Volume 43, Issue 1 p. 66-88
REVIEW ARTICLE
Open Access

Environmental exposure of the general population to cadmium as a risk factor of the damage to the nervous system: A critical review of current data

Agnieszka Ruczaj

Corresponding Author

Agnieszka Ruczaj

Department of Toxicology, Medical University of Bialystok, Bialystok, Poland

Correspondence

Agnieszka Ruczaj and Małgorzata M. Brzóska, Department of Toxicology, Medical University of Bialystok, Adama Mickiewicza 2C Street, 15-222 Bialystok, Poland.

Email: [email protected]; [email protected]

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Małgorzata M. Brzóska

Corresponding Author

Małgorzata M. Brzóska

Department of Toxicology, Medical University of Bialystok, Bialystok, Poland

Correspondence

Agnieszka Ruczaj and Małgorzata M. Brzóska, Department of Toxicology, Medical University of Bialystok, Adama Mickiewicza 2C Street, 15-222 Bialystok, Poland.

Email: [email protected]; [email protected]

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First published: 18 March 2022
Citations: 10

Abstract

Nowadays, more and more attention has been focused on the risk of the neurotoxic action of cadmium (Cd) under environmental exposure. Due to the growing incidence of nervous system diseases, including neurodegenerative changes, and suggested involvement of Cd in their aetiopathogenesis, this review aimed to discuss critically this element neurotoxicity. Attempts have been made to recognize at which concentrations in the blood and urine Cd may increase the risk of damage to the nervous system and compare it to the risk of injury of other organs and systems. The performed overview of the available literature shows that Cd may have an unfavourable impact on the human's nervous system at the concentration >0.8 μg Cd/L in the urine and >0.6 μg Cd/L in the blood. Because such concentrations are currently noted in the general population of industrialized countries, it can be concluded that environmental exposure to this xenobiotic may create a risk of damage to the nervous system and be involved in the aetiopathogenesis of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as worsening cognitive and behavioural functions. The potential mechanism of Cd neurotoxicity consists in inducing oxidative stress, disrupting the activity of enzymes essential to the proper functioning of the nervous system and destroying the homoeostasis of bioelements in the brain. Thus, further studies are necessary to recognize accurately both the risk of nervous system damage in the general population due to environmental exposure to Cd and the mechanism of this action.

Abbreviations

  • 8-OHdG
  • 8-hydroxy-2-deoxyguanosine
  • AChE
  • acetylcholinesterase
  • AD
  • Alzheimer's disease
  • ALS
  • amyotrophic lateral sclerosis
  • amyloid β
  • BBB
  • blood–brain barrier
  • BChE
  • butyrylcholinesterase
  • bw
  • body weight
  • Ca2+
  • calcium ions
  • Ca2+/Mg2+-ATPase
  • calcium–magnesium adenosine triphosphatase
  • Ca2+-ATPase
  • calcium adenosine triphosphatase
  • CAT
  • catalase
  • Cd
  • cadmium
  • Cd2+
  • cadmium ions
  • CNS
  • central nervous system
  • CSF
  • cerebrospinal fluid
  • GM
  • geometric mean
  • GPx
  • glutathione peroxidase
  • GSH
  • reduced glutathione
  • GSSG
  • oxidized glutathione
  • GST
  • glutathione S-transferase
  • IQ
  • intelligence quotient
  • LOD
  • level of detection
  • MDA
  • malondialdehyde
  • Mg2+
  • magnesium ions
  • Mg2+-ATPase
  • magnesium adenosine triphosphatase
  • MT
  • metallothionein
  • Na+/K+-ATPase
  • sodium–potassium adenosine triphosphatase
  • NO
  • nitric oxide
  • NTPDase
  • nucleoside triphosphate phosphohydrolase
  • PD
  • Parkinson's disease
  • ROS
  • reactive oxygen species
  • SE
  • standard error
  • SOD
  • superoxide dismutase
  • TSH
  • total sulphydryl groups
  • 1 INTRODUCTION

    The frequency of diseases of the nervous system, including neurodegenerative diseases, is growing all over the world (Huat et al., 2019). It has been estimated that by the year 2050, as many as 152 million people around the world will suffer from dementia and Alzheimer's disease (AD) will consist about 60%–80% of this number (Huat et al., 2019). Moreover, according to the World Health Organization (WHO, 2020), in 2019, AD and other dementias were the seventh leading cause of death worldwide and the second in highly developed countries. The growing incidence of diseases of the nervous system, including especially neurodegenerative diseases, together with the forecasts of the rise of their occurrence makes it very crucial to recognize the possible risk factors and effective ways of eliminating their negative impact.

    It is recognized that factors such as trauma, genetic alterations, mental stress and multiple diseases can be the causes of the dysfunction of the nervous system (Iqubal et al., 2020; Sharma et al., 2020). Moreover, the unfavourable impact on the development and function of this system may also be exerted by numerous chemical factors, including toxic metals (Ball et al., 2019; Mir et al., 2020; Sharma et al., 2020). Recently, due to the growing use of chemical substances and hence human exposure to numerous chemicals that have proven neurotoxic effects, at least in experimental animals, increasing attention has been paid to xenobiotics as one of the risk factors for nervous system diseases (Ball et al., 2019; Mir et al., 2020; Sharma et al., 2020). These refer, among others, to toxic metals, including cadmium (Cd), that accumulates both in the environment and the human body (Akatsu et al., 2012; Gellein et al., 2003; Nordberg et al., 2018).

    Due to common Cd occurrence, exposure of the general population to this xenobiotic is inevitable, and prognoses show that it will increase in the future decades (Bakulski et al., 2020; Mężyńska & Brzóska, 2018; Nordberg et al., 2018). Moreover, there is growing evidence from epidemiological studies that relatively low and even low-level chronic exposure to this xenobiotic, currently taking place in industrialized countries, may create a risk for human health and contribute to the development of civilization diseases, including first of all damage to the kidneys, skeletal system, cardiovascular system and cancers, as well as is connected with shorter life expectancy (Bhardwaj et al., 2021; Deering et al., 2018; Lin et al., 2016; Mężyńska & Brzóska, 2018; Suwazono et al., 2020; Wallin et al., 2016; Wang, Sun, et al., 2016). The toxicity of this heavy metal to different organs and tissues is relatively well known and widely reported (Mężyńska & Brzóska, 2018; Nordberg et al., 2018; Rafati Rahimzadeh et al., 2017; Rehman et al., 2018), but the neurotoxic action of this metal is not so well understood. Cd is supposed to be involved in the aetiopathogenesis of multiple disorders of the central nervous system (CNS) such as AD, parkinsonism and Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (Akatsu et al., 2012; Bakulski et al., 2020; Basun et al., 1991; Dhillon et al., 2008; Forte et al., 2005; Gupta et al., 2017; Min & Min, 2016; Mir et al., 2020; Okuda et al., 1997; Paknejad et al., 2019; Peng et al., 2017; Roos et al., 2013). It can also be involved in cognitive and behavioural deteriorations (Ciesielski et al., 20122013; Gustin et al., 2018; Hart et al., 1989; Jeong et al., 2015; Kippler et al., 20122016; Li et al., 2018; Nordberg et al., 2000; Przybyla et al., 2017; Rodríguez-Barranco et al., 2014; Sioen et al., 2013; Tian et al., 2009; Yousef et al., 2013; Yu et al., 2011).

    Taking the above into consideration, in the present review, interest has been focused on the neurotoxicity of Cd, and particular attention has been paid to its impact on the human's nervous system. This paper aimed to review critically the actual knowledge on the impact of Cd on the nervous system and analyse if there is sufficient evidence to recognize whether the current environmental exposure to Cd in developed countries may create a risk of damage to the nervous system in humans. Moreover, attempts have been made, for the first time, to state at which concentrations in the blood or urine Cd may be dangerous for the nervous system, as well as to compare the risk of this system damage to the risk of damage to the other organs and systems due to environmental exposure to Cd. Based on the available data of experimental studies, potential mechanisms of Cd neurotoxicity have been proposed as well.

    In preparing this review, we searched for data in the databases such as Medline, Scopus and SpringerLink using keywords such as cadmium and exposure, general population, nervous system, CNS, oxidative–antioxidative balance, oxidative stress, lipid peroxidation, neurotoxicity, brain, blood–brain barrier (BBB), mechanism of action, acetylcholinesterase (AChE), adenosine triphosphatase (ATPase), PD, AD, cognitive and behavioural functions, human, and experimental animals.

    2 THE CNS: A KEY ROLE IN THE BODY AND CAUSES OF DAMAGE

    The CNS consists of the brain and the spinal cord (Thau et al., 2021). The role of this system is to locate signals from the environment and react to them appropriately (Ludwig et al., 2020; Thau et al., 2021). It is also engaged in crucial live functions, including control of muscles function or blood pressure regulation and reflexes such as vomiting and sneezing. Moreover, the CNS is responsible for memory, attention, speech and regulating consciousness (Ludwig et al., 2020; Thau et al., 2021).

    The proper role of the CNS may be negatively influenced by numerous causes, including exposure to chemical substances (Mir et al., 2020; Sharma et al., 2020; Thau et al., 2021). All factors disturbing the proper function of the nervous tissue or causing damage to its structure may lead to the development of various diseases of the CNS. The symptoms of these diseases include difficulties with communication (e.g. speech without meaning and problems in understanding language) and impairment of memory and cognitive functions (Thau et al., 2021). Other symptoms are, for instance, dizziness, paralysis, loss of consciousness or involuntary movements (Thau et al., 2021). What is important to underline is that the most often occurring neurodegenerative disorders — AD and PD — are irreversible and their symptoms are progressive (Gallegos et al., 2015; Mir et al., 2020).

