Abstract
Lead (Pb2+), a naturally occurring common heavy metal found in the earth’s crust, replaces other cations in living creatures, disturbing many biological processes such as metal transport, energy metabolism, apoptosis, and cell signalling. Additionally, it has a significant influence on the central nervous system, specifically on the developing brain. It has severe neurotoxic effects on youngsters. Lead can act as a calcium ion replacement, crossing the blood–brain barrier and causing damage in brain areas, resulting in neurological problems. It possesses genotoxic characteristics and disrupts cellular activity. Neurotoxicity is a major problem, especially in the developing central nervous system, where it can cause long-term cognitive, motor, and behavioural deficits. Paediatric lead poisoning is more common, and early detection requires a high level of precision. The molecular processes and cellular effects of lead toxicity are discussed in this chapter. The pathophysiology, aetiology, and epidemiology of lead exposure are also reviewed in this chapter. It also investigates the neuropsychological issues linked with Intelligence Quotient (IQ), memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and effects on mood. The chapter also discusses lead-induced oxidative stress and its consequences. It will provide an in-depth understanding of the neuropsychological effects of lead toxicity at different levels, which will be helpful for its better management and finding remedies for the related toxic effects.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
Lead (Pb) is considered to be a significant and naturally occurring toxic metal among the various heavy metals present in the Earth’s crust. Lead, which has an atomic number of 82 and is derived from the Latin word Plumbum, is a prevalent toxic substance found throughout various locations (Patra et al. 2011). In ancient times, lead was used for several purposes (Maiti et al. 2017). The presence of lead can be identified in both living organisms and non-living surroundings. The increase in anthropogenic activities and vehicle emissions is primarily accountable for the increase in lead concentration within the human body through inhalation, ingestion, and dermal contact. In particular, the liver, spleen, and kidney have been recognised as significant target areas for lead poisoning. Lead in the form of a toxin generates a variety of biochemical, physiological, and behavioural dysfunctions (Bandyopadhyay et al. 2014). Lead is one of the most toxic heavy chemicals to people for humans and has been for thousands of years. Lead makes us sick when it gets into our bodies through food, air, and water because it reacts with biological molecules that contain sulphur, oxygen, or nitrogen (Maiti et al. 2017). Lead poisoning is usually found when the amount of lead in the blood rises. But short-term exposure to lead can cause problems like neurobehavioral and brain damage, memory problems, high blood pressure, and damage to the kidneys. The parts and systems of the body that are most likely to be affected by high levels of lead are the blood, kidney, reproductive, and central nervous systems (Assi et al. 2016). Jalali et al. state that when the amount of malondialdehyde (MDA) increases, the activities of erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPx) increase along with the total number of erythrocytes (Jalali et al. 2017). Rats exposed to lead had a low number of cells, lymphocytes, and neutrophils, leading to microcytic anaemia. Chelation treatment is generally recommended for low levels of lead poisoning that have caused brain damage (encephalopathy). But researchers are still looking at treatments that use less medicine but last longer. An important part of treating chronic diseases is determining how much lead is in the body and what happens when people are exposed to low levels of lead in the surroundings (Singh et al. 2017). Heavy metal lead (Pb) is a common pollution in the environment, and it has been said to cause poisoning in many people (Karri et al. 2016). The detrimental impact of Pb-induced oxidative stress on the Central Nervous System (CNS) is widely acknowledged. Exposure of rodents to Pb has been found to be associated with persistent alterations in brain-derived neuronal factor (BDNF), β-amyloid (Aβ) aggregation, and oxidative damage. These findings pose significant environmental and public health challenges due to their close association with impaired intelligence and growth (Feng et al. 2015; Li et al. 2018).
A research study has shown that developmental exposure to Pb results in an over accumulation of Pb in the hippocampus, which is associated with a decline in cognitive abilities that is directly proportional to the dose of Pb (Wei et al. 2022). It is worth noting that exposure to environmental insults during developmental stages, specifically prepuberty and adolescence, has a substantial influence on neural plasticity and subsequent behaviour in adulthood (Encinas et al. 2006; Sanders et al. 2015). Studies have shown that exposure to Pb during early stages of life in animals such as rodents and primates can lead to cognitive impairment and a subsequent increase in amyloid biomarkers that are relevant to Alzheimer’s disease in later stages of life (Bihaqi et al. 2014a; Liu et al. 2014). The presence of increased apoptotic markers has been reported in conjunction with the aforementioned condition. The issue of childhood lead poisoning persists (Chandramouli et al. 2009).
2 Sources of Lead Exposure
Lead is a naturally occurring heavy metal that is very poisonous. Lead can be found everywhere in nature, but most of it comes from human actions such as mining, making things, and burning fossil fuels. There are three distinct forms of lead, namely metallic lead, inorganic lead, and lead compounds, also known as lead salts, as well as organic lead that contains carbon. Lead in the environment rarely occurs in its elemental state but rather in its + 2 oxidation state (Pb2+) in various ores throughout the earth. Lead has been found in at least 1272 of the 1684 National Priority List (NPL) sites identified by the United States (U.S.) Environmental Protection Agency (EPA) (Gerberding and Falk 2005). Lead is one of the most durable heavy metals in nature. Groundwater, soil, dust from metal ores, brass plumbing fixtures, several industrial activities, folk remedies, burning petroleum, making lead battery, paint industries, and mining processes, contaminating food, and certain herbal products made with lead are all sources of lead in the environment (Fig. 6.1). People are always getting lead from things such as contaminated air, water, earth, house dust, and food, as well as by breathing it in. Lead paints and lead chips are the main and most common ways for children to get too much lead (Patra et al. 2011). Lead has various applications, such as in leaded petrol, paints, ceramics, ammunition, water pipes, solders, hair dye, cosmetics, farm equipment, aeroplanes, shielding for X-ray machines and in the production of corrosion and acid resistant materials utilised in the construction sector (Sanders et al. 2009). Various sources of lead poisoning include the production of ammunition, ceramic glazes, circuit boards, caulking, sheet lead, solder, certain brass and bronze plumbing, radiation shields, intravenous pumps, foetal monitors, as well as specific surgical and military equipment, such as jet turbine engines and military tracking systems, among others (Fig. 6.1). Employees are at an increased risk of being exposed to lead at different construction locations (Levin and Goldberg 2000; Mitra et al. 2017). When taking part in hobbies or activities that increase exposure, kids can be exposed to lead-based paint that is peeling or flaking or weathered powdered paint. Particularly at risk are kids with pica, which is the compulsive, habitual ingestion of non-food substances (Mitra et al. 2017). The severity of the toxic reaction depends on a number of things, such as the dose, the age of the person exposed, the stage of a woman’s life (children, breastfeeding, menopause), the person’s job, the length of time they were exposed, their health and lifestyle, and their nutritional status.
