Alzheimer’s disorder is primarily regarded as a condition of degenerative ageing, with the majority of instances diagnosed in individuals aged 65 and over (Park et al., 2005). Alzheimer’s disease is so far the most prevalent neurological disorder (Bauer et al., 2021). It is a severe condition with dementia as a characteristic symptom (Guest et al., 2020). Multiple theories have been suggested to address the etiology of Alzheimer’s disease, such as genetic abnormalities, oxidative stress (Decourt et al., 2021), β-amyloid toxicity, and environmental factors (Salahuddin et al., 2021). Alzheimer’s disease or an associated type of dementia affects roughly 50 million individuals worldwide, with that figure estimated to rise to 152 million by 2050 (Thapa et al., 2020). Alzheimer’s disease affects more than 5.8 million individuals in the United States, with 13.8 million Americans over 65 estimated to be affected by the disease by 2050 (Calderón-Garcidueñas et al., 2019). Environmental factors have a role in the development of Alzheimer’s disease, which is characterized by gradual impairments in cognitive, learning capacity, memory function, and executive thinking (Więckowska-Gacek et al., 2021). The average lifespan for patients with Alzheimer’s disease ranges from 3–10 years. Since age is the most important determinant of life span, therefore patients diagnosed with diseases in their 60s and early 70s have an average life expectancy of 7–10 years, whereas patients diagnosed with difficulties in their 90s have an average life span of 3 years or less (Zanetti et al., 2009). Early-onset instances also exist and are often caused by hereditary factors (van der Flier et al., 2011; Zou et al., 2014). A plethora of studies have been conducted in recent years to investigate the role of environmental elements including solvents, heavy metals, and pesticides in the neurodegenerative process.

Parkinson’s disease is a prevalent neurological illness, next to Alzheimer’s disease in terms of global prevalence (Song et al., 2020). Parkinson’s disease is more common as individuals become older, although around 4% of individuals with the condition are identified before they are 50. Men are 1.5 times more likely than women to get Parkinson’s disease (Edinoff, et al., 2020). It affects over 10⁷ individuals globally. Parkinson’s disease affects almost one million individuals in the United States, which is higher than the total number of persons identified with disorders like multiple sclerosis, down’s syndrome, and amyotrophic lateral sclerosis (Fritsch et al., 2012). By 2030, this number is predicted to reach 1.2 million (Tanner, 2020). Annually, over 60,000 Americans are identified with Parkinson’s disease (Chakraborty et al., 2020). Motor symptoms such as bradykinesia with stiffness (hypomimia), resting tremor, freezing, festination, dyskinesia, dystonia, sialorrhea, micrographia shuffling gait, and hypophonia along with postural instability at a later phase, define Parkinson’s disease (Rawat and Pandey, 2022). Non-motor symptoms such as dementia, depression, seborrheic dermatitis, excessive sweating, orthostatic hypotension, weight loss, hallucinations, delusions, and autonomic dysfunction may also be present (Goldman and Guerra, 2020). Thus, neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease are becoming more common as the global population ages (Cummings, 2017). Among the major contributors are air pollutants, heavy metals for instance lead, arsenic, manganese, aluminium, etc, rapid urbanization, industrialization, and extensive use of synthetic chemicals such as solvents, pesticides, fungicides, and herbicides (Vardhan et al., 2019). This review provides an analysis of the role of various environmental toxicants on neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.