    Chemical factors that may be involved in the aetiopathogenesis of the diseases of the nervous system are presented in Figure 1. They include metals (among others Cd), organic solvents, pesticides, compounds used as antimicrobials and psychostimulants and numerous other substances (Ball et al., 2019; Carrino et al., 2021; Małkiewicz et al., 2020; Mir et al., 2020; Sharma et al., 2020; Shukla et al., 1996).

    Details are in the caption following the image
    Chemical substances characterized by neurotoxic action recognized based on studies in humans and experimental animals [Colour figure can be viewed at wileyonlinelibrary.com]

    3 Cd AS A NEUROTOXIC FACTOR

    For a long time, the attention of researchers has been paid mainly to the damaging impact of Cd on the kidneys, lungs and bones recognized as target organs at occupational and environmental exposure in polluted areas (Mężyńska & Brzóska, 2018; Nordberg et al., 2018; Rafati Rahimzadeh et al., 2017; Wallin et al., 2016; Wang, Sun, et al., 2016). The first evidence of the neurotoxic action of this xenobiotic comes from the 1970s and 1980s. They are derived from the demonstration that children with neurological and learning disorders or behavioural difficulties had higher Cd concentration in hair than healthy ones (Marlowe et al., 1985; Pihl & Parkes, 1977). Moreover, cases of neuropathy and deterioration of memory, attention and psychomotor functions were noted due to occupational exposure to Cd (Hart et al., 1989; Nusioł et al., 1981). In the last 20 years, growing attention to the role of this xenobiotic in the aetiopathogenesis of neurodegenerative diseases has been paid (Akatsu et al., 2012; Alimonti et al., 2007; Bocca et al., 2005; Dhillon et al., 2008; Forte et al., 20052007; Gellein et al., 2003; Gerhardsson et al., 200820092011; Gupta et al., 2017; Komatsu et al., 2011; Koseoglu et al., 2017; Min & Min, 2016; Mir et al., 2020; Palacios et al., 2014; Panayi et al., 2002; Peng et al., 2017; Yu et al., 2010). Reports that Cd may be involved in the development of neurodegenerative diseases have increased the interest in explaining the mechanism of its influence on the nervous system and recognizing the critical levels of exposure. However, so far, most of the data concerning Cd accumulation in the brain and its neurotoxicity have been derived from animal models.

    3.1 Cd accumulation in the brain

    Results of experimental studies conducted in animal models provided clear evidence that Cd accumulation in the brain, evaluated based on its concentration or content, is markedly lower than in other organs (Brzóska et al., 20132015). These may be explained by the existence of the BBB. The entrance of this xenobiotic into the brain is limited when the barrier is fully developed (Montes et al., 2015). During chronic exposure to this metal, the BBB becomes more permeable, and, as a consequence, this xenobiotic can reach the brain more easily (Branca et al., 2020). The damage to the BBB during the repeated exposure to Cd can be connected with the disturbance of the oxidative–antioxidative balance of microvessels, resulting in the development of oxidative stress, which is more prominent when the exposure lasts for a long time (Branca et al., 2020; Shukla et al., 1996). It is worth underlining that after acute intoxication with Cd, the highest concentrations of this xenobiotic were assayed in the structures of the nervous system that are not protected by the BBB, for example, pineal gland and meninges (Arvidson & Tjälve, 1985; Branca et al., 2020).

    Although the BBB is physiologically relatively impermeable, several factors (Figure 2) can result in the opening of tight junction (a connection between endothelial cells), alterations of transport systems or decomposition of the basement membrane of this barrier and, as a consequence, result in a loss of its properties (Gawdi & Emmady, 2020; Kadry et al., 2020). The permeability of this barrier changes during ageing and depends on the health condition (Amaraneni et al., 2017; Montagne et al., 2015; Nyúl-Tóth et al., 2021; van de Haar et al., 2016; Wu et al., 2021). The damage to the BBB with its enhanced permeability is observed in various neurodegenerative diseases and can result from the accumulation of tau protein and amyloid β (Aβ) and degeneration of endothelium, dysfunction of astrocytes (cells that are the components of the structure separating the blood vessels from the neuronal cells) and pericytes (cells that are placed in the basement membrane), as well as immunological processes, including the infiltration of immune cells (Wu et al., 2021). Other factors that can lead to the dysfunction of the BBB are the traumatic injury of the brain and stroke (Gawdi & Emmady, 2020; Kadry et al., 2020). Moreover, exposure to various substances, including toxic metals (e.g. Cd and lead), medicines and substances of abuse (e.g. ethyl alcohol and nicotine), increases the permeability of the barrier (Barr et al., 2020; Carrino et al., 2021; Gawdi & Emmady, 2020; Kim, Byun, et al., 2013; Małkiewicz et al., 2020; Viscusi & Viscusi, 2020). Taking the above into account, it is very important to underline that Cd accumulation in the brain, and thus its neurotoxicity, may be modified by the co-existence of various factors influencing the permeability of the BBB. It seems that the breakdown of the BBB, regardless of cause, will facilitate the entry of Cd into the brain. As Cd damages the BBB under chronic exposure, it can influence its own entrance into the brain in this way.

    Details are in the caption following the image
    Factors influencing the permeability of the BBB [Colour figure can be viewed at wileyonlinelibrary.com]

    When Cd enters the brain, it undergoes retaining in its structures; however, the accumulation of this element in the nervous tissue is low (Al-Brakati et al., 2020; Brzóska et al., 2015; Gonçalves et al., 2012; Sadek et al., 2017). In animal models (rats) of repeated exposure to Cd, it has been revealed that the accumulation of this xenobiotic in the brain is dose dependent and markedly lower than in the liver and kidneys, being the main organs of this element storage in the body (Brzóska et al., 20132015). Revealing enhanced Cd concentration in the brain of rats maintained on a diet containing 1 mg Cd/kg for from 3 up to 24 months (Table 1), corresponding to low environmental human exposure, provided evidence that this xenobiotic crosses the BBB even at its low presence in the blood, ranging from 0.103 to 0.324 μg/L, and low concentration in the urine ranging from 0.085 to 0.354 μg/g creatinine (Brzóska et al., 2015) and being comparable to its concentrations nowadays determined in the blood and urine (main markers of exposure to Cd) of the general population in industrialized countries. The concentration of Cd currently noted in inhabitants of developed countries ranges between 0.004 and 7.03 μg/L in the blood and 0.03 and 13.90 μg/g creatinine in the urine (Table S1). It has been revealed, in the rat's model of low-level lifetime general population exposure to Cd (1 mg Cd/kg diet for 24 months) that the content of this xenobiotic in the brain (0.100 ± 0.011 μg; mean ± standard error [SE]) was 44 times lower compared with its content in the liver (4.442 ± 0.345 μg) and 52 times lower than in the kidneys (5.247 ± 0.478 μg) and consisted 1% of the total pool of this element retained in internal organs such as the liver, kidneys, spleen, heart and brain (9.857 ± 0.882 μg). Due to the exposure to 5 mg Cd/kg diet for the same time, the content of Cd in the brain (0.112 ± 0.007 μg) was 357 times lower compared with its content in the liver (39.932 ± 1.780 μg) and 198 times lower than in the kidneys (22.177 ± 0.971 μg) and accounted for 0.2% of its total content in internal organs (62.386 ± 1.471 μg) (Brzóska et al., 2015). Similarly, after exposure to Cd at the concentration of 50 mg/L of drinking water for 16 weeks, the content of this metal in the brain (0.045 ± 0.004 μg; mean ± SE) was 5038 and 2019 times lower, respectively, compared with its content in the liver (226.72 ± 7.535 μg) and kidneys (90.873 ± 3.162 μg) (Brzóska et al., 2013).

    TABLE 1. Time-related changes in the accumulation of Cd in the brain tissue of rats under low-level and moderate chronic exposure (based on Brzóska et al., 2015)a
    Exposure duration
    Cd accumulation in the brainb 3 months 10 months 17 months 24 months Time-related changesc
    Control
    Content [μg] 0.048 ± 0.006 0.055 ± 0.004 0.035 ± 0.002 0.050 ± 0.007 10–17
    Concentration [μg/g] 0.026 ± 0.009 0.028 ± 0.005 0.018 ± 0.004 0.025 ± 0.009 NS
    1 mg Cd/kg diet
    Content [μg] 0.073 ± 0.006** (↑ 51%) 0.076 ± 0.010# (↑ 37%) 0.061 ± 0.010* (↑ 72%) 0.100 ± 0.011** (↑ 99%) 3–24, 17–24
    Concentration [μg/g] 0.042 ± 0.010* (↑ 63%) 0.044 ± 0.007*** (↑ 59%) 0.031 ± 0.014* (↑ 77%) 0.048 ± 0.016*** (↑ 91%) NS
    5 mg Cd/kg diet
    Content [μg] 0.124 ± 0.009*** †† (↑ 1.6-fold) 0.093 ± 0.009** (↑ 70%) 0.093 ± 0.007*** (↑ 1.7-fold) 0.112 ± 0.005*** (↑ 1.2-fold) 3–10, 3–17
    Concentration [μg/g] 0.075 ± 0.022*** †† (↑ 1.9-fold) 0.051 ± 0.009*** (↑ 84%) 0.051 ± 0.010*** †† (↑ 1.9-fold) 0.056 ± 0.006*** (↑ 1.2-fold) NS
    • a At the beginning of the study rats were at the age of 3–4 weeks.
    • b Cd accumulation in the brain was estimated based on the total content of this toxic metal in the brain and its concentration in the brain tissue of the control rats and those maintained on the diet containing 1 and 5 mg Cd/kg diet. The content and concentration of Cd are presented as mean ± SE. ↑, increase versus the respective control group.
    • c Statistically significant differences (p < 0.05) between each two of the four time points are indicated. NS, p > 0.05 between each two of the four time points.
    • * p < 0.05.
    • ** p < 0.01.
    • *** p < 0.001.
    • # p = 0.06 versus the control group.
    • p < 0.05.
    • †† p < 0.01 versus the group exposed to 1 mg Cd/kg diet.