3 Lead Exposure in Humans
Exposure to lead (Pb) is still a major public health issue around the world. Pb is a toxic metal that can be found in the environment because of things like lead mining, battery recycling, and the use of lead petrol. Children and pregnant women are especially vulnerable to the effects of Pb exposure. The quantification of the exposure of Pb and its body burden in human studies is primarily accomplished by measuring the measurement of metal concentration in both blood and bone. There is a lack of consensus regarding the exposure levels required to elicit the initial symptoms of neurotoxicity in individuals who are occupationally exposed. However, the majority experts concur that overt neurotoxic effects can manifest at blood Pb levels of 60 μg/dL whole blood. Consequently, it is recommended that workers maintain a maximum concentration of approximately 40 μg/dL (CDC 2018).
But other studies found a link between exposure to lead and changes in thinking in workers whose blood lead levels were between 20 and 40 g/dL (Barth et al. 2002; Lucchini et al. 2012; Murata et al. 2009). The World Health Organisation says that adults who live in communities should keep the amount of lead in their blood below 10 g/dL. But there does not seem to be a safe amount of exposure to Pb, and levels of 1–3 g/dL have been linked to subtle neurotoxic effects (Kosnett et al. 2007). The concentration of Pb in bone is believed to be a measure of total exposure. It is measured mostly by K-shell X-ray fluorescence spectroscopy in the tibia and patella, which are cortical and trabecular bone, respectively. The half-life of Pb in bone is reported to be different depending on where it is in the body and on factors like age, previous exposure, and other situations that affect bone turnover (Farooqui et al. 2017).
According to a study done in China, children’s mean BLL was 4.71 g/dL, with 41.4% of those having BLLs higher than 5 g/dL (Li et al. 2020).
4 Neuropsychological Effects of Lead Toxicity
Lead exposure has a wide range of adverse effects on cognitive functioning. Prenatal exposure, as assessed by lead levels in umbilical cord blood, has been linked to Cord blood, was associated with worse scores on the Bayley Scales of Infant Development in the sensorimotor and visuomotor subscales (Koller et al. 2004; McMichael et al. 1988). Numerous cross-sectional and longitudinal studies on children have demonstrated that lead exposure reduces children’s overall cognitive functioning, but the majority of these studies examine global measures of intellectual functioning rather than domain-specific effects. Chronic exposure to lead is more detrimental to cognitive function in adults than acute exposure (Bellinger 2004; Koller et al. 2004; Lidsky and Schneider 2003; Needleman 2004). Studies on domain-specific cognitive affects are listed below.
4.1 Intelligence
Most of the time, when children are exposed to lead, their intelligence scores go down. Reviewing paediatric cross-sectional studies on brain problems caused by exposure to lead, it was found that IQ dropped by three points when blood lead levels went from 5 to 20 g/dL and dropped by 5.3 points when blood lead levels went from 5 to 50 g/dL (Winneke et al. 1996). When lead levels in the blood went from 10 to 20 g/dL, there was a pretty consistent link between a drop and a three-point drop (Pocock et al. 1994; Winneke et al. 1996). Based on these results, it seems that exposing someone to lead lowers their intelligence in a way that depends on how much lead they are exposed to. Even though it has not been seen as often in adults as it has in kids, some adults have shown signs of having less intelligence. The Task Group on the Effects of Inorganic Lead of the World Health Organisation’s Programme for Chemical Safety (Joint FAO/WHO Expert Committee on Food Additives 2002). After conducting a comprehensive analysis of the existing literature, it was determined that human intellectual functioning may be negatively affected by blood levels below 25 μg/dL. Furthermore, it was found that for every 10 μg/dL increase in blood lead levels, there is a predicted decrease in IQ of 1–5 points. The findings suggest that there is a correlation between occupational lead exposure and decreased cognitive and intelligence scores in adults, with the effect being dependent on the dosage (Khalil et al. 2009). When researchers first looked at the effects of lead on the brain, they focused on how it affected the brain as a whole. However, more recent research shows that it is important to examine how lead affects the brain in different areas.
4.2 Memory
Several studies have indicated a decrease in learning and memory performance among adults who have been exposed to lead in their occupation. The findings indicate that lead exposure has a more pronounced negative impact on cognitive function in the elderly population, as evidenced by reduced scores in learning and memory tasks, among other cognitive impairments. Specifically, individuals 55 years and above appear to be more vulnerable to the deleterious effects of exposure to lead. Although older adults are particularly vulnerable, research has also observed reduced memory performance in individuals under 55 years of age who have been exposed to elevated levels of lead. Subjects exhibited a decline in their ability to recall verbal and visual information after exposure to lead (Khalil et al. 2009; Stewart and Schwartz 2007). There has been constant evidence of lower visuospatial memory scores, which suggests that lead exposure affects spatial skills and the ability to remember what you see. Lead exposure on the job is also linked to lower visual memory scores, especially a delay in remembering a complex figure (Schwartz et al. 2000). Lead exposure has also been associated with lower verbal memory scores, which affects instant recall, delayed recall, and identification. Chronic contact seems to not only affect both vocal and nonverbal memories, but also to cause them to get worse over time. In this group, the results on both verbal and nonverbal memory tests kept going down over time. This means that long-term contact may cause gradual loss of memory over many years (Mason et al. 2014).
4.3 Processing Speed
Lead poisoning has been shown to slow processing speed, and the results suggest that the link is dose-dependent. People exposed to high amounts of lead took longer to make decisions and respond. For example, significant slowing down of decision-making speed and wider gaps in a detection/reaction time task have been found to be caused by contact (Winneke et al. 1996). These results also revealed slight deficiencies in classification speed and precision during a category search task. Only individuals with blood lead concentrations of 40 g/dL or higher exhibited these deficits. The dose-dependence of neurobehavioral deficits was confirmed by a follow-up study with the same participants and testing battery. However, the primary finding of both studies was a delayed sensory-motor reaction time, which may have artificially hampered overall processing speed (Stollery et al. 1991).
4.4 Executive Functioning and Attention
Several investigations have demonstrated that occupational exposure to lead decreases executive functioning. Impaired executive functioning abilities in switching and inhibition tasks (Trails Making Test B and Stroop Task, respectively) were also observed in a group with a maximum lead exposure of 20 g/g (tibia bone lead measurement). Lower executive functioning scores were also discovered in earlier studies employing comparable assessments and scores (Schwartz et al. 2000, 2005).