Air pollution has been linked to neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and other neurological conditions (Genc et al., 2012; Bandyopadhyay, 2016; Costa et al., 2020). Several air pollutants, including nanoparticles, have been found to rapidly translocate to the CNS and may stimulate innate immune responses (Block and Calderón-Garcidueñas, 2009). Recent findings demonstrate that atmospheric contaminant-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular impairment, and changes in the blood-brain barrier all contribute to CNS disorders (Lee et al., 2017). Particulate matter, gases such as ground-level ozone, carbon monoxide, sulphur oxides, and nitrogen oxides are all examples of air pollutants that may be present in both indoor and outdoor atmospheres (Genc et al., 2012). The most prevalent and hazardous components appear to be particulate matter and ground-level ozone, which are primarily produced by nitrogen oxides and volatile organic compounds. Particulate matter is a mixture of solid particles and liquid droplets suspended in the air that is particularly detrimental to the CNS (Liu et al., 2015). The Particulate matter having a diameter of 2.5 µm (PM_2.5) is mainly comprised of both organic and inorganic substances, such as sulphates, nitrates, carbon, ammonium, hydrogen ions, lipopolysaccharide, metals, and water (Wang et al., 2018). Oil refineries, metal processing industries, tailpipe and brake emissions, domestic fuel burning, power plants, and wildfires are all primary sources of PM_2.5 particles (Xie et al., 2021). The blood-brain barrier and olfactory neurons are two key mechanisms for PM_2.5 to penetrate the CNS (Shou et al., 2019). PM_2.5 toxicity in the brain is caused by two main pathways: 1) the inflammatory response and 2) oxidative stress (Zhang et al., 2018; Wang et al., 2021). The neuroinflammatory process is triggered when PM_2.5 activates microglia inappropriately. PM_2.5 has been related to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease in several epidemiological (Zanobetti et al., 2014; Kioumourtzoglou et al., 2016; Rhew et al., 2021) and toxicological studies (Wang et al., 2021). However, limited studies have been conducted on the in-vivo and molecular pathways of neurotoxicity caused by PM_2.5 exposure. In this context, Liu et al. (2019) explored the link between PM_2.5 exposure and neurodegeneration. For 7 days, specific-pathogen-free (SPF) male C57BL/6 J mice were intranasally exposed to PM_2.5 at a dosage of 0.193 mg/kg/day. Acute PM_2.5 exposure led to various changes, including cognitive impairments, neuronal death, protein aggregation, and so on. Oxidative damage and inflammation may have an impact on these damaging pathways.

Diet is one of the environmental components that influence Alzheimer’s (Hu et al., 2013) and Parkinson’s disorders (Agim and Cannon, 2015), for instance, a hyperlipidemic diet may promote β-amyloid deposition (Hu et al., 2020). Calorie consumption, caffeine, alcohol, and metals absorbed through food and lipids, among other factors, have been linked to Alzheimer’s related parameters such as epigenetic, β-amyloid, tau proteins, oxidative stress, and oxygen reactive species (ROS) (Fernández-Sanz et al., 2019). Several in-vitro, in-vivo, and human epidemiological investigations have demonstrated a range of dietary components that influence the incidence of Parkinson’s and Alzheimer’s disease (Rossi et al., 2008; Vauzour et al., 2010). Gao et al. (2007) investigated relationships between dietary habits and the risk of Parkinson’s disease in the health professional’s follow-up study (1986–2002) and the nurse’s health study (1984–2000). The principal components analysis was applied to identify main diet trends and the Alternate Healthy Eating Index (AHEI) and the alternate Mediterranean diet score (aMed) to measure dietary quality in 49,692 males and 81,676 females who were free of Parkinson’s disease at the beginning of the study. Within each cohort, relative risks were calculated using Cox proportional hazards models and then aggregated using a random-effects model. After 16 years of follow-up, they discovered 508 Parkinson’s disease cases. Two eating trends emerged from the analysis of main components: prudent and western. The prudent dietary pattern, marked by high consumption of fruit, vegetables, and fish, was found to be inversely related to the prevalence of Parkinson’s disease, but not the Western pattern. As a result, researchers concluded that a diet rich in fruits, vegetables, legumes, whole grains, nuts, fish, and poultry, as well as a reduced saturated fat consumption and limited alcohol use, may help prevent Parkinson’s disorder (Gao et al., 2007).

Intrinsic bio-metals like copper, iron, and zinc, as well as extrinsic metals like aluminium, potentially play a significant role as factors/cofactors in the etiology of various neurological disorders for instance Alzheimer’s disease (Zatta et al., 2002). Whereas, heavy metals including lead, cadmium, arsenic, and manganese are often used and possibly lead to neurological conditions namely, Parkinson’s and Alzheimer’s disease by elevating neuronal oxidative stress, mitochondrial dysfunction, inflammatory processes, and apoptosis (Chen et al., 2016; Karri et al., 2016). Some of the metals associated with neurodegeneration are discussed below.