    It is well known that the permeability of the BBB differs dependent on age (Amaraneni et al., 2017; Montagne et al., 2015; Nyúl-Tóth et al., 2021). The permeability of this barrier in an immature organism is higher than in an adult one (Amaraneni et al., 2017). Moreover, the breakdown of the BBB occurs during ageing, and it depends on the brain region (Montagne et al., 2015). Montagne et al. (2015) have found age-dependent deteriorations in the integrity of the BBB in hippocampus and caudate nucleus, with no significant alterations in other brain regions. In the available literature, there are no data on the impact of age and ageing on Cd accumulation in the human brain; however, our study in the experimental rat's model of low-level and moderate environmental human exposure to this xenobiotic in industrialized countries (1 and 5 mg Cd/kg diet for 3, 10, 17 and 24 months resulting in a daily dosage of 0.038–0.085 mg Cd/kg bw and 0.197–0.405 mg Cd/kg bw, respectively) allowed to estimate age- and dose-related changes in its retention in the brain (Brzóska et al., 2015). The findings of this study are summarized in the current review in Table 1. The higher Cd content (by 37% to 1.7-fold) and concentration (by 59% to 1.9-fold) in the brain of the rats maintained on the diet containing 1 and 5 mg Cd/kg for 3–24 months, than in the control group (fed a diet containing 0.0584 mg Cd/kg), confirms this element accumulation in the brain at moderate and low-level repeated exposure. These together with the lack of any differences in this element concentration in the brain tissue between every two time points at particular levels of the 24-month exposure and its content in the brain after 3 and 24 months of the treatment with 5 mg Cd/kg diet, despite the exposure continuation, show that Cd was the most effectively retained in the brain during the first 3 months of the treatment, reflecting the stage of the most intensive growth and development in the human life (Sengupta, 2013). This conclusion is also based on the fact that the brain content of this element after 3 months of the experiment in the animals fed with the diet containing 1 mg Cd/kg reached 73% of that noted after 24 months (reflecting approximately 70 years of human life; Sengupta, 2013), whereas in the case of the 5 mg Cd/kg diet, it was even 10% higher after 3 months. Moreover, the lack of differences in the content and concentration of Cd in the brain of young control animals (after 3 months of the study) and the elderly ones (after 24 months) kept on a diet containing only trace amounts of Cd (0.0584 mg/kg) also confirms that the process of accumulation of this toxic element in the brain is the most effective in the early stage of life (Table 1). Detailed analysis of the data presented in Table 1 shows that at the low-level exposure, Cd content in the brain at the stage of adulthood (i.e. after 10–17 months of the study what corresponds to about 30–50 years in humans) may be lower than in the elderly (i.e. after 24 months of the study), whereas at the moderate exposure, it may be lower in the adulthood than in the young age (i.e. after 3 months of the study). Based on the above-discussed results of our experimental study, it can be concluded that, due to the higher permeability of the not fully developed BBB at a young age, Cd accumulation in the brain of children may be higher than in adults. The fact that in the animals exposed to the 1 mg Cd/kg diet, the brain content of this element after 24 months was higher than after 3 and 17 months may indicate that at low-level exposure, the accumulation of this xenobiotic may progress with the exposure duration and in the elderly it may be higher than in the young age and adulthood. Unlike the low exposure, at the moderate intoxication, the content of Cd in the brain in the elderly may be similar as in the young age and adulthood. We are aware that the above-presented extrapolation of our findings on Cd accumulation in the brain of rats into humans may be imprecise and these considerations must be approached with caution; however, as so far our study (Brzóska et al., 2015) is the only attempt to estimate Cd accumulation in the brain tissue during the lifetime low-level and moderate exposure. Moreover, it is necessary to underline that our investigation in the experimental rat model allowed eliminating the impact of various factors that may compromise the permeability of the BBB (Figure 2) and, in this way, influence the entry of Cd into the brain and its accumulation in this organ. In humans, it never can be excluded that the process of Cd accumulation in the brain was not influenced by the co-existence of various factors modifying the BBB permeability. It is also important to indicate that in our experimental model, Cd content in the brain at each time point during the first 17 months was dependent on the level of exposure (in the animals maintained on the diet containing 5 mg Cd/kg it was higher by 70%, 22% and 53%, after 3, 10 and 17 months, respectively, than in the case of the 1 mg Cd/kg diet). However, after 24 months, there were no differences in the brain content and concentration of this element in the animals intoxicated with the 1 and 5 mg Cd/kg of diet (Brzóska et al., 2015). It is difficult to explain why after 24 months of the experiment, despite a fivefold difference in the intensity of exposure and differences in Cd concentration in the blood and urine, the content and concentration of this xenobiotic in the brain of animals exposed to 1 and 5 mg Cd/kg of diet did not differ. These may indicate that in the elderly, the brain status of Cd, at different levels of exposure, can be modified in various ways by confounding factors. Such a factor might be a different extent of damage to the BBB. It might variously influence the permeability of this barrier and modify the transport of Cd into and from the brain. To better understand Cd accumulation in the brain during a lifetime, further investigations are necessary.

    3.2 Cd neurotoxicity in experimental animals

    Cd can affect both the structure of the nervous system and its function. Structural abnormalities in the different parts of the brain including the cerebral cortex, cerebellum, pallium and hippocampus were observed in the experimental animals after short- and long-lasting exposure to various doses or concentrations of this heavy metal (Tables 2 and 3) (Ibiwoye et al., 2019; PM et al., 2019; Pulido et al., 2019; Yang et al., 20152016). Numerous studies in animal models have revealed that short- and long-term intoxication with different doses of Cd decreases locomotor activity, as well as causes memory dysfunction, raised anxiety, aggressiveness and disturbances of sleep (Table 4) (Chouit et al., 2021; Haider et al., 2015; Pan et al., 2017; Pulido et al., 2019; Terçariol et al., 2011; Unno et al., 2014; Wang, Zhang, et al., 2018; Yang et al., 20152016). It is worth underlining that exposure to Cd of adult animals can result in occurring neurotoxic effects in their offspring (Tian et al., 2020; Zhao et al., 2015). The abnormalities in offspring include decreased locomotor activity, disruption in the expression of neurotransmitters and decreased neuromotor maturation (Tian et al., 2020; Zhao et al., 2015). Moreover, perinatal exposure to Cd and exposure during lactation have been proved to increase the activity of the sodium–potassium adenosine triphosphatase (Na+/K+-ATPase) in the brain (Liapi et al., 2013; Stolakis et al., 2013).

    TABLE 2. Changes in the structure of the brain of experimental animals due to acute and subacute exposure to Cd
    Type of exposure Animal species Dose, duration and way of exposure Alterations Reference
    Acute Rat 4 mg CdCl2/kg bw, single dose, i.p. Reduced immunoreactivity and number of microvessels, blurred cytoplasm, enlarged and hyperchromatic nuclei of astrocytes Ibiwoye et al. (2019)
    Subacute Mouse 3.74 mg CdCl2/kg bw, 10 days, p.o. Structural alterations of cerebral cortex: slight separation of pia mater from cerebral cortex layer; degenerated vacuoles of granule cells; hyperaemia of blood capillaries; increase in vessel peripheral clearance; fusion of nuclear membranes; ambiguous ultrastructure, vacuoles and vague cristae in mitochondria Yang et al. (2015)
    7.48 mg CdCl2/kg bw, 10 days, p.o. Structural alterations of cerebral cortex: remarkable separation of pia mater from cerebral cortex layer; severe hyperaemia of blood capillaries; increase in vessel peripheral clearance; apoptosis; infiltration of eosinophil leukocytes; degenerated vacuoles in granule cells; marginalized heterochromatin; enlargement of perinuclear space; fused nuclear membranes; ambiguous ultrastructure vacuoles and vague cristae in mitochondria; declined synaptic cleft; fusion of presynaptic and postsynaptic membrane Yang et al. ( 2015)
    • Abbreviations: bw, body weight; CdCl2, cadmium chloride; i.p., intraperitoneally; p.o., per os.
    TABLE 3. Changes in the structure of the brain of experimental animals due to subchronic and chronic exposure to Cd
    Type of exposure Animal species Dose, duration and way of exposure Alterations Reference
    Subchronic Rat 3 mg CdCl2/kg bw, 28 days, p.o. Alterations in the cerebellum: damaged nuclei; lack of structural integrity of Purkinje cells PM et al. (2019)
    Mouse 1.87 mg CdCl2/kg bw, 40 days, p.o. Structural alterations of pallium: slight separation of pia mater from layer of pallium; raised quantity of capillaries; slightly degenerated vacuoles of neurocytes; karyopyknosis of a few granule cells; swelling and enlargement of rough endoplasmic reticulum; ambiguous cristae and vacuoles in mitochondria Yang et al. (2016)
    3.74 mg CdCl2/kg bw, 40 days, p.o. Structural alterations in the pallium: distinct separation of pia mater parts from pallium; raised quantity of capillaries; slight swelling of some neurocytes; karyopyknosis of some granule cells; apoptosis; local haemorrhage in cortex tissue; degenerated vacuoles of neurocytes; swelling of rough endoplasmic reticulum; syncretism within neuron nuclear membranes; ambiguous cristae and vacuoles in mitochondria; some of them swelled; syncretism and reduction of number of synapse vesicles Yang et al. (2016)
    7.48 mg CdCl2/kg bw, 40 days, p.o. Structural alterations in the pallium: congested capillaries under pia mater; degenerated vacuoles; raised number of capillaries; karyopyknosis; hypertrophy and apoptosis; separation of pia mater parts from the cortex; local haemorrhage; infiltration of inflammatory cells; enlargement of rough endoplasmic reticulum; marginalization of heterochromatin; distinct enlargement of perinuclear space; swelling mitochondria with vacuoles and ambiguous cristae; swelled synapses; fused presynaptic and postsynaptic membrane Yang et al. (2016)
    Chronic Rat 32.5 mg Cd/L, 2, 3 or 4 months, p.o. Time-dependent structural and functional abnormalities in the hippocampal neurons Pulido et al. (2019)
    • Abbreviations: bw, body weight; CdCl2, cadmium chloride; p.o., per os.
    TABLE 4. Changes in the behaviour, motor activity and memory function of experimental animals due to exposure to Cd
    Type of exposure Animal species Dose, duration and way of exposure Changes Reference
    Acute Rat 1, 2 or 3 mg CdCl2/kg bw, a single dose, i.p. Declined locomotor activity and memory abilities; raised anxiety; presence of depression-like symptoms Haider et al. (2015)
    Rat 100 mg CdCl2/L, 28 h, p.o. Raised non-rapid-eye-movement sleep; declined locomotor activity at night Unno et al. (2014)
    Zebrafish 4.26, 42.6 or 85.2 mg CdCl2/L, 48 h, p.o. Declined locomotor activity Pan et al. (2017)
    Subacute Mouse 1.87, 3.74 or 7.48 mg CdCl2/kg bw, 10 days, p.o. Declined activity and sensitivity to outside stimulation; lethargy Yang et al. (2015)
    Subchronic Mouse 1.87, 3.74 or 7.48 mg CdCl2/kg bw, 40 days, p.o. Declined daily activities and reactions to outside stimulation; increased sleepiness Yang et al. (2016)
    Rat Mean: 6.90 mg Cd/kg bw, 4 weeks, p.o. Raised aggressiveness (when co-exposed with immobilization stress) Terçariol et al. (2011)
    Chronic Rat 0.017 mg CdCl2/kg bw, 60 days, i.g. Raised anxiety; declined activity; impaired cognitive functions Chouit et al. (2021)
    Rat 32.5 mg Cd/L, 3 or 4 months, p.o. Impaired recognition memory Pulido et al. (2019)
    Mouse 3 mg Cd/L, 20 weeks, p.o. Impaired memory and learning abilities Wang, Zhang, et al. (2018)
    • Abbreviations: bw, body weight; CdCl2, cadmium chloride; i.g., intragastrically; i.p, intraperitoneally; p.o., per os.