5 Cellular Effects of Lead Neurotoxicity
In recent decades, new information about how lead affects cells and how it works has helped us to learn more about its neurotoxicity. Using cellular models of learning and memory, researchers have investigated how lead might cause brain problems. A new study shows that exposure to lead is bad for the Central Nervous System (CNS), that environmental factors make people more sensitive to lead, and that being exposed to lead as a child can cause neurodegeneration as an adult.
As the CNS is the main target of lead poisoning, the brain is the most studied when it comes to lead poisoning. Lead neurotoxicity occurs when the CNS is exposed to enough lead to change how it normally works and cause damage to the CNS. Lead’s direct neurological effects include apoptosis (programmed cell death), excitotoxicity, which affects neurotransmitter storage and release and changes neurotransmitter receptors, mitochondria, second messengers, cerebrovascular endothelial cells, and both astroglia and oligodendroglia. Loss of memory, vision, cognitive and behavioural problems, and brain damage/mental retardation are some of the symptoms that can show up right away or later (Sanders et al. 2009). Although most of the early studies focused on the neurocognitive effects of lead, more recent research has shown that higher exposures are linked to morbidities such as antisocial behaviour, delinquency, and violence. To explain the mechanism of lead toxicity on the CNS, several theories have been put forth (Hwang 2007).
6 Effect of Lead on Signalling Pathways
The first publication pertaining to lead-mediated oxidative stress was released in 1965. The present study revealed that certain metals have the ability to increase the rate of oxidation of crucial fatty acids. The efficacy of lead as a material during that period was reportedly inadequate. Subsequent to a considerable period of time, it was noted that lead was responsible for the escalation in lipid peroxidation, as determined by the analysis of Malondialdehyde (MDA). The lead-induced lipid peroxidation in rat brain was also documented by a number of researchers. A positive correlation was found between elevated lead concentration and increased lipid peroxidation, similar effect was observed in hepatic tissues as well (Shafiq-ur-Rehman 2003). Lead-induced oxidative stress is primarily attributed to cellular membrane and DNA, as well as inhibition of key enzymes such as catalase, GPx, SOD, and G6PD, and non-enzymatic antioxidant molecules such as thiols (GSH) in mammalian organisms (Flora et al. 2008; Valko et al. 2005).
Several studies have suggested that metal-induced toxicity involves a multifactorial mechanism, as illustrated in Fig. 6.3. Multifactorial mechanisms may be linked to various biological processes such as oxidative stress, enzyme inhibition, DNA damage, alterations in gene expression, and phenomena such as adventitious mimicry. The mechanism of metal-induced generation of free radicals, particularly Reactive Oxygen Species (ROS).
The precise mechanisms underlying lead-induced oxidative stress remain unclear, likely due to the limited capacity of lead to undergo rapid valence changes. Lead exhibits a propensity for covalent bonding with sulphydryl groups because of its electron-sharing affinities. The interaction between lead and GSH is crucial for the manifestation of its toxic effects (Hultberg et al. 2001).
In the context of a signaling pathway, lead acts as a calcium mimic and binds to the calmodulin protein (a Ca2+ 134 binding protein) that has been implicated in the induction of lead toxicity. The findings indicate that lead binding exhibits a higher relative affinity compared to calcium (Kirberger et al. 2013), as illustrated in Fig. 6.2. Various mechanisms for lead-mediated oxidative stress have been suggested.
7 Lead-Induced Neurotoxicity and Its Mechanisms of Action
One of the most vulnerable parts of the body to lead is the nervous system. In general, it damages the nervous system, but it affects children’s brains a lot more. Neurotoxicity is also linked to the production of too many free radicals, which can change how the brain works. Lead quickly penetrates the Blood–Brain Barrier (BBB) and replaces calcium ions, disrupting intracellular calcium regulation in brain cells. Long-term lead poisoning in children can cause comas, seizures, and changes in their mental state. Several clinical studies have been conducted on the link between lead poisoning and the way the brain develops and works (Brochin et al. 2008). Blood lead levels are negatively correlated with neurological development and function. Lead-poisoned children exhibited abnormal behaviour such as melancholy, aggression, destruction, social withdrawal, and atypical body movements (Hou et al. 2013; Mărginean et al. 2016).
Neurological differences are mostly caused by the way ions work. When lead replaces calcium ions, it becomes able to cross the BBB at a good rate (Fig. 6.3). After crossing the BBB, lead builds up in astroglial cells with lead-binding proteins. Lead is more dangerous for growing nervous systems because they do not have enough mature astroglial cells. Immature astroglial cells do not have any proteins that bind to lead. Lead can easily harm undeveloped astroglial cells and interfere with the development of myelin sheaths (Wang et al. 2011). Lead is also moved by Divalent Metal Transporter 1 (DMT1), a protein with 12 transmembrane domains that is found in capillary cells. DMT-1’s job is to move essential metals, but it also moves toxic metals that look like important minerals (Moos et al. 2006). Protein Kinase C (PKC) is an enzyme that plays a crucial role in many physiological processes, including cell proliferation and brain development, and can be stimulated by subnanomolar concentrations of lead ions.
8 Lead Affects Movement of Calcium
Lead changes the brain and behaviour in complicated ways that are hard to understand. Still, work on cells and molecules has led to a better understanding of how lead affects how the brain works. The effects of lead on biological processes that rely on calcium are especially important. Calcium is an important ion for neural function, such as cell growth and development, the release of neurotransmitters, and biochemical reactions inside the cell.
Lead and calcium are divalent cations that share similarities in terms of their ionic charge and size. The capacity of lead to imitate or hinder calcium-mediated impacts is fundamental to its biological and behavioural consequences. A less regulated ligand in the human body in comparison to calcium.
A heavy metal that lacks regulation. Lead has the ability to bind to the same sites as calcium and can enter the cell via calcium channels. This results in the displacement, inhibition, substitution, and/or activation of calcium-dependent processes (Bridges and Zalups 2005; Habermann et al. 1983; Kerper and Hinkle 1997).
The widespread occurrence of calcium in cellular signalling and the crucial significance of the spatial and temporal arrangement of calcium signals in cellular operation imply that interference with calcium-dependent mechanisms can result in significant cellular outcomes. This notion is supported by various studies (Berridge et al. 2003; Bootman 2012; Bootman et al. 2001, 2002; Bridges and Zalups 2005). The impact of lead on the calcium dynamics of neurons provides insight into numerous extensive alterations in brain activity and conduct.
9 Effect of Lead on NMDA Receptor
Lead is an antagonist of the N-Methyl-d-aspartate receptor (NMDA-R) that operates in a non-competitive manner.
The N-methyl-d-aspartate receptors (NMDA-Rs) are a type of ionotropic receptor that is stimulated by the neurotransmitter glutamate. These receptors play a crucial role in various physiological processes, such as neural development, neuronal plasticity, learning and memory, and long-term potentiation, which is a physiological manifestation of learning (Cory-Slechta et al. 1997; Gilbert and Lasley 2007; Hubbs-Tait et al. 2005; Nihei and Guilarte 2001).