As per the epidemiological studies, most pesticides elevate the incidence of neurodegeneration (Sanchez-Santed et al., 2016). The most well-defined pathway for this link is mitochondrial toxicity, which leads to an upsurge in ROS (Re et al., 2008). In Parkinson’s disease, insoluble, misfolded proteins aggregate to form Lewy bodies, which are abnormal protein aggregations that develop inside the nerve cells severely affected by Parkinson’s disease (Breydo et al., 2012). While neurofibrillary tangles (NFTs) are hyperphosphorylated tau protein aggregates that are widely recognized as a basic biomarker of Alzheimer’s disease (Bengoa-Vergniory et al., 2021). Pesticide exposure can be minimized in school premises, workplaces, and residences by changing dietary habits and using sustainable pest management strategies (McBurney, 2017).

Polychlorinated biphenyls are a broad category of organochlorines with different modes of action based on the level and placement of the chlorine atoms on the biphenyl rings (Adetutu et al., 2020). These were manufactured globally from around 1930 until they were limited by the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2001, despite prior prohibitions issued by various institutions, such as the US-EPA and the Eu-Commission (El-Shahawi et al., 2010). Despite these restrictions, they are still present in the environment owing to a variety of biochemical aspects, like lipid solubility and lengthy half-lives. PCBs mostly accumulate in fatty organs, namely the brain, where their presence has been related to a variety of disorders and symptoms, notably Parkinson’s disorder and cognitive impairment (Gagnon-Chauvin et al., 2020). Lyng et al. (2007) used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to study the impact of PCBs on the developing basal ganglia Dopamine (DA) system VM. The co-cultures were exposed to an environmentally relevant blend of PCBs for 1, 3, 7, and 14 days, causing changes in DA neurochemistry, DAergic protein downregulation, and elevated oxidative stress, which led to the extraneuronal injury and the eventual deterioration of both VM and striatal GABA neurons, prior to the death of VM DA neurons. The authors suggested that the co-culture technique was an effective model for studying the sequence of PCB-induced neurotoxic events in developing basal ganglia and that it could have significant implications for conditions including Parkinson’s disease, as well as cognitive impairments associated with PCB exposure and toxicologically identical environmental toxins. Wang et al. (2022) studied the toxicity of a lab-processed blend of PCBs intended to mimic an indoor school environment on female Sprague-Dawley rats via nose-only exposure techniques, incorporating transcriptomics, metabolomics, and neuro-behavioural outcomes. Its exposure has been proven to impair memory, cause anxiety-like behaviour, substantially lower white blood cell counts, slightly affect plasma metabolomics, and impact transcription brain activity, with 274 genes upregulated and 58 genes downregulated. Although they have been related to oxidative stress and cellular dysfunction in several in-vivo as well as in-vitro models their effect on astrocytes has received less attention (McCann et al., 2021).

Solvents are volatile substances, and most environmental exposures are caused by inhaling solvent vapour (Dick, 2006). Organic solvents are used extensively in industries all over the world. Paints, medicines, lubricants, printing inks, insecticides, cosmetics, and home cleansers all require organic solvents, which are omnipresent in today’s society (Ciriminna et al., 2014). Isopropanol, toluene, xylene, solvent mixes like white spirits, and chlorinated solvents like methylene chloride, trichloroethylene, and perchloroethylene are all extensively employed solvents (Gupta, 2020). The coatings sector is the greatest major consumer, as solvents are critical to the quality and longevity of paints, adhesives, varnishes, etc (Dick, 2006). Organic solvent usage is falling in several industries, such as laundry detergent, owing to advances in machinery and processes. Solvents are progressively being recovered and recycled, mainly as a result of environmental restrictions on volatile organic compound emissions (Gani et al., 2006). 1-Bromopropane, a solvent capable of replacing ozone-depleting chemicals like 1,1,1trichloroethane (methyl chloroform), has recently been found to possess neurotoxicity in humans (Saygun et al., 2012). Trichloroethylene (TCE), a chlorinated halocarbon organic solvent, is a mitochondrial toxin associated with dopaminergic neurodegeneration (Castro et al., 2020). Solvents such as n-hexane, methyl n-butyl ketone, 2,5-hexanedione, acetone, methyl ethyl ketone, methyl isobutyl ketone, carbon disulphide, styrene, and 1,1,1-trichloroethane have been associated with peripheral neurotoxins (Xiao and Levin, 2000). De Miranda et al. (2021) studied whether long-term and systemic trichloroethylene exposure at a 200 mg/kg dose activated wild-type LRRK2 and resulted in nigrostriatal dopaminergic impairment dose in aged rats. The authors proposed a gene-environment link between ambient mitochondrial toxins and the protein kinase LRRK2 because it increased LRRK2 kinase activity in the brain, causing a severe dopaminergic lesion in the nigrostriatal area, increased oxidative stress, and induced endolysosomal impairment, and α-synuclein deposition. Chronic toxic encephalopathy, psycho-organic syndrome, or solvent neurotoxicity are all terms used to describe a syndrome of changes in personality, cognitive impairment, and neuropathies caused by chronic, high-level solvent exposure (Spee et al., 2012).