    It is well known that the protection against the toxic action of Cd in various tissues can be, to some extent, ensured by metallothioneins (MT). Proteins from this group are expressed mainly in the liver and kidneys and can form complexes with Cd ions (Cd2+) (Borowska et al., 2017; Sandbichler & Höckner, 2016). Isoforms of MT that take part in the process of detoxification of heavy metals (MT-I and MT-II) are also expressed in the nervous system, but in low amounts and their presence is restricted mainly to the glias (Thirumoorthy et al., 2011). MT-III that is mainly expressed in neurons is insensitive to Cd (Thirumoorthy et al., 2011). Thus, even small amounts of this xenobiotic present in the brain tissue may exert toxic action (Chouit et al., 2021).

    As can be seen from the data presented in Tables 2–6, Cd has been reported to have a destroying impact on the nervous system at various doses and concentrations in the drinking water or food administered for various periods. Different effects, including both functional and structural changes in the nervous system, were reported (Tables 2–6). All the studies provided important findings in regard to Cd neurotoxicity; however, detailed analysis of the data, summarized in Tables 2–6, shows that almost all investigated levels of exposure, except for that in the study by Wang, Zhang, et al. (2018) and Chouit et al. (2021), were too high to be possible in humans. To proper understand Cd neurotoxicity, including the mechanism of this action and the risk of damage to the nervous system, experimental studies in in vivo models reflecting human exposure to this xenobiotic should be carried out. To assess if the animal model reflects the level of exposure to Cd that is possible in human life, the measurement of biomarkers of exposure to this heavy metal (Cd concentration in the blood and urine) should be conducted. However, in almost all the studies on the impact of Cd on the nervous system, the researchers did not assess these parameters. The lack of data on the concentrations of this xenobiotic in the blood or urine makes it difficult or even impossible to recognize whether the effects of Cd noted in animal models can occur in humans. In the available literature, we have found only one study by Wang, Zhang, et al. (2018) on Cd neurotoxicity conducted in an experimental in vivo model reflecting current human exposure in which the level of the exposure was estimated based on the measurement of this heavy metal concentration in the blood. The authors (Wang, Zhang, et al., 2018) reported impaired memory and learning abilities in male mice orally exposed to 3 mg Cd/L for 20 weeks at the blood concentration of Cd reaching 2.125–2.25 μg/L and being within the range of values currently sometimes noted in the general population (Table S1).

    Although categorizing the studies presented in Tables 2–6 according to whether or not they reflect exposure that would occur in human life based on the administered dose or concentration and the exposure duration is difficult, the effects reported by Chouit et al. (2021) (0.017 mg CdCl2/kg bw for 60 days) seem to be possible to occur in humans. The authors have noted that the administration of this xenobiotic resulted in raised anxiety, declined activity and impaired cognitive functions of animals, as well as the destruction of oxidative–antioxidative balance (Tables 4 and 5). Pulido et al. (2019) reported the structural changes within the hippocampal neurons and the memory impairment in rats exposed to 32.5 mg Cd/L for 2–4 months. Taking into account Cd concentrations in the blood and urine determined in our experimental models of repeated rat's exposure to 5 and 50 mg Cd/L (Brzóska et al., 2013), the exposure in the study by Pulido et al. (2019) may be described as relatively high and higher than current environmental exposure. Similarly, the exposure to approximately 6.90 mg Cd/kg bw for 4 weeks that caused raised aggressiveness (Terçariol et al., 2011) is not likely to occur in the human population, taking into the consideration that the maximum daily dose of this xenobiotic in the case of the administration in our study of the diet containing 5 mg Cd/kg, which corresponded to the moderate exposure of the general population to this xenobiotic, reached 0.405 mg Cd/kg bw or 0.660 mg CdCl2/kg bw (Brzóska et al., 2015). The same refers to the exposure to 3.74 or 7.84 mg CdCl2/kg bw for 40 days in the study by Yang et al. (2016) that led to serious structural alterations of the pallium, decreased daily activity and increased sleepiness.

    TABLE 5. The impact of exposure to Cd on the oxidative–reductive status of the brain tissue of experimental animals
    Type of exposure Animal species Dose, duration and way of exposure Alterations Reference
    Acute Rat 1, 2 or 3 mg CdCl2/kg bw Positive correlation between the dose of Cd and MDA concentration; negative correlation between the dose of Cd and SOD activity Haider et al. (2015)
    One injection, i.p.
    Subacute Mouse 10 mg Cd/kg bw Decreased activities of GPx (42%), SOD (30%) and CAT (31%); increased activity of GST (1.3 times); increased concentrations of GSH (1.2 times), H2O2 (1.8 times) and MDA (1.5 times) in the hippocampus Zhang, Zhang, et al. (2017)
    21 days, p.o.
    Rat 5 mg CdCl2/kg bw Increased concentration of MDA (3 times) in the brain Adefegha, Omojokun, et al. (2016)
    21 days, p.o.
    Rat 6 mg CdCl2/kg bw Increased concentration of MDA (1.7 times); decreased activities of CAT (50%), GSH (51%) and GPx (45%) in the brain Adefegha, Oboh, et al. (2016)
    21 days, p.o.
    Rat 2.5 mg CdCl2/kg bw Decreased concentration of NO (74%) and increased concentration of MDA (87%) in the cerebral cortex Akinyemi et al. (2017)
    7 days, i.p.
    Rat 5 mg CdCl2/kg bw Increased concentration of MDA (3 times) in the brain Adefegha, Omojokun, et al. (2016)
    21 days, p.o.
    Subchronic Rat 3 mg CdCl2/kg bw Enhanced lipid peroxidation (increased by 40% generation of TBARS) and decreased concentration of GSH (55%) in the cerebellum PM et al. (2019)
    28 days, p.o.
    Rat 5 mg CdCl2/kg bw Decreased concentrations of GSH (48%), TSH (39%) and vitamins C (44%) and E (43%) and activities of SOD (30%), CAT (66%), GPx (62%) and GST (26%); increased concentration of TBARS (35%), lipid hydroperoxides (36%) and protein carbonyl content (2.1 times) in the brain Shagirtha et al. (2011)
    28 days, p.o.
    Rat 5 mg CdCl2/kg bw Decreased activities of SOD (43%), CAT (64%), GPx (52%) and GST (43%); decreased concentrations of GSH (63%), vitamin C (56%) and vitamin E (43%); increased concentration of MDA (2.1 times) in the brain Hao et al. (2015)
    30 days, p.o.
    Rat 4.5 mg CdCl2/kg bw Decreased activities of SOD (27%), CAT (25%), GPx (23%) and GR (29%) and decreased mRNA expression of these enzymes; decreased concentration of GSH (35%); increased concentration of MDA (48%) and NO (2.3 times) in the cortical tissue of the brain Al-Brakati et al. (2020)
    30 days, i.p.
    Rat 5 mg CdCl2/kg bw Decreased activities of SOD (50%), CAT (33%) and GPx (26%); decreased concentration of GSH (40%); increased concentrations of MDA (2.9 times), NO (2.2 times), GSSG (5 times) and 8-OHdG (1.5 times) in the cerebral cortex of the brain Al Omairi et al. (2018)
    28 days, p.o.
    Chronic Rat 0,017 mg CdCl2/kg bw Decreased activities of mitochondrial CAT (37%) and GST (28%); decreased concentration of GSH (50%) in the striatum; decreased activity of mitochondrial CAT (37%) and GST (39%) in the hippocampus; increased concentration of MDA in the striatum (63%) and hippocampus (60%) Chouit et al. (2021)
    60 days, i.g.
    Rat 1 mg CdCl2/kg bw Increased concentration of MDA in the striatum (94%), cerebral cortex (92%), hippocampus (2.2 times) and cerebellum (2.5 times) da Costa et al. (2017)
    3 months (5 times a week), p.o.
    Rat 5 mg CdCl2/kg bw Decreased concentration of GSH (52%); increased concentration of MDA (3 times) and decreased activities of SOD (56%) and CAT (48%) in the brain Sadek et al. (2017)
    8 weeks (2 times a week), p.o.
    Rat 15 mg CdCl2/kg bw Decreased mRNA expression of GST and GPx in the brain El-Tarras et al. (2016)
    3 months, p.o.
    • Abbreviations: 8-OHdG, 8-hydroxy-2-deoxyguanosine; bw, body weight; CAT, catalase; CdCl2, cadmium chloride; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; GST, glutathione S-transferase; i.g.; intragastrically; i.p., intraperitoneally; MDA, malondialdehyde; mRNA, messenger ribonucleic acid; NO, nitric oxide; p.o., per os; SOD, superoxide dismutase; TBARS, thiobarbituric acid-reactive substances; TSH, total sulphydryl groups.