When glutamate binds to NMDA-Rs, calcium flows in through a ligand-gated ion channel. This can cause an excitatory post-synaptic potential and has a big effect on how neurons work by starting second messenger pathways that depend on calcium. The blocking of postsynaptic NMDA-Rs by lead results in the inhibition of activity-dependent calcium influx. This can subsequently interfere with NMDA receptor-dependent developmental processes, neural plasticity, learning and memory, as well as Long-Term Potentiation (LTP). The induction of LTP is hindered by chronic and developmental exposure to lead across a broad spectrum of concentrations, resulting in a higher threshold. This phenomenon is linked to compromised learning and memory (Lasley et al. 2001; Lasley and Gilbert 2000, 2002; Luo et al. 2011; Nihei and Guilarte 2001). Blocking NMDA receptors or other effects of lead on calcium-dependent processes may have something to do with how well LTP and learning work.
Apoptosis is another thing that happens when NMDA receptors are blocked. This is a type of cell death that is planned and caused by a well-known biological process (Anastasio et al. 2009; Hansen et al. 2004; Léveillé et al. 2010; Lyall et al. 2009; Yuede et al. 2010). During brain growth, apoptosis is usually used to get rid of unwanted links and ‘sculpt’ the brain. Pathological apoptosis, on the other hand, can happen in some situations. Low amounts of lead during development have also been shown to cause apoptosis and mess up brain development in both human and zebrafish models by blocking NMDA receptors (Dou and Zhang 2011; Dribben et al. 2011; Liu et al. 2010).
Due to the important role NMDA receptors play in many neuro and behavioural processes and the fact that lead can block NMDA receptors, knowing how lead affects the brain and behaviour depends on these receptors.
10 Effect of Lead on Calmodulin
Lead also targets calmodulin (CaM), or ‘calcium-modulated protein’, a significant intracellular calcium-activated protein (Heizmann and Hunzlker 1991). Calmodulin is involved in calcium signalling, neurotransmitter receptors, ion channels, and neural plasticity (McCue et al. 2010). Calmodulin possesses four distinct binding sites that are naturally bound by calcium ions. Calmodulin exhibits functional activity upon complete binding of calcium to all four of its sites (Costa 1998).
According to several studies (Fullmer et al. 1985; Habermann et al. 1983; Sandhir and Gill 1994; Shirran and Barran 2009), at levels that are relevant to physiological processes, calmodulin exhibits a higher binding affinity towards lead compared to calcium, thereby leading to the activation of the protein. Upon the occurrence of this event, calmodulin undergoes activation in a manner that is not consistent with normal physiological processes. The signalling of calmodulin undergoes a state of tonic activation and becomes independent of external stimuli. The extensive involvement of calmodulin in calcium signalling implies that uncontrolled activation of calmodulin can result in various outcomes, including but not limited to the disruption of signal transduction that is dependent on calmodulin and interference with calmodulin-mediated learning and memory (Rocha and Trujillo 2019).
11 Effect of Lead on Protein Kinase C
Protein Kinase C (PKC) is an intracellular signalling enzyme that is dependent on calcium and phospholipids and is involved in diverse cellular functions (Markovac and Goldstein 1988). Protein Kinase C (PKC) catalyses the phosphorylation of proteins through the transfer of phosphate groups from Adenosine Triphosphate (ATP). The regulation of cellular growth and differentiation is reliant on the phosphorylation of transport proteins via PKC. The Protein Kinase C (PKC) has been found to be involved in cytoskeletal function and signal transduction (Pears 1995). Additionally, PKC has been observed to have a significant impact on learning and memory, as noted (Van der Zee et al. 1992; Xu et al. 2014).
Lead replaces calcium in the activation of PKC at a clinically meaningful picomolar dose, raising intracellular calcium, and obstructing neurotransmitter release (Goldstein 1993). According to Bouton et al. (2001), lead mimics calcium at the synaptotagmin site and competes for it with higher affinity than calcium. Extended exposure to lead results in elevated PKC activity, which in turn triggers a compensatory reduction in activity, potentially through downregulation or decreased effectiveness of calcium activity.
The significance of PKC in calcium-mediated long-term potentiation (LTP) has been established. Studies have shown that PKC inhibitors, such as polymyxin B, impede the initiation and preservation of calcium-induced LTP (Cheng et al. 1994). The negative impact of lead on cognitive abilities such as learning and memory is believed to be caused, at least partially, by interference with typical PKC operation. Furthermore, the influence of lead on PKC activity has consequences for various cellular processes such as cell division, neural communication, neural plasticity, and cytoskeletal organisation (Bressler et al. 1999) Additionally, it affects cellular proliferation and differentiation (Markovac and Goldstein 1988).
12 Lead as Neurotransmitter Releaser
Typically, the depolarization of neurons results in the activation of voltage-gated calcium channels, thereby facilitating the entry of calcium ions into the presynaptic terminal. Upon calcium influx, a series of enzymes are activated, thereby facilitating the fusion of the synaptic vesicle with the cellular membrane and subsequent liberation of neurotransmitters. Lead has been found to have a converging impact on neurotransmitter release by binding to voltage-gated calcium channels and subsequently decreasing the influx of calcium. Furthermore, it has been observed that lead engages in competition with calcium for the binding sites of various proteins that play a role in the release of neurotransmitters, such as calmodulin, CaM kinase II (CaMKII), and synaptotagmin (Bouton et al. 2001; Kern et al. 2000; Westerink et al. 2002).
Collectively, these measures lead to a decrease in the discharge of neurotransmitters at the presynaptic terminal. The inhibition of neuronal release of glutamate and GABA can be observed at nanomolar concentrations of lead. The perturbation of regular neurotransmitter release can result in diverse outcomes for the brain and conduct, contingent on the particular neurotransmitter and its placement within the brain (Braga et al. 1999).
13 Lead and Neurodegenerative Diseases
Recent studies offer compelling evidence that lead exposure has detrimental impacts on the CNS in both adult and paediatric populations. Lead-induced damage within the brain can result in various neurological disorders, including but not limited to brain damage, mental retardation, behavioural problems, nerve damage, and potential development of Alzheimer’s disease, Parkinson’s disease, and schizophrenia. The prefrontal cerebral cortex, hippocampus, and cerebellum are particularly vulnerable to such damage. These findings suggest the need for further investigation into the potential long-term effects of lead exposure on the brain (Sanders et al. 2009).