The vascular endothelium in the brain is a vital component of the blood-brain-barrier (BBB) due to its highly compact structure, which helps to maintain a functional and molecular barrier between the brain and the rest of the body, as well as to shield neurons from infections and toxins (Noe et al., 2020). Simultaneously, the BBB coordinates molecular transportation in and out of the CNS. BBB disruption and failure in cerebrovascular disorders cause component leakage into the CNS, leading to neurodegenerative impairments (Sweeney et al., 2019). BBB dysfunction has been found in neurodegenerative conditions such as multiple sclerosis, Parkinson’s, and Alzheimer’s disease (Zhao et al., 2015). Neuronal cells are highly susceptible to pro-inflammatory cytokines such as IL-1, IL-6, TNF-α, lipid mediators, free radicals, vasogenic agents such as glutamate, serotonin, and histamine, and other endogenous stimuli such as extracellular K⁺ and intracellular Ca²⁺ (Muralidharan and Kofke, 2016). Most of them are produced under pathophysiological circumstances, and alterations in their levels in the BBB play an important role in the genesis and progression of CNS impairment (Gonzalez-Candia et al., 2021). Li et al. (2020) studied indoor nanoscale particulate matter (INPM)-induced BBB disruption and possible cellular responses using a 3D human organotypic model. Human astrocytes and human umbilical vein endothelial cells were co-cultured in 3D within a microfluidic system to replicate the micro-complex physiological responses of the BBB to INPM exposure. INPM exacerbated inflammation caused by ROS and stimulated abnormal expression of the nuclear transcription factor Nrf2 following ROS accumulation. This activity disrupted the synthesis of γ-glutamate synthase (γ-GCS) and heme oxygenase (HO-1), exacerbating the antioxidant system’s imbalance and thereby influencing BBB bio-function by Keap1-Nrf2-ARE pathways. According to Liu et al. (2020) triphenyl phosphate (TPP) and its metabolite diphenyl phosphate (DPP) produced metabolomic and transcriptome changes in the brain. TPP (0, 50, or 150 mg/kg/day) was administered orally to weaned male mice (C57/BL6) for 30 days. The thalamus and hippocampus of mice exposed to high doses showed signs of inflammation, as well as changes in glutamic acid, N-acetyl CoA metabolites, and organic acid levels. TPP exposure seemed to interfere with amino acid and lipid metabolism, as well as brain transcription and cell death processes (FOXO and MAPK signalling pathways). Anti-inflammatory cytokines such as TNF-α and interleukin-6 (IL-6) were upregulated, but antioxidant genes such as nuclear factor-E2-related genes were downregulated.

