Early-life lead exposure and neurodevelopmental disorders

Abstract

Lead (Pb²⁺) exposure is a global public health problem of major proportion with an alarming number of children with blood Pb²⁺ levels > 10 >g/dL, twice the current CDC reference level for Pb²⁺ exposure. Mounting evidence from population-based studies suggests an association between chronic early life Pb²⁺ exposure (CELLE) and psychiatric disorders, specifically schizophrenia (SZ). Preclinical studies suggest a common mechanism in the pathophysiology of CELLE and SZ, NMDA receptor hypofunction.

Here we describe human and experimental animal studies providing the evidence for such an association. Further, recent preclinical studies indicate that Pb²⁺-induced changes in neurotransmitter receptors that mediate the action(s) of drugs of abuse are increased in brain regions associated with addiction circuits in adolescence, a period of increased susceptibility to drug use and abuse and expression of psychiatric disease in humans. In summary, the relationship between the global burden of childhood Pb²⁺ exposure and the latent onset of psychiatric disorders and predisposition to drug use requires further investigations in human populations.

1. Environmental lead exposure: A global public health problem

Public health policy implemented in the late 1970s to remove lead (Pb²⁺) from gasoline, paint, and other consumer products has been highly successful in lowering blood Pb²⁺ levels (BLL) of the general US population [1]. Despite these important achievements, and as a result of the legacy of the millions of tons of Pb²⁺ contamination deposited in the global environment from anthropogenic sources, an unacceptable number of children continue to be exposed to Pb²⁺ in many parts of the US, in particular in poor inner-city communities where the legacy of Pb²⁺ contamination continues today [2,3]. Globally, the vast majority of Pb²⁺-intoxicated children live in developing or underdeveloped countries where living conditions are conduits for chronic exposure during and beyond childhood and where monitoring and screening programs for Pb²⁺ exposure oftentimes do not exist. This sad reality is best described in the latest 2020 UNICEF report of children’s Pb²⁺ exposure in the US and around the world entitled: The Toxic Truth-Children’s Exposure to Lead Pollution Undermines a Generation of Future Potential [4]. The ANNEX in this report shows that today, even in the US with a significant Pb²⁺ testing program, the estimates of the number of children with BLL > 10 >g/dL (twice the current CDC blood Pb²⁺ reference value) is 123-269 thousand. Globally, the estimates of the number of children with BLL > 10 >g/dL is 157-574 million. Today, the only measure is primary prevention and there is no proven therapeutic strategy. When BLL are above 40-45 >g/dL, chelation therapy to lower the Pb²⁺ body burden is used but has no impact in improving learning performance [5,6]. Therefore, there is no current recourse for the millions of children with elevated BLL except for removing them from the contaminated environment, but for many, this is not a reality.

A common misconception is that Pb²⁺ exposure is only relevant in a child’s early life, but in fact, in many countries including the US, Pb²⁺ exposure continues into young adulthood. In the US, the prevalence rate of adults with BLL above 10 >g/dL from environmental or occupational exposures is quite significant and much higher in many developing and underdeveloped countries [4]. The current data indicates the magnitude of the problem with untold consequences to children’s neurodevelopment, school performance, and the possibility of psychiatric disease and drug use later in life.

2. Childhood lead exposure and psychiatric disorders

An emerging body of population-based and preclinical studies support an association between developmental Pb²⁺ exposure and mental disorders such as major depression, mood disorders, attention-deficit hyperactivity disorder, and schizophrenia [7–9]. Schizophrenia (SZ) is a prevalent (1% of the world’s population) and devastating psychiatric disorder of unknown etiology with an estimated annual cost of $155.7 billion [10]. There is consensus that SZ is a developmental disorder in which both genes and environment come together to produce a SZ phenotype later in life [11,12]. The clinical expression of SZ typically begins in late adolescence/early adulthood after which lifelong disability ensues [13]. The symptoms of SZ are grouped into positive (hallucinations, delusions, and disorganized thinking), negative (affective flattening, alogia, apathy, avolition, and social withdrawal), and cognitive function deficits, a core feature of the disorder [9]. Cognitive deficits often precede positive symptoms and include deficits in working memory, attention, long-term memory, and cognitive flexibility [14–16] and dictate the severity and course of illness [17].

Population-based studies providing the first association of chronic early life Pb²⁺ exposure (CELLE) and SZ were described by Opler and colleagues [18,19]. Using two different large population-based cohorts, they found that prenatal Pb²⁺ exposure was associated with a significant increase in the risk of SZ later in life. Following these landmark studies, other reports have provided additional support to this association. For example, a study using childhood-shed teeth and laser ablation inductively coupled plasma mass spectrometry showed higher levels of Pb²⁺ in diagnosed SZ subjects relative to controls [20]. They found a positive correlation between CELLE and psychotic experiences in adulthood and a negative correlation with adult IQ [20]. Another study found increased plasma Pb²⁺ levels in newly diagnosed SZ subjects [21]. A multidecade longitudinal study of Pb²⁺-exposed children indicated that higher BLL were associated with greater adult psychopathology and difficult personality traits [22]. Also, assessments on the burden of Pb²⁺ exposure as a risk factor for mental illness estimated that Pb²⁺ exposure accounts for a large portion of the prevalence of mental disorders including SZ [22]. Finally, a recent study found that CELLE was associated with deficits in pre-pulse inhibition of the startle response (PPI), a SZ-endophenotype, in children/adolescents similar in magnitude to those obtained in SZ subjects [7]. Therefore, an increasing number of studies continue to provide evidence of an association between CELLE and SZ.

2.1. NMDA receptor hypofunction: A common mechanism in Chronic Early Life Lead Exposure and Schizophrenia

GABAergic interneurons shape