13.1 Alzheimer’s Disease (AD)
Numerous research studies have examined the impact of lead exposure on cognitive abilities and IQ in children. However, investigations into developmental lead exposure in non-human primates and rodents have revealed associations with the onset of Alzheimer’s disease during the later stages of life. Alzheimer’s disease is widely recognised as the prevailing neurodegenerative disorder. The condition is distinguished by cognitive decline and dementia, accompanied by brain pathology consisting of proteinaceous plaques composed of Amyloid beta (Aβ). The globus pallidus, dentate gyrus, temporal cortex, and temporal white matter of postmortem human brains affected by Alzheimer’s disease have exhibited significantly elevated levels of lead in comparison to control healthy brains of the same age group, as per the findings of Haraguchi et al. (2001). The exposure to Pb has been found to raise the mRNA of Amyloid Precursor Protein (APP) and the aggregation of Aβ in rats, leading to amyloidogenesis and the deposition of senile plaques. Additionally, in nonhuman primates who were exposed to lead during infancy, there was an upregulation of APPs (Bihaqi et al. 2014a, b; Wu et al. 2008). Exposed mice to lead across the course of different life spans and discovered that there is a window of sensitivity to lead toxicity in the developing brain. Cognitive impairment only occurred in mice exposed to Pb as newborns, not as adults (Bihaqi et al. 2014a). According to Bihaqi et al. (2014a) and Masoud et al. (2016), the exposure of mice to lead during their early life stages results in increased expression of tau protein associated with Alzheimer’s disease and changes in epigenetic markers linked to the development of the same disease (Bihaqi et al. 2014a; Masoud et al. 2016).
The relationship between lead exposure during infancy and AD is being explained by an emerging theory that suggests an epigenetic basis for the increased production of proteins relevant to AD and cognitive decline. Exposures experienced during the foetal or early developmental stages have the potential to induce epigenetic modifications in the brain, thereby resulting in gene reprogramming. According to Schneider et al. (2013), a study was conducted on rats that were exposed to Pb either in utero or in postnatally. The results indicated a reduction in the expression of DNA methyl transferase in the hippocampus of female rats that were exposed to Pb. This suggests that there may be a decrease in DNA methylation, which could lead to the expression of genes that are typically suppressed (Schneider et al. 2013).
The investigation conducted by Schneider involved the examination of gene expression pertaining to DNA methyl transferases, which was carried out at postnatal day (Schneider et al. 2013). On the other hand, a study was conducted by Dosunmu wherein infant mice exposed to Pb were subjected to genome-wide expression and methylation profiling until postnatal day 700. The results showed that a specific group of genes, which are typically expressed in aged mice, were repressed. The aforementioned genes were found to be implicated in the immune response, metal binding, and metabolism. Suppression of their expression resulting from developmental exposure to Pb has been observed to impede the brain’s capacity to counteract stressors associated with ageing (Dosunmu et al. 2012).
13.2 Parkinson’s Disease (PD)
According to research findings, lead has been observed to decrease the production of catecholamine as well as synaptic neurotransmission. The decrease in GABA (gamma-aminobutyric acid) could be a common factor in all human neurodegenerative disorders caused by unusual levels of calcium inside cells (Błaszczyk 2016). The occurrence of oxidative stress resulting from chronic lead intoxication has been verified through the observation of elevated levels of lipid peroxide in the brain and liver of rats. Exposure to lead has been found to diminish dopaminergic neurotransmission through mechanisms such as mitochondrial dysfunction, oxidative stress, and heightened gliofilament expression in astrocytes (Patra et al. 2011).
Lead toxicity poses a greater risk to children through dietary exposure and can result in adverse effects on the nervous system and pica behaviour, as documented in literature (Zeng et al. 2016). The study conducted by Loikkanen et al. provides evidence that lead has an impact on cellular processes through the regulation of calcium and calcium-binding proteins. Additionally, the study suggests that lead affects the release and reuptake of various neurotransmitters. The aforementioned study indicates that it inhibits the acetylcholine and dopamine releases that are dependent on Ca2+ and activity (Loikkanen et al. 1998).
The hippocampus region of the brain is subject to tau hyperphosphorylation and α-synuclein accumulation, which are the primary factors that trigger apoptosis and autophagy. This phenomenon has been extensively studied and documented (Zhang et al. 2012). The study conducted by Rogers et al. revealed that the APP is a significant contributor to lead toxicity via iron regulatory pathways, as observed in human dopaminergic SH-SY5Y neuroblastoma cells.
The involvement of PKC in dopamine transport function and the induction of oxidative stress through PKC activation by lead, leading to neurotoxicity, has been reported (Rogers et al. 2016).
Lead is easily able to cross the BBB and binds to sulfhydryl groups, which changes anti-oxidant enzymes and raises the amount of lipid peroxidation. In the same way, lead poisoning can happen when –ALAD (Delta-aminolevulinic acid dehydratase) is stopped from working and too much of its substrate, –ALA, builds up. –ALA quickly oxidises to make free radicals and release ferrous ions, which start the process of lipid peroxidation (Ashafaq et al. 2016).
14 Conclusion
The neurotoxic effects of lead exposure and its considerable effects on human neuropsychology are discussed here. Pb toxicity can cause the central nervous system to suffer from a variety of negative consequences, altering cognitive functioning. Lead works by a mechanism that interferes with calcium dynamics, which are critical to many cellular activities. Lead obstructs calcium’s ability to regulate itself, which impairs synaptic transmission and neuronal activity. In addition, mounting data point to a possible connection between lead exposure and the emergence of neurodegenerative disorders. An increased risk of neurodegenerative diseases including Alzheimer’s and Parkinson’s has been linked to chronic lead exposure. Complex processes, including oxidative stress, inflammation, protein aggregation, and mitochondrial dysfunction, underlie these correlations. It is crucial for public health to comprehend lead’s neurotoxic effects and how they affect neuropsychology in humans. Reduced lead exposure is essential for preventing neurodegenerative illnesses and long-term cognitive deficits in sensitive populations like children. To reduce the neurotoxic effects of lead on human neuropsychology, more study is required to understand the underlying mechanisms and create efficient preventive, early detection, and intervention measures.