    Taking into account the lack of data from in vivo studies on Cd neurotoxicity at the exposure real to occur currently in the general population, we have undertaken such study in the created by us rat's model of human lifetime exposure to this xenobiotic (1 and 5 mg Cd/kg diet for up to 24 months corresponding to the daily doses of Cd reaching 0.038–0.085 mg/kg bw and 0.197–0.405 mg/kg bw, respectively, or 0.062–0.139 mg CdCl2/kg bw and 0.321–0.660 mg CdCl2/kg bw, respectively), and the findings will be published as quickly as possible.

    3.3 Mechanism of Cd neurotoxicity

    The mechanism of the neurotoxic action of Cd is complex and multidirectional. It includes mainly an induction of oxidative stress, influencing the activity of enzymes of paramount importance for the functioning of the nervous system and homoeostasis of various elements within the brain, affecting the cell cycle and the processes of apoptosis and necrosis (Branca et al., 2019; Garza-Lombó et al., 2018; Labudda et al., 2011; Figure 3).

    Details are in the caption following the image
    The mechanism of neurotoxic action of Cd [Colour figure can be viewed at wileyonlinelibrary.com]

    The main mechanism of the neurotoxic action of Cd is its ability to induce oxidative stress in the nervous tissue (Table 5). Although Cd is not able to produce reactive oxygen species (ROS) directly, it can act via indirect mechanisms by weakening enzymatic (catalase [CAT], glutathione S-transferase [GST], glutathione peroxidase [GPx], superoxide dismutase [SOD]) and non-enzymatic antioxidative barrier (reduced glutathione [GSH], total sulphydryl groups [TSH], vitamins C and E) (Adefegha, Oboh, et al., 2016; Adefegha, Omojokun, et al., 2016; Akinyemi et al., 2017; Al Omairi et al., 2018; Al-Brakati et al., 2020; Chouit et al., 2021; da Costa et al., 2017; El-Tarras et al., 2016; Haider et al., 2015; Luo et al., 2021; Mimouna et al., 2018; PM et al., 2019; Sadek et al., 2017; Shagirtha et al., 2011; Valko et al., 2016; Zhang, Zhang, et al., 2017). It is important to underline that an increased concentration of GSH in the brain tissue due to exposure to Cd, noted by some authors (Zhang, Zhang, et al., 2017), can be an adaptative response to this xenobiotic.

    Cd-induced destroying of the oxidative–reductive balance in the nervous tissue results in the development of oxidative stress defined as the state of an imbalance between antioxidants and oxidants in favour of the later ones that leads to a disruption of redox signalling and control and/or oxidative damage to biomolecules in the cells (e.g. lipids, proteins and nucleic acids) (Chouit et al., 2021; PM et al., 2019). Nervous tissue seems to be particularly sensitive to oxidative damage due to the high content of lipids susceptible to oxidation and great use of oxygen (Agnihotri et al., 2015; Garza-Lombó et al., 2018). The occurrence of oxidative stress and oxidative modifications of cellular molecules is reflected in increased concentrations of malondialdehyde (MDA), nitric oxide (NO), oxidized glutathione (GSSG) and 8-hydroxy-2-deoxyguanosine (8-OHdG) in the nervous tissue (Adefegha, Oboh, et al., 2016; Adefegha, Omojokun, et al., 2016; Akinyemi et al., 2017; Al Omairi et al., 2018; Al-Brakati et al., 2020; Chouit et al., 2021; da Costa et al., 2017; Hao et al., 2015; Sadek et al., 2017; Zhang, Zhang, et al., 2017). It is important to underline that even low-level chronic exposure to this xenobiotic may result in oxidative stress in the brain tissue of rats (Chouit et al., 2021; own unpublished data). Moreover, the pro-oxidative action of Cd is dose dependent. Haider et al. (2015) have noted a negative correlation between the dose of Cd and the activity of SOD and a positive correlation between the dose of this metal and the concentration of MDA in the brain of male rats. The oxidative stress induced by Cd in turn leads to an increase in the permeability of the BBB and facilitates this element entrance into the brain and destroys the proper functioning of the nervous tissue (Branca et al., 2019; PM et al., 2019).

    Another mechanism of Cd neurotoxicity is influencing the homoeostasis of different bioelements in the brain. The exposure to this xenobiotic results in a decrease in the activity of calcium adenosine triphosphatase (Ca2+-ATPase) and calcium–magnesium adenosine triphosphatase (Ca2+/Mg2+-ATPase) (Table 6) and, as a consequence, modifies the concentration of calcium ions (Ca2+), which is an important secondary messenger in the nervous system (Hao et al., 2015; Shagirtha et al., 2011; Zhang, Zhang, et al., 2017). Cd also decreases the activity of magnesium adenosine triphosphatase (Mg2+-ATPase), which is responsible for maintaining the intracellular concentration of magnesium ions (Mg2+) (Hao et al., 2015; Shagirtha et al., 2011; Zhang, Zhang, et al., 2017). What is more, the exposure influences the activity of Na+/K+-ATPase (Table 6), which main function is regulating the potential of cellular membranes. Numerous studies in rat models in which animals were exposed to Cd in the doses from 5 to 25 mg CdCl2/kg bw for 21 days to 5 months revealed a decrease in the concentration of this enzyme in the brain or its structures— cerebral cortex, cerebellum and hypothalamus (Table 6) (Adefegha, Oboh, et al., 2016; Gonçalves et al., 2012; Hao et al., 2015; Shagirtha et al., 2011). However, in the study by Adefegha, Omojokun, et al. (2016), the exposure to 5 mg CdCl2/kg bw for 21 days resulted in an increase by 50% in the concentration of Na+/K+-ATPase in the brain.

    TABLE 6. Changes in the activities of enzymes of paramount importance for the functioning of the nervous system in experimental animals due to exposure to Cd
    Type of exposure Animal species Dose, duration and way of exposure Alterations Reference
    Subacute Mouse 10 mg Cd/kg bw, 21 days, p.o. Decreased activities of Ca2+-ATPase (41%) and Ca2+/Mg2+-ATPase (29%) in the hippocampus Zhang, Xing, and Li (2017)
    Rat 6 mg CdCl2/kg bw, 21 days, p.o. Decreased activity of Na+/K+-ATPase (10%); increased activities of AChE (51%) and BChE (49%) in the brain Adefegha, Oboh, et al. (2016)
    Rat 2.5 mg CdCl2/kg bw, 14 days, i.p. Increased activity of AChE in the prefrontal cortex (2.3 times) and hippocampus (2.2 times) Akinyemi and Adeniyi (2018)
    Rat 2.5 mg CdCl2/kg bw, 7 days, i.p. Increased activity of AChE (92%) in the cerebral cortex Akinyemi et al. (2017)
    Rat 5 mg CdCl2/kg bw, 21 days, p.o. Increased activities of MAO (5.5 times), AChE (70%), BChE (40%) and Na+/K+-ATPase (50%) in the brain Adefegha, Omojokun, et al. (2016)
    Mouse 100 mg Cd/kg bw, 14 days (once a day), p.o. Decreased activity of AChE in the brain (80% in males, 85% in females) Abu-Taweel (2016)
    Rat 2 mg CdCl2/kg bw, 21 days, p.o. Decreased activity of AChE in the hippocampus (56%) Kim et al. (2016)
    Subchronic Rat 5 mg CdCl2/kg bw, 30 days, p.o. Decreased activities of Na+/K+-ATPase (48%), Mg2+-ATPase (68%) and Ca2+-ATPase (56%) in the brain Hao et al. (2015)
    Rat 5 mg CdCl2/kg bw, 28 days, p.o. Decreased activities of Na+/K+-ATPase (42%), Ca2+-ATPase (37%), Mg2+-ATPase (41%) and AChE (71%) in the brain Shagirtha et al. (2011)
    Rat 4.5 mg CdCl2/kg bw, 30 days, i.p. Decreased activity of AChE (39%) in the cortical tissue of the brain Al-Brakati et al. (2020)
    Rat 5 mg CdCl2/kg bw, 28 days, p.o. Decreased activity of AChE (49%) in the frontal cortex Al Omairi et al. (2018)
    Chronic Rat 5 mg CdCl2/kg bw, 8 weeks (2 times a week), p.o. Decreased activity of AChE (68%) in the brain Sadek et al. (2017)
    Rat 1 mg CdCl2/kg diet, 5 months, p.o. Increased activity of AChE in cerebellum (45%) and striatum (44%) Gonçalves et al. (2012)
    Rat 5 mg CdCl2/kg diet, 5 months, p.o. Increased activity of AChE in hypothalamus (63%), cerebellum (32%) and striatum (57%); decreased activity of Na+/K+-ATPase (25%) in cerebral cortex Gonçalves et al. (2012)
    Rat 25 mg CdCl2/kg diet, 5 months, p.o. Increased activity of AChE in hippocampus (25%), hypothalamus (52%), cerebellum (39%) and striatum (56%); decreased activity of Na+/K+-ATPase in cerebellum (27%), hypothalamus (28%) and cerebral cortex (39%) Gonçalves et al. (2012)
    Rat 1 mg Cd/kg bw, 3 months (5 times a week), p.o. Increased activity of AChE in the cerebral cortex (83%), hypothalamus (43%), hippocampus (63%) and striatum (68%); increased activity of NTPDase (23%) and decreased activity of 5′-nucleotidase (50%) in the cerebral cortex da Costa et al. (2017)
    Rat 5 mg CdCl2/kg bw, 8 weeks (2 times a week), p.o. Decreased activity of AChE (68%) in the brain Sadek et al. (2017)
    • Abbreviations: AChE, acetylcholinesterase; BChE, butyrylcholinesterase; bw, body weight; Ca2+-ATPase, calcium adenosine triphosphatase; CdCl2, cadmium chloride; i.g., intragastrically; i.p., intraperitoneally; MAO, monoamine oxidase; Na+/K+-ATPase, sodium–potassium adenosine triphosphatase; Mg2+-ATPase, magnesium adenosine triphosphatase; NTDPase, nucleoside triphosphate phosphohydrolase; p.o., per os.

