defense and ensuing brain disorders, so that before we can explain toxicant-induced neurotoxicities in any meaningful sense, we must understand how they reach brain parenchyma and whether they cause damage to the protective barriers in the first place. With rapid advancement in imaging and molecular technologies, the century-old subject of BBBs will become a new frontier in toxicological sciences.
FUNDING
National Institutes of Health (NIEHS R01ES008146 and R01ES027078 to W.Z.).
DECLARATION OF CONFLICTING INTERESTS
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article..
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