References
Anastasio NC, Xia Y, O’Connor ZR, Johnson KM (2009) Differential role of N-methyl-d-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits. Neuroscience 163(4):1181–1191
Ashafaq M, Tabassum H, Vishnoi S, Salman M, Raisuddin S, Parvez S (2016) Tannic acid alleviates lead acetate-induced neurochemical perturbations in rat brain. Neurosci Lett 617:94–100. https://doi.org/10.1016/j.neulet.2016.02.001
Assi MA, Hezmee MNM, Sabri MYM, Rajion MA (2016) The detrimental effects of lead on human and animal health. Vet World 9(6):660
Bandyopadhyay D, Ghosh D, Chattopadhyay A, Firdaus SB, Ghosh AK, Paul S, Bhowmik D, Mishra S, Dalui K (2014) Lead induced oxidative stress: a health issue of global concern. J Pharm Res 8(9):1198–1207
Barth A, Schaffer A, Osterode W, Winker R, Konnaris C, Valic E, Wolf C, Rüdiger H (2002) Reduced cognitive abilities in lead-exposed men. Int Arch Occup Environ Health 75(6):394–398. https://doi.org/10.1007/s00420-002-0329-1
Bellinger DC (2004) Lead. Pediatrics 113(Supplement_3):1016–1022. https://doi.org/10.1542/peds.113.S3.1016
Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4(7):517–529
Bihaqi SW, Bahmani A, Adem A, Zawia NH (2014a) Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: relevance to AD. Neurotoxicology 44:114–120. https://doi.org/10.1016/j.neuro.2014.06.008
Błaszczyk JW (2016) Parkinson’s disease and neurodegeneration: GABA-collapse hypothesis. Front Neurosci. https://doi.org/10.3389/fnins.2016.00269
Bihaqi SW, Bahmani A, Subaiea GM, Zawia NH (2014b) Infantile exposure to lead and late-age cognitive decline: relevance to AD. Alzheimer’s Dement 10(2):187–195
Bootman MD (2012) Calcium signaling. Cold Spring Harb Perspect Biol 4(7):a011171
Bootman MD, Lipp P, Berridge MJ (2001) The organisation and functions of local Ca2+ signals. J Cell Sci 114(12):2213–2222
Bootman MD, Berridge MJ, Roderick HL (2002) Calcium signalling: more messengers, more channels, more complexity. Curr Biol 12(16):R563–R565
Bouton CM, Frelin LP, Forde CE, Godwin HA, Pevsner J (2001) Synaptotagmin I is a molecular target for lead. J Neurochem 76(6):1724–1735
Braga MF, Pereira EF, Albuquerque EX (1999) Nanomolar concentrations of lead inhibit glutamatergic and GABAergic transmission in hippocampal neurons. Brain Res 826(1):22–34
Bressler J, Kim K, Chakraborti T, Goldstein G (1999) Molecular mechanisms of lead neurotoxicity. Neurochem Res 24:595–600
Bridges CC, Zalups RK (2005) Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204(3):274–308
Brochin R, Leone S, Phillips D, Shepard N, Zisa D, Angerio A (2008) The cellular effect of lead poisoning and its clinical picture. GUJHS 5(2):1–8
CDC (Centers for disease control and prevention) (2018) The national institute for occupational safety and health (NIOSH). Adult blood lead epidemiology and surveillance (ABLES). https://www.cdc.gov/niosh/topics/ables/description
Chandramouli K, Steer CD, Ellis M, Emond AM (2009) Effects of early childhood lead exposure on academic performance and behaviour of school age children. Arch Dis Child 94(11):844–848. https://doi.org/10.1136/adc.2008.149955
Cheng G, Rong X-W, Feng T-P (1994) Block of induction and maintenance of calcium-induced LTP by inhibition of protein kinase C in postsynaptic neuron in hippocampal CA1 region. Brain Res 646(2):230–234
Cory-Slechta DA, McCoy L, Richfield EK (1997) Time course and regional basis of Pb-induced changes in MK-801 binding: reversal by chronic treatment with the dopamine agonist apomorphine but not the D1 agonist SKF-82958. J Neurochem 68(5):2012–2023
Costa LG (1998) Signal transduction in environmental neurotoxicity. Annu Rev Pharmacol Toxicol 38(1):21–43
Dosunmu R, Alashwal H, Zawia NH (2012) Genome-wide expression and methylation profiling in the aged rodent brain due to early-life Pb exposure and its relevance to aging. Mech Ageing Dev 133(6):435–443
Dou C, Zhang J (2011) Effects of lead on neurogenesis during zebrafish embryonic brain development. J Hazard Mater 194:277–282
Dribben WH, Creeley CE, Farber N (2011) Low-level lead exposure triggers neuronal apoptosis in the developing mouse brain. Neurotoxicol Teratol 33(4):473–480
Encinas JM, Vaahtokari A, Enikolopov G (2006) Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci 103(21):8233–8238
Farooqui Z, Bakulski KM, Power MC, Weisskopf MG, Sparrow D, Spiro A, Vokonas PS, Nie LH, Hu H, Park SK (2017) Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: the VA Normative Aging Study. Environ Res 152:102–108. https://doi.org/10.1016/j.envres.2016.10.007
Feng X, Chen A, Zhang Y, Wang J, Shao L, Wei L (2015) Central nervous system toxicity of metallic nanoparticles. Int J Nanomed 10:4321
Flora SJS, Mittal M, Mehta A (2008) Heavy metal induced oxidative stress & its possible reversal by chelation therapy. Indian J Med Res 128(4):501–523
Fullmer CS, Edelstein S, Wasserman RH (1985) Lead-binding properties of intestinal calcium-binding proteins. J Biol Chem 260(11):6816–6819
Gerberding JL, Falk H (2005) Agency for Toxic Substances and Disease Registry justification of appropriation estimates for Appropriations Committees fiscal year 2006
Gilbert ME, Lasley SM (2007) Developmental lead (Pb) exposure reduces the ability of the NMDA antagonist MK-801 to suppress long-term potentiation (LTP) in the rat dentate gyrus, in vivo. Neurotoxicol Teratol 29(3):385–393
Goldstein GW (1993) Evidence that lead acts as a calcium substitute in second messenger metabolism. Neurotoxicology 14(2–3):97–101
Habermann E, Crowell K, Janicki P (1983) Lead and other metals can substitute for Ca2+ in calmodulin. Arch Toxicol 54:61–70
Hansen HH, Briem T, Dzietko M, Sifringer M, Voss A, Rzeski W, Zdzisinska B, Thor F, Heumann R, Stepulak A (2004) Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiol Dis 16(2):440–453
Haraguchi T, Ishizu H, Kawai K, Tanabe Y, Uehira K, Takehisa Y, Terada S, Tsuchiya K, Ikeda K, Kuroda S (2001) Diffuse neurofibrillary tangles with calcification (a form of dementia): X-ray spectrometric evidence of lead accumulation in calcified regions. Neuroreport 12(6):1257–1260. https://doi.org/10.1097/00001756-200105080-00040