    The neurotoxic action of Cd may also be associated with the disruption of the activity of AChE (Table 6); however, the results are inconsistent concerning the direction of the change in the activity of this enzyme (Abu-Taweel, 2016; Adefegha, Oboh, et al., 2016; Adefegha, Omojokun, et al., 2016; Akinyemi & Adeniyi, 2018; Akinyemi et al., 2017; Al-Brakati et al., 2020; Al Omairi et al., 2018; da Costa et al., 2017; El-Tarras et al., 2016; Gonçalves et al., 2012; Hao et al., 2015; Kim et al., 2016; Sadek et al., 2017; Shagirtha et al., 2011; own unpublished data). It has been revealed that exposure of rats to this xenobiotic in the dose ranging from 2.5 to 6 mg CdCl2/kg bw for 7–21 days increased the activity of AChE in the brain (Table 6) (Adefegha, Omojokun, et al., 2016; Akinyemi & Adeniyi, 2018; Akinyemi et al., 2017). However, the exposure to Cd in the dose of 2 mg CdCl2/kg bw for 21 days as well as 100 mg Cd/kg bw has been reported to decrease the concentration of this enzyme in the brain tissue (Table 6) (Abu-Taweel, 2016; Kim et al., 2016). Moreover, subchronic exposure to this metal in the dose of 4.5–5 mg CdCl2/kg bw (for 1–2 months) also decreased the concentration of AChE in the brain (Table 6) (Al Omairi et al., 2018; Al-Brakati et al., 2020; Hao et al., 2015; Sadek et al., 2017; Shagirtha et al., 2011). Longer exposure to Cd (3–5 months) in different doses (1 mg Cd/kg bw and 1–25 mg CdCl2/kg diet) increased the concentration of this enzyme in the brain (da Costa et al., 2017; Gonçalves et al., 2012). However, according to our recent study (unpublished data), conducted in a rat model of environmental human exposure to Cd during a lifetime (1 and 5 mg Cd/kg diet for up to 24 months), the long-term low-level treatment resulted in a decrease in the concentration of AChE in the brain tissue. Although different directions of changes in the activity and concentration of AChE were reported due to exposure to Cd, numerous data indicate that subacute, subchronic and chronic intoxication with this element may affect the nervous system via influencing the activity of one of the key enzymes in the nervous tissue such as AChE. However, in the study on zebrafish, no impact of Cd (0.05–1 mM Cd) on the activity of this enzyme in the brain was noted (Senger et al., 2006). Moreover, an increase in the activity of butyrylcholinesterase (BChE) in rat's brain tissue after the exposure to 5 and 6 mg CdCl2/kg bw for 21 days was also reported (Adefegha, Oboh, et al., 2016; Adefegha, Omojokun, et al., 2016). The Cd-induced changes in the activities of AChE and BChE in the brain can result in a disruption of the impulse transmission and consequently may lead to cognitive and memory dysfunction (Adefegha, Omojokun, et al., 2016; Labudda et al., 2011).

    The next mechanism of the neurotoxic action of Cd is its impact on the cell cycle and the processes of apoptosis and necrosis. Cd can be an inductor of the cell cycle arrest (Luo et al., 2021; Ospondpant et al., 2019). It has been shown that this xenobiotic blocks proliferation of astrocytes, induces apoptosis and necrosis of neurons and damages their differentiation (Wang et al., 20142019; Yuan et al., 2013). Cd-induced apoptosis of the neuronal cells can be connected with an increase in the intracellular concentration of Ca2+ and enlarged production of ROS, as well as increased immunoreactivity of caspases, increased expression of proapoptotic Bax and Bak proteins and decreased expression of anti-apoptotic Bcl-2 protein (Chen et al., 2011; Chouit et al., 2021; Kim, Cheon, et al., 2013; Labudda, 2011; Ospondpant et al., 2019; Pulido et al., 2019; Sivaprakasam et al., 2016; Wang, Yang, et al., 2018; Xu et al., 2011; Yuan et al., 2013; Zhang, Zhang, et al., 2017). Moreover, Cd influences cytoskeletal integrity in neurons by inhibiting an expression of cytoskeletal proteins (Ge et al., 2019).

    Cd can exert neurotoxic action also via other mechanisms. This xenobiotic can impair the system of base excision DNA repair (Antoniali et al., 2015). It decreases the levels of adenosine triphosphate (ATP) and influences the activity of 5′-nucleotidase and nucleoside triphosphate phosphohydrolase (NTPDase) in the cerebral cortex (da Costa et al., 2017; Wang, Wang, et al., 2016). Moreover, exposure to this xenobiotic inhibits the secretion of glutamate, damages its transport and induces changes in postsynaptic dopaminergic signalling (Borisova et al., 2011; Ge et al., 2019; Gupta et al., 2018; Kim et al., 2016).

    4 Cd AS A RISK FACTOR FOR THE NERVOUS SYSTEM DAMAGE IN HUMAN

    Nowadays, the general population is continuously exposed to multiple xenobiotics, many of which are neurotoxic (Ball et al., 2019; Mir et al., 2020; Sharma et al., 2020). Because of it, an evaluation of the involvement of the environmental exposure to Cd in the development of abnormalities in the nervous system is difficult. Taking the above into consideration, to assess the possible impact of this xenobiotic on the nervous system, some authors searched for the existence of the relationship between biomarkers of exposure to Cd such as its concentration in the blood and urine and the occurrence or severity of the disease. The concentration of Cd in the urine is the most useful parameter to assess chronic exposure to this metal, whereas its concentration in the blood is used to assess a current intoxication (Bernard, 2016; Satarug, 2018). Available data on the relationship between effects of neurotoxic action of this xenobiotic in children and adults and its concentration in the blood and urine are presented in Figure 4 and reported in further subsections of this chapter. Moreover, in some studies, Cd concentration in different structures of the brain of patients suffering from diseases of the nervous system, compared with the healthy individuals, was also assessed; however, due to difficulties in receiving samples of the nervous tissue for analysis, such data are very limited (Table 7). It is important to emphasize that Cd concentration in various structures of the human brain may be influenced by the co-existence of various compromising factors, including diseases of the nervous system, that modify the permeability of the BBB (Figure 2). Because the entry of Cd into the brain depends on the permeability of the BBB, with increases in neurodegenerative diseases and with age, it is difficult to recognize whether the increased Cd concentration in the brain, noted by some authors in patients with AD, PD or other diseases of the nervous system (Akatsu et al., 2012; Gellein et al., 2003), could be a consequence of these diseases or whether this it contributed to the development of these diseases.