Misfolded protein aggregates are a typical histopathological feature in various neurological disorders (Lázaro et al., 2020). Aggregates can result in the formation of disease-specific protein alterations that make them prone to aggregation or elevate their cellular level (Guo and Lee, 2014). Furthermore, environmental parameters and the impacts of ageing perform major functions. The potential to maintain cellular proteostasis, in particular, decreases considerably with age. There are two types of aggregates: 1) tiny, soluble oligomeric aggregates that can evolve into 2) larger insoluble protein aggregates termed inclusion bodies (IBs), which have been found to adopt amyloidogenic and amorphous forms (Bäuerlein et al., 2020). The existence of tiny soluble oligomeric aggregates is linked to toxicity in several conditions, such as Alzheimer’s, Parkinson’s, and other neurodegenerative disorders, and IB production is frequently seen as a protective strategy (Vendredy et al., 2020). Furthermore, in addition to oligomers, IBs have been found to have significant cytotoxic activities in these disorders for α-synuclein, Tau, TAR DNA-binding protein 43 (TDP-43), and β-amyloid. IBs carrying α-synuclein have been identified in Parkinson’s disease, Lewy-body disease, etc. (Stefanis, 2012). Hyperphosphorylated tau protein precipitates cytosolically as neurofibrillary tangles are observed in IBs of Alzheimer’s disease (Bäuerlein et al., 2020). TDP-43 accumulates in IBs observed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but also Lewy-body disease, Alzheimer’s, Parkinson’s, and other diseases. β-amyloid is the primary component of the extracellular neuritic plaques observed in Alzheimer’s diseases (Jansen et al., 2014). Although the IBs of diverse neurological conditions are produced via distinct proteins, they are usually cross β-sheet amyloid fibrils. Inside a neuron, axonal damage and protein aggregation promote an equivalent reactive pathway (Serrano-Pozo et al., 2011). Aggregates like β-amyloid might indicate damage or produce physical deformity or damage to structural proteins like tau and neurofilament (NF) triplet proteins, which subsequently initiate a sequence of cytoskeletal alterations leading to dystrophic neurite production and the eventual onset of apoptosis (Vickers et al., 2000). Protein aggregates may quicken the aggregation process via binding with pathogenic proteins such as chaperones. In glia, αB-crystallin (a chaperone protein) binds to the unfolded proteins and suppresses protein aggregation (Segura-Aguilar and Kostrzewa, 2006). Furthermore, cytoplasmic protein aggregates are currently considered to have a neuro-protective effect by sequestration and neutralization of harmful peptides and proteins (Mangione et al., 2016). The interaction between α-synuclein oligomers and lipid membranes (Musteikytė et al., 2021) or parts of the ubiquitin-proteasome system is hypothesized to cause toxicity (Cook and Petrucelli, 2009). Moreover, the lipid-soluble component of α-synuclein is elevated in Alzheimer’s disease (Larson et al., 2012). Metallothioneins are cytoplasmic proteins that are thought to be neuroprotective since they bind heavy metals, have antioxidant and antiapoptotic properties and reduce cellular inflammation (Zalewska et al., 2014). Advanced glycation end products (AGEs) are age-related protein aggregates seen in amyloid plaques, neurofibrillary tangles, and α-synuclein that develop when reactive dicarbonyls like methylglyoxal combine (Krautwald and Münch, 2010). Srivastava et al. (2020) evaluated the toxicity of α-synuclein conformers on neuronal SH-SY5Y cells in the presence of rotenone via MTT test, Annexin-V apoptosis assay, ROS detection assay, and the mitochondrial membrane potential evaluation. The findings revealed that rotenone increased the production of structurally unique oligomers and fibrils that function as templates, as well as enhanced the development of conformers likely to spread to nearby neuronal cells. Furthermore, the involvement of the NAC region and the helical conformations formation resulted in structural alterations in oligomers and fibrils, which affects their cytotoxic activity, where β-sheet rich oligomers and fibrils modify the membrane potential of neuronal cells and cause early cell death. The mechanism of protein aggregation in neurodegenerative disorders is presented in Figure 2.

The development of neurodegenerative conditions, such as Alzheimer’s, Parkinson’s, and other related disorders have been linked to both mitochondrial dysfunction and oxidative stress (Elfawy and Das, 2019). Severe oxidative stress to lipids, proteins, and DNA characterizes these disorders, which can trigger apoptosis through various pathways, including the deactivation of critical functions or the activation of fatal processes (Finkel and Holbrook, 2000). Oxidative stress is produced by a loss of balance in the pro-oxidant/antioxidant equilibrium, resulting in the formation of deleterious ROS (Guerin et al., 2001). ROS are specific to the brain and cause oxidative stress and are highly active in the brain and neuronal tissue as excitative amino acids and neurotransmitters, whose metabolism is a producer of ROS (Gilgun-Sherki et al., 2002). They target post-mitotic cells like glial cells and neurons, which are more vulnerable to free radicals, causing neurological injury (Uttara et al., 2009). Furthermore, ROS build-up and oxidative stress might be caused by impaired ROS removal capabilities. Redox imbalance is caused by a decrease in the quantity of GSH, an essential intracellular antioxidant, in various conditions, such as Parkinson’s disorder, cystic fibrosis, and others (Ballatori et al., 2009). Mitochondria in association with the endoplasmic reticulum are involved in calcium regulation, inorganic ROS production, and lipid signalling and metabolism (Rana, 2019). Furthermore, they are a major source of amyloid and tau accumulation in Alzheimer’s disorder in brain tissue (Ferreiro et al., 2012). Oxidative stress affects dopaminergic neurons, cholinergic receptors, and a variety of other structures implicated in neurodegeneration, triggering a chain of events that includes mitochondrial malfunction and neuroinflammation (Rekatsina et al., 2020). As a result, the degeneration of neurons is aided by the damage of nuclear and mitochondrial DNA (mtDNA) (Mandavilli et al., 2002). Since neurons have high energy requirements, mitochondrial oxygen consumption accounts for over 90% of mammalian oxygen consumption. Moreover, complex-I inhibition reduces mitochondrial ATP synthesis and promotes the formation of ROS, which in turn damage mitochondrial DNA, respiratory chain components, and other mitochondrial factors, resulting in a deadly cycle of mitochondrial malfunction and oxidative stress (Exner et al., 2012). Adult male Sprague Dawley rats were administered mitochondria-targeted antioxidant (Mito-Q (250 μM)) in drinking water for 4 weeks, followed by simulated vehicle exhaust exposure (SVEE) for 2 weeks (5 h/day), and then behavioural and biochemical tests were performed. The findings revealed that VEE caused behavioural and cognitive abnormalities, elevated oxidative stress, a decreased antioxidant response, and mitochondrial impairment as a result of electron transport chain (ETC) disruption, decreased oxygen consumption, low ATP synthesis, and a modification in mitochondrial biochemical dynamics as measured by protein expression profiles of mitochondrial fission, dynamin-related protein-1, and fusion markers, mitofusin-1/2 in the hippocampus (HIP), amygdala (AMY) and the prefrontal cortex (PFC). Mito-Q administration reduced behavioural abnormalities, oxidative stress, and averted mitochondrial damage caused by SVEE (Salvi et al., 2020). Kaur et al. (2007) studied the effect of dichlorvos (organophosphate) on mitochondrial calcium uptake, oxidative stress generation, and neuronal death using an in-vivo rat model. Dichlorvos was given subcutaneously at a dose of 6 mg/kg/day for 12 weeks, and the results showed a substantial increase in mitochondrial Ca²⁺ absorption, reduced cytochrome oxidase (complex-IV) electron transfer activities, and modified mitochondrial complex-I, and complex-II activity. Furthermore, reduced GSH levels and manganese superoxide dismutase (Mn-SOD) activity in mitochondria isolated from dichlorvos-treated rat brain induced an increase in malondialdehyde, protein carbonyl, and 8-hydoxydeoxyguanosine synthesis, as well as protein and mtDNA oxidation as a result of elevated oxidative stress. Chronic low-level dichlorvos exposure resulted in oligonucleosomal DNA fragmentation, a characteristic sign of apoptosis. The mechanism of mitochondrial dysfunction and oxidative stress in Alzheimer’s and Parkinson’s disorders is presented in Figure 3. Mitochondria are a potential therapeutic target in neurological disorders due to their neuroprotective effect when functioning effectively (Camara et al., 2017). Although it is a new area of study, there are presently no treatments in clinical trials that specifically target mitochondrial quality control. Previous therapies aiming at correcting mitochondrial dysfunction failed to produce the desired outcomes, in part due to the delays of the intervening window (Almannai et al., 2020).