Heizmann CW, Hunzlker W (1991) Intracellular calcium-binding proteins: more sites than insights. Trends Biochem Sci 16:98–103
Hou S, Yuan L, Jin P, Ding B, Qin N, Li L, Liu X, Wu Z, Zhao G, Deng Y (2013) A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model 10(1):1–9
Hubbs-Tait L, Nation JR, Krebs NF, Bellinger DC (2005) Neurotoxicants, micronutrients, and social environments: individual and combined effects on children’s development. Psychol Sci Public Interest 6(3):57–121
Hultberg B, Andersson A, Isaksson A (2001) Interaction of metals and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol. Toxicology 156(2–3):93–100
Hwang L (2007) Environmental stressors and violence: lead and polychlorinated biphenyls. Rev Environ Health 22(4):313–328
Jalali SM, Najafzadeh H, Mousavi SM (2017) Comparative effect of silymarin and D-penicillamine on lead induced hemotoxicity and oxidative stress in rat. Iran J Toxicol 11(3):11–18
Joint FAO/WHO Expert Committee on Food Additives (2002) Safety evaluation of certain food additives and contaminants. World Health Organization
Karri V, Schuhmacher M, Kumar V (2016) Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol 48:203–213
Kern M, Wisniewski M, Cabell L, Audesirk G (2000) Inorganic lead and calcium interact positively in activation of calmodulin. Neurotoxicology 21(3):353–363
Kerper LE, Hinkle PM (1997) Cellular uptake of lead is activated by depletion of intracellular calcium stores. J Biol Chem 272(13):8346–8352
Khalil N, Morrow LA, Needleman H, Talbott EO, Wilson JW, Cauley JA (2009) Association of cumulative lead and neurocognitive function in an occupational cohort. Neuropsychology 23(1):10
Kirberger M, Wong HC, Jiang J, Yang JJ (2013) Metal toxicity and opportunistic binding of Pb2+ in proteins. J Inorg Biochem 125:40–49
Koller K, Brown T, Spurgeon A, Levy L (2004) Recent developments in low-level lead exposure and intellectual impairment in children. Environ Health Perspect 112(9):987–994
Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, Hu H, Woolf A (2007) Recommendations for medical management of adult lead exposure. Environ Health Perspect 115(3):463–471. https://doi.org/10.1289/ehp.9784
Lasley SM, Gilbert ME (2000) Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity. Neurotoxicology 21(6):1057–1068
Lasley SM, Gilbert ME (2002) Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicol Sci 66(1):139–147
Lasley SM, Green MC, Gilbert ME (2001) Rat hippocampal NMDA receptor binding as a function of chronic lead exposure level. Neurotoxicol Teratol 23(2):185–189
Léveillé F, Papadia S, Fricker M, Bell KF, Soriano FX, Martel M-A, Puddifoot C, Habel M, Wyllie DJ, Ikonomidou C (2010) Suppression of the intrinsic apoptosis pathway by synaptic activity. J Neurosci 30(7):2623–2635
Levin SM, Goldberg M (2000) Clinical evaluation and management of lead-exposed construction workers. Am J Ind Med 37(1):23–43
Li H, Li H, Li Y, Liu Y, Zhao Z (2018) Blood mercury, arsenic, cadmium, and lead in children with autism spectrum disorder. Biol Trace Elem Res 181(1):31–37. https://doi.org/10.1007/s12011-017-1002-6
Li M-M, Gao Z-Y, Dong C-Y, Wu M-Q, Yan J, Cao J, Ma W-J, Wang J, Gong Y-L, Xu J, Cai S-Z, Chen J-Y, Xu S-Q, Tong S, Tang D, Zhang J, Yan C-H (2020) Contemporary blood lead levels of children aged 0–84 months in China: a national cross-sectional study. Environ Int 134:105288. https://doi.org/10.1016/j.envint.2019.105288
Lidsky TI, Schneider JS (2003) Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126(1):5–19
Liu J, Han D, Li Y, Zheng L, Gu C, Piao Z, Au WW, Xu X, Huo X (2010) Lead affects apoptosis and related gene XIAP and Smac expression in the hippocampus of developing rats. Neurochem Res 35:473–479
Liu J, Chen L, Cui H, Zhang J, Zhang L, Su C-Y (2014) Applications of metal–organic frameworks in heterogeneous supramolecular catalysis. Chem Soc Rev 43(16):6011–6061. https://doi.org/10.1039/C4CS00094C
Loikkanen JJ, Naarala J, Savolainen KM (1998) Modification of glutamate-induced oxidative stress by lead: the role of extracellular calcium. Free Radical Biol Med 24(2):377–384. https://doi.org/10.1016/S0891-5849(97)00219-0
Lucchini RG, Zoni S, Guazzetti S, Bontempi E, Micheletti S, Broberg K, Parrinello G, Smith DR (2012) Inverse association of intellectual function with very low blood lead but not with manganese exposure in Italian adolescents. Environ Res 118:65–71. https://doi.org/10.1016/j.envres.2012.08.003
Luo Y, Zhu D-M, Ruan D-Y (2011) Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus. Toxicology 289(1):45–51
Lyall A, Swanson J, Liu C, Blumenthal TD, Turner CP (2009) Neonatal exposure to MK801 promotes prepulse-induced delay in startle response time in adult rats. Exp Brain Res 197:215–222
Maiti S, Acharyya N, Ghosh TK, Ali SS, Manna E, Nazmeen A, Sinha NK (2017) Green tea (Camellia sinensis) protects against arsenic neurotoxicity via antioxidative mechanism and activation of superoxide dismutase activity. Cent Nerv Syst Agents Med Chem (Curr Med Chem Cent Nerv Syst Agents) 17(3):187–195
Mărginean CO, Meliţ LE, Moldovan H, Lupu VV, Mărginean MO (2016) Lead poisoning in a 16-year-old girl: a case report and a review of the literature (CARE compliant). Medicine 95(38)
Markovac J, Goldstein GW (1988) Picomolar concentrations of lead stimulate brain protein kinase C. Nature 334(6177):71–73
Mason LH, Harp JP, Han DY (2014) Pb neurotoxicity: neuropsychological effects of lead toxicity. BioMed Res Int 2014
Masoud AM, Bihaqi SW, Machan JT, Zawia NH, Renehan WE (2016) Early-life exposure to lead (Pb) alters the expression of microRNA that target proteins associated with Alzheimer’s disease. J Alzheimer’s Dis 51(4):1257–1264
McCue HV, Haynes LP, Burgoyne RD (2010) The diversity of calcium sensor proteins in the regulation of neuronal function. Cold Spring Harb Perspect Biol 2(8):a004085
McMichael AJ, Baghurst PA, Wigg NR, Vimpani GV, Robertson EF, Roberts RJ (1988) Port Pirie Cohort Study: environmental exposure to lead and children’s abilities at the age of four years. N Engl J Med 319(8):468–475