    Details are in the caption following the image
    (A) The relationship between Cd concentration in the blood and neurotoxic effects in children and adults. Children: (1a) learning disorders (Yousef et al., 2013); adults: (2a) higher mortality in Alzheimer's disease (Min & Min, 2016), (2b) amyotrophic lateral sclerosis (Vinceti et al., 1997). (B) the relationship between Cd concentration in the urine and neurotoxic effects in children and adults. Children: (1a) learning difficulties and special education (Ciesielski et al., 2012), (1b ) lower IQ score in boys (Gustin et al., 2018), (1c) lower IQ score (Kippler et al., 2012); adults: (2a) decreased attention/perception score (Ciesielski et al., 2013); pregnant women: (3a) worsening cognitive functions in children (Kippler et al., 2016), (3b) worsening of verbal function, visual perception and IQ score in children (Kippler et al., 2012)
    TABLE 7. The concentration of Cd in the human's brain in different diseases of the nervous system
    Disease Brain structure Cd concentration Reference
    Patients Control group
    Alzheimer's disease Frontal cortex 20 ± 12 ng/g ww* 30 ± 12 ng/g ww Szabo et al. (2016)
    Amygdala 1.0 ± 0.4 μM ww* 0.7 ± 0.4 μM ww Akatsu et al. (2012)
    Hippocampus 1.0 ± 0.5 μM wwNS 0.7 ± 0.5 μM ww Akatsu et al. (2012)
    Superior frontal gyrus 24 ± 11 ng/g ww (left hemisphere)NS 36 ± 44 ng/g ww (left hemisphere) Panayi et al. (2002)
    26 ± 14 ww (right hemisphere)NS 22 ± 13 ww (right hemisphere)
    Superior parietal gyrus 26 ± 19 ng/g ww (left hemisphere)NS 33 ± 27 ng/g ww (left hemisphere) Panayi et al. (2002)
    28 ± 10 ng/g ww (right hemisphere)NS 19 ± 9 ng/g ww (right hemisphere)
    Medial temporal gyrus 30 ± 13 ng/g ww (left hemisphere)NS 22 ± 14 ng/g ww (left hemisphere) Panayi et al. (2002)
    25 ± 10 ng/g ww (right hemisphere)NS 20 ± 9 ng/g ww (right hemisphere)
    Hippocampus 30 ± 12 ng/g ww (left hemisphere)NS 20 ± 12 ng/g ww (left hemisphere) Panayi et al. (2002)
    32 ± 16 ng/g ww (right hemisphere)NS 21 ± 14 ng/g ww (right hemisphere)
    Thalamus 58 ± 34 ng/g ww (left hemisphere)NS 41 ± 29 ng/g ww (left hemisphere) Panayi et al. (2002)
    51 ± 24 ng/g ww (right hemisphere)NS 35 ± 22 ng/g ww (right hemisphere)
    Parkinson's disease White matter 0.06 ± 0.04 μg/g dwNS 0.10 ± 0.07 μg/g dw Gellein et al. (2003)
    Grey matter 0.10 ± 0.07 μg/g dwNS 0.09 ± 0.06 μg/g dw
    Amyotrophic lateral sclerosis White matter 0.23 ± 0.19 μg/g dw* 0.10 ± 0.07 μg/g dw Gellein et al. (2003)
    Grey matter 0.33 ± 0.24 μg/g dw** 0.09 ± 0.06 μg/g dw
    • Note: NS indicates p > 0.05 versus the control group.
    • Abbreviations: dw, dry tissue weight; ww, wet tissue weight.
    • * p < 0.05, **  p < 0.01 versus the control group.
    • **  p < 0.01 versus the control group.

    4.1 AD

    AD is one of the forms of dementia and is characterized by progressive symptoms, including cognitive and behavioural dysfunction (Bakulski et al., 2020; Mir et al., 2020). As AD is irreversible, finding the environmental factors involved in its aetiopathogenesis can be helpful in the development of strategies to prevent this disease (Bakulski et al., 2020; Mir et al., 2020).

    Studies concerning the concentrations of Cd in the blood and urine of patients with AD are very limited. According to Min and Min (2016), the frequency of death in AD patients was almost four times higher in people with the concentrations of Cd in the blood >0.6 μg/L than in those with concentrations ≤0.3 μg/L (Figure 4A). It is important to underline that in the general population of some countries, the concentrations of Cd around 0.6 μg/L and above this value are noted (Table S1). However, in some studies, the differences in the concentration of this heavy metal in the blood between AD patients and healthy people have not been revealed (Basun et al., 1994; Bocca et al., 2005). The study on the population of the United States showed that higher mortality was observed in AD patients with higher concentrations of Cd in the blood and urine (Peng et al., 2017). However, in the analysis done separately in both genders, the association was noted only within the first 12.7 years of the observation (Peng et al., 2017).

    It has been revealed that in patients with AD, Cd accumulates in the amygdala, whereas in the frontal cortex its concentration is lower compared with the healthy people (Table 7) (Akatsu et al., 2012; Szabo et al., 2016). No differences were observed in the concentration of this heavy metal in various brain structures, including the hippocampus, thalamus and some parts of the cortex (Akatsu et al., 2012; Panayi et al., 2002). Moreover, it has been revealed that Cd accumulates in the liver of patients with AD in higher amounts than in healthy people (Lui et al., 1990).

    Basun et al. (1991) have reported lower concentrations of Cd in the cerebrospinal fluid (CSF) in patients with AD compared with the control group, but later studies have not confirmed these results (Gerhardsson et al., 200820092011). Moreover, inconsistent results have been obtained on Cd concentration in the serum and plasma (Arslan et al., 2016; Basun et al., 1991; Bocca et al., 2005; Gerhardsson et al., 2008; Park et al., 2014). However, it is essential to underline that Cd concentration should be assayed in the whole blood because this element occurs in the form bound to erythrocytes, and thus, its concentration measured in the serum or plasma is unreliable. Lower concentration (mean ± standard deviation) of Cd in the nail (0.39 ± 0.25 μg/g of dry tissue in AD vs. 0.73 ± 0.82 μg/g of dry tissue in controls) and hair (0.21 ± 0.36 μg/g of dry tissue in AD vs. 0.31 ± 0.32 μg/g of dry tissue in controls) in patients with AD has also been observed (Koseoglu et al., 2017).

    Based on the available literature data, it can be recognized that the involvement of Cd in the aetiopathogenesis of AD consists in its interaction with Aβ and Aβ1–42 and stimulation of aggregation of Aβ (Huat et al., 2019; Kabir et al., 2021; Mir et al., 2020). Moreover, exposure to Cd results in degeneration of cholinergic neurons of the basal forebrain, which is one of the characteristic changes in AD (del Pino et al., 2014). Cd is also involved in the process of aggregation of Alzheimer's tau fragment R3, intensifies its aggregation induced by heparin and increases phosphorylation of tau protein (Jiang et al., 2007; Wang, Wang, et al., 2016). Moreover, exposure to Cd is connected, mainly in males, with a higher expression of genes related to AD (Krauskopf et al., 2020).

    4.2 PD

    PD is a neurodegenerative disorder characterized by difficulties in movements and maintaining equilibrium (Dhillon et al., 2008; Thau et al., 2021). Both genetic and environmental factors are involved in the aetiopathogenesis of this disease (Gupta et al., 2017). As oxidative stress is involved in the aetiopathogenesis of PD, attention has been paid to metals destroying the oxidative–antioxidative balance, including Cd (Alimonti et al., 2007; Banerjee et al., 2020).

    Although the exposure to Cd results in changes in genes connected with PD, including upregulation of Snca gene connected with the production of α-synuclein which is one of the most characteristic features in PD (Yu et al., 2010), the possible role of this metal in the aetiopathogenesis of this disease is not clear. For the first time, the involvement of Cd in the development of parkinsonism was suggested in 1997 after acute Cd exposure via inhalation (Okuda et al., 1997). The concentration of Cd noted in the patient was 14.9 μg/L in the blood and 47.9 μg/L in the urine (Okuda et al., 1997). In the cohort study in the population of East Texas, history of exposure to Cd has been associated with a tendency to an increased risk of PD (Dhillon et al., 2008). In a prospective analysis of the nurse cohort, there was no correlation between the concentration of Cd in the air (interquartile range: 0.025–0.204 ng/m3) and the occurrence of PD (Palacios et al., 2014).

    It is important to underline that in PD patients, lower Cd concentrations in the blood were noted than in healthy people (Forte et al., 2005; Gupta et al., 2017). In the study by Gupta et al. (2017), the blood concentration of Cd in patients with PD was below the level of detection (LOD; LOD = 0.003 μg/mL) and reached 0.457 ± 0.280 μg/mL in the control group, whereas Forte et al. (2005) detected this element at the level of 0.77 ± 0.32 μg/L in PD patients and 1.06 ± 0.48 μg/L in the control group. The lower concentration of Cd in PD patients can be the result of malnutrition and little exposure to environmental agents (Gupta et al., 2017). To our best knowledge, there are no studies concerning the concentration of Cd in the urine of patients with PD. Because the intensity of exposure to Cd may be estimated based on this element concentration in the urine, such data could help understand its possible role in the aetiopathogenesis of PD.

    Some authors have reported a lack of differences in Cd concentration in CSF (0.04 ± 0.02 ng/mL in patients vs. 0.05 ± 0.03 ng/mL in the control group), white matter and grey matter (Table 7) between PD patients and healthy subjects (Alimonti et al., 2007; Gellein et al., 2003). However, the above studies included a small group of examined people, and because of this, the value of these findings can be limited. Although Forte et al. (2007) did not report differences in the concentration of Cd in the hair of patients with PD (10.6 ± 7.86 ng/g) and the control group (8.44 ± 4.69 ng/g), according to Komatsu et al. (2011), PD patients have higher concentrations of this xenobiotic than healthy counterparts.

    4.3 Cognitive and behavioural deteriorations

    Most of the studies concerning the impact of Cd on behavioural and cognitive functions have been focused on the children population. The concentrations of maternal urinary Cd during the pregnancy higher than 0.8 μg/L were connected with the worsening of 4-year-old children's cognitive functioning (Kippler et al., 2016; Figure 4B). Such concentrations have been obtained only in women who were active tobacco smokers during the pregnancy (Kippler et al., 2016). In another study, the concentration of this metal in the urine of pregnant women (5th to 95th percentile: 0.18–2.0 μg/L, median value: 0.63 μg/L) negatively correlated with verbal function, visual perception and intelligence quotient (IQ) score of children at the age of 5 years (Kippler et al., 2012). Worsening of these functions has been noted for women with the concentration of Cd in the urine >2.0 μg/L when comparing with the ones with the concentration <0.18 μg Cd/L (Kippler et al., 2012; Figure 4B). Moreover, Cd concentration in these children at the age of 5 (5th to 95th percentile: 0.078–0.63 μg/L, median value: 0.22 μg/L) inversely correlated with verbal function and IQ score and at the age of 10 years (range: 0.016–2.6 μg/L, median value: 0.24 μg/L)—with IQ score, with stronger correlation in boys (Gustin et al., 2018; Kippler et al., 2012). It has been observed that children at the age of 5 with this element concentration >0.63 μg/L have lower IQ score compared with the children with this element concentration lower than 0.078 μg/L and boys at the age of 10 with the concentration of Cd within the range 0.3–2.6 μg/L have lower IQ score than boys with the concentration within the range 0.04–0.18 μg/L (Gustin et al., 2018; Kippler et al., 2012; Figure 4B). A negative correlation between the concentration of Cd in the urine (<LOD—0.986 μg/L, 7.439 μg/g creatinine; geometric mean [GM]: 0.221 μg/L, 0.769 μg/g creatinine) and cognitive function (measured with the use of the Wechsler Intelligence Scale for Children — Fourth Edition) was found in boys aged 6–9 years (Rodríguez-Barranco et al., 2014). A similar correlation was not observed in girls (<LOD—1.502 μg Cd/L, 10.074 μg Cd/g creatinine; GM: 0.208 μg Cd/L, 0.725 μg Cd/g creatinine), which can be the result of biological differences between genders (Rodríguez-Barranco et al., 2014). In the study among the Italian children aged 6–12 years, a trend to a negative correlation between Cd concentration in the urine (0.0–1.8 μg/L, median value: 0.4 μg/L) and IQ score was found (Lucchini et al., 2019). Ciesielski et al. (2012) have reported that children with Cd concentration in the urine ranging from 0.1802 to 14.94 μg/L had learning difficulties and special education more frequently than participants with the lower urinary excretion of this toxic element (0.0000–0.0576 μg/L) (Figure 4B). Moreover, a negative correlation between the concentration of Cd in the urine (range: 0.016–2.6 μg/L, median value: 0.24 μg/L) and prosocial behaviour in 10-year-old children was revealed (Gustin et al., 2018).

    In the available literature, there is only one study concerning the dependence between Cd concentration in the blood of children and their cognitive functioning (Yousef et al., 2013). It revealed that children with learning disorders had higher Cd concentration in the blood (0.38 ± 0.34 μg/L) compared with the control group (0.26 ± 0.08 μg/L) (Yousef et al., 2013; Figure 4A). Moreover, it has been observed that an increase in the concentration of Cd in the blood by 0.1 μg/L resulted in a 38.4% increase in the odds ratio of learning disorder (Yousef et al., 2013).

    The negative correlation between Cd concentration in the blood of Korean women measured in the early pregnancy (mean values: 1.49 ± 0.39 μg/L) and visual perception in their children has been observed (Jeong et al., 2015). However, concentrations of Cd determined in the study exceeded the ones noted in the general population of various countries, including Korea (Ahn et al., 2019; Eom et al., 2018; Gać et al., 2017; Ghoochani et al., 2019; Jeong et al., 2015; Kim et al., 2017; Martins et al., 2020; Nisse et al., 2017; Takeda et al., 2017; Tratnik et al., 2019). It has also been revealed that concentration of Cd in the cord blood (range: 0.02–0.78 μg/L) inversely correlated with IQ scores at the age of 4.5 years (Tian et al., 2009). What is important, for the examined group of pregnant women, the only source of Cd was environmental exposure (Tian et al., 2009). In the study conducted in Shanghai, Cd concentration in the cord blood ≥0.37 μg/L was connected with worse neurodevelopment of infants compared with the group with a lower concentration of this toxic element (Yu et al., 2011). Moreover, Sioen et al. (2013) have reported that a twofold increase in the concentration of Cd in the cord blood (median value: 0.22 μg/L) resulted in a 1.53 times increased risk of emotional problems in boys.

    The evidence of the connection between exposure to Cd and cognitive function in the adult population was delivered in the study among workers exposed to this xenobiotic (Hart et al., 1989). Workers with a higher concentration of Cd in the urine had impaired attention, memory and psychomotor speed (Hart et al., 1989). In a more recent study, it has been shown that non-smoking adults non-exposed to Cd occupationally with the concentration of this element in the urine >0.82 μg/L have lower attention/perception scores compared with ones with the concentration <0.19 μg/L (Ciesielski et al., 2013; Figure 4B). Moreover, the inverse correlation between Cd concentration in the urine and attention/perception score values has been found in the examined group (Ciesielski et al., 2013). It is important to underline that the concentrations of Cd in the urine noted in the study by Ciesielski et al. (2013) are comparable with those determined in the general populations in different countries (Table S1).

    Li et al. (2018) have reported that Cd concentration in the blood ranging from 0.24 to 0.56 μg/L negatively correlated with cognitive function in elderly adults in the age of 60–80 years. On the contrary, in the study among the population of the United States aged 60–84 years, no correlation has been shown between the concentration of Cd in the blood (range: 0.2–4.7 μg/L, GM: 0.49 μg/L) and cognitive function (Przybyla et al., 2017). The relationship was also not found in the older population (mean age: 87) (Nordberg et al., 2000).

    4.4 Other effects

    In the available literature, some other effects of the neurotoxic action of Cd have been reported. The study among retired and active workers chronically exposed to Cd (mean exposure duration: 12.6 years) revealed that in the exposed group, symptoms such as peripheral neuropathy, difficulties with maintaining equilibrium and problems with concentration appeared more often than in the unexposed group (Viaene et al., 2000). However, Cd concentration determined in the urine (mean concentration: 4.6 ± 4.1 μg Cd/g creatinine in workers vs. 0.7 ± 0.5 μg Cd/g creatinine in the control group) multiple exceeded the values noted in the general populations of the world. Moreover, increased concentration of Cd in the blood has been observed in patients with brain tumours (concentration in the red blood cells: 0.10 ± 0.27 ng/g in the patients vs. 0.01 ± 0.00 ng/g in the control group), hydrocephalus (concentration in the red blood cells: 0.21 ± 0.18 ng/g in the patients vs. 0.01 ± 0.00 ng/g in the control group) and multiple sclerosis (concentration in the blood: 1.80 ± 0.13 μg/L in the patients vs. 1.47 ± 0.11 μg/L in the control group) (Paknejad et al., 2019; Vujotić et al., 2019).

    The study in patients who suffered from ALS showed that they had a higher concentration of Cd in the CSF (median concentration: 0.156 μg/L) compared with the healthy people (median concentration: 0.062 μg/L) (Roos et al., 2013). On the contrary, another investigation revealed that the concentration of Cd in this biological fluid is lower in people with ALS (median concentration: 0.0359 μg/L) compared with the healthy ones (median concentration: 0.0716 μg/L) (Vinceti et al., 2017).

    In the study by Vinceti et al. (1997), the concentration of Cd (Figure 4a) in the blood of patients with ALS (mean concentration: 1.25 ± 0.42 μg/L) was higher compared with the control group (mean concentration: 0.98 ± 0.3 μg/L); however, the difference was observed only when the individuals with advanced disease were not included in this analysis. The concentrations of Cd noted in this study are higher than those currently observed within the general population of various countries (Table S1). On the contrary, in the study by Bocca et al. (2015), there were no differences in the concentration of Cd in the blood and urine between patients with ALS and healthy controls (median concentration of Cd in ALS patients: 0.85 μg/L in the blood and 0.51 μg/L in the urine; median concentration of Cd in the control group: 0.81 μg/L in the blood and 0.44 μg/L in the urine).

    5 CONCLUSION

    The critical overview of the available literature data on the impact of Cd on the nervous system in humans provided evidence allowing the recognition that current environmental exposure to Cd in developed countries may create a risk of damage to the human's nervous system. This xenobiotic may be recognized as an environmental factor involved in the aetiopathogenesis of neurodegenerative diseases, such as AD and PD, and worsening cognitive and behavioural functioning. It can be assumed that Cd may be dangerous to the nervous system of the adult population at the concentration >0.8 μg/L in the urine and >0.6 μg/L in the blood. At a similar concentration of Cd in the blood (0.53 μg/L) risk of kidney dysfunction, being a critical organ under chronic exposure to this toxic metal has been reported (Lin et al., 2014; Mężyńska & Brzóska, 2018). It is also important to underline that in children Cd can be dangerous to the functioning of the nervous system at lower concentrations (>0.38 μg/L in the blood and >0.1802 μg/L in the urine) than in the adult population, which suggests that greater attention should be paid to the exposure to Cd as the potential cause of these disorders in children. The fact that the nervous system in children may be damaged at lower Cd concentrations in the blood and urine than in adults may be explained, at least partly, by the higher permeability of the BBB. Moreover, the content of this xenobiotic in the brain depends on the co-existence of various factors that influence the structure and function of the BBB, including its permeability, such as other toxic metals, substances of abuse and medicines, and the occurrence of neurodegenerative diseases. It should also be emphasized that although the accumulation of Cd in the brain is much lower compared with its accumulation in other body organs, even a low concentration of this xenobiotic creates a risk of the dysfunction of the nervous system. The potential mechanism of Cd neurotoxicity consists in inducing oxidative stress, disrupting the activity of enzymes essential to the proper functioning of the nervous system and destroying the homoeostasis of bioelements (Ca2+ and Mg2+) in the nervous tissue. Nowadays, it is known that current environmental exposure to Cd may create a threat mainly for the kidney and liver and skeletal and cardiovascular systems, as well as contribute to the development of cancers. The present review shows that the exposure may also lead to destroying the proper function of the nervous system. However, further study is necessary to both explain the mechanism of Cd neurotoxicity and evaluate the critical for the nervous system level of exposure to this xenobiotic. As even low-level exposure to this metal can be dangerous for the functioning of the brain, greater attention of the researchers should be paid to the exposure to Cd and concentration of this element in the blood and urine of patients suffering from neurodegenerative diseases and searching for substances that can perform protective action against the neurotoxic action induced by this xenobiotic.

    CONFLICT OF INTEREST

    The authors declare that they have no conflict of interest.

    AUTHOR CONTRIBUTIONS

    AR and MMB contributed to the conception and visualization of the article. The literature search and the first draft of the manuscript was prepared by AR. AR and MMB commented on previous versions of the manuscript and were involved in writing—review and editing of the manuscript. All authors read and approved the final manuscript.

    DATA AVAILABILITY STATEMENT

    Data sharing not applicable—no new data generated, or the article describes entirely theoretical research.