Mitra P, Sharma S, Purohit P, Sharma P (2017) Clinical and molecular aspects of lead toxicity: an update. Crit Rev Clin Lab Sci 54(7–8):506–528
Moos T, Skjoerringe T, Gosk S, Morgan EH (2006) Brain capillary endothelial cells mediate iron transport into the brain by segregating iron from transferrin without the involvement of divalent metal transporter 1. J Neurochem 98(6):1946–1958
Murata K, Iwata T, Dakeishi M, Karita K (2009) Lead toxicity: does the critical level of lead resulting in adverse effects differ between adults and children? J Occup Health 51(1):1–12. https://doi.org/10.1539/joh.K8003
Needleman H (2004) Lead poisoning. Annu Rev Med 55:209–222
Nihei MK, Guilarte TR (2001) Molecular changes in glutamatergic synapses induced by Pb2+: association with deficits of LTP and spatial learning. Neurotoxicology 22(5):635–643
Patra RC, Rautray AK, Swarup D (2011) Oxidative stress in lead and cadmium toxicity and its amelioration. Vet Med Int 2011:1–9. https://doi.org/10.4061/2011/457327
Pears C (1995) Structure and function of the protein kinase C gene family. J Biosci 20:311–332
Pocock SJ, Smith M, Baghurst P (1994) Environmental lead and children’s intelligence: a systematic review of the epidemiological evidence. BMJ 309(6963):1189–1197
Rocha A, Trujillo KA (2019) Neurotoxicity of low-level lead exposure: history, mechanisms of action, and behavioral effects in humans and preclinical models. Neurotoxicology 73:58–80. https://doi.org/10.1016/j.neuro.2019.02.021
Rogers JT, Venkataramani V, Washburn C, Liu Y, Tummala V, Jiang H, Smith A, Cahill CM (2016) A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity. J Neurochem 138(3):479–494. https://doi.org/10.1111/jnc.13671
Sanders T, Liu Y, Buchner V, Tchounwou PB (2009) Neurotoxic effects and biomarkers of lead exposure: a review. Rev Environ Health 24(1):15–46
Sanders AP, Claus Henn B, Wright RO (2015) Perinatal and childhood exposure to cadmium, manganese, and metal mixtures and effects on cognition and behavior: a review of recent literature. Curr Environ Health Rep 2(3):284–294. https://doi.org/10.1007/s40572-015-0058-8
Sandhir R, Gill KD (1994) Calmodulin and cAMP dependent synaptic vesicle protein phosphorylation in rat cortex following lead exposure. Int J Biochem 26(12):1383–1389. https://doi.org/10.1016/0020-711X(94)90181-3
Schneider JS, Kidd SK, Anderson DW (2013) Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Toxicol Lett 217(1):75–81
Schwartz BS, Stewart WF, Bolla KI, Simon D, Bandeen-Roche K, Gordon B, Links JM, Todd AC (2000) Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology 55(8):1144–1150
Schwartz BS, Lee B-K, Bandeen-Roche K, Stewart W, Bolla K, Links J, Weaver V, Todd A (2005) Occupational lead exposure and longitudinal decline in neurobehavioral test scores. Epidemiology 106–113
Shafiq-ur-Rehman (2003) Lead-exposed increase in movement behavior and brain lipid peroxidation in fish. J Environ Sci Health Part A 38(4):631–643
Shirran SL, Barran PE (2009) The use of ESI-MS to probe the binding of divalent cations to calmodulin. J Am Soc Mass Spectrom 20(6):1159–1171. https://doi.org/10.1016/j.jasms.2009.02.008
Singh N, Gupta VK, Kumar A, Sharma B (2017) Synergistic effects of heavy metals and pesticides in living systems. Front Chem 5:70
Stewart WF, Schwartz BS (2007) Effects of lead on the adult brain: a 15-year exploration. Am J Ind Med 50(10):729–739
Stollery BT, Broadbent DE, Banks HA, Lee WR (1991) Short term prospective study of cognitive functioning in lead workers. Occup Environ Med 48(11):739–749
Valko M, Morris H, Cronin MTD (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12(10):1161–1208
Van der Zee EA, Compaan JC, De Boer M, Luiten PG (1992) Changes in PKC gamma immunoreactivity in mouse hippocampus induced by spatial discrimination learning. J Neurosci 12(12):4808–4815
Wang L, Xu T, Lei W, Liu D, Li Y, Xuan R, Ma J (2011) Cadmium-induced oxidative stress and apoptotic changes in the testis of freshwater crab, Sinopotamon henanense. PLoS ONE 6(11):e27853
Wei Z, Wei M, Yang X, Xu Y, Gao S, Ren K (2022) Synaptic secretion and beyond: targeting synapse and neurotransmitters to treat neurodegenerative diseases. Oxid Med Cell Longev 2022
Westerink RH, Klompmakers AA, Westenberg HG, Vijverberg HP (2002) Signaling pathways involved in Ca2+- and Pb2+-induced vesicular catecholamine release from rat PC12 cells. Brain Res 957(1):25–36
Winneke G, Lilienthal H, Krämer U (1996) The neurobehavioural toxicology and teratology of lead. In: Toxicology—from cells to man: proceedings of the 1995 EUROTOX congress meeting held in Prague, Czech Republic, 27–30 Aug 1995, pp 57–70
Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D (2008) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28(1):3–9
Xu C, Liu Q-Y, Alkon DL (2014) PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons. Neuroscience 268:75–86
Yuede CM, Wozniak DF, Creeley CE, Taylor GT, Olney JW, Farber NB (2010) Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain. PLoS ONE 5(6):e11374. https://doi.org/10.1371/journal.pone.0011374
Zeng X, Xu X, Boezen HM, Huo X (2016) Children with health impairments by heavy metals in an e-waste recycling area. Chemosphere 148:408–415. https://doi.org/10.1016/j.chemosphere.2015.10.078
Zhang J, Cai T, Zhao F, Yao T, Chen Y, Liu X, Luo W, Chen J (2012) The role of α-synuclein and tau hyperphosphorylation-mediated autophagy and apoptosis in lead-induced learning and memory injury. Int J Biol Sci 8(7):935–944. https://doi.org/10.7150/ijbs.4499
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Gudadhe, S., Singh, S.K., Ahsan, J. (2024). Cellular and Neurological Effects of Lead (Pb) Toxicity. In: Kumar, N., Jha, A.K. (eds) Lead Toxicity Mitigation: Sustainable Nexus Approaches. Environmental Contamination Remediation and Management. Springer, Cham. https://doi.org/10.1007/978-3-031-46146-0_6
Download citation
DOI: https://doi.org/10.1007/978-3-031-46146-0_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-46145-3
Online ISBN: 978-3-031-46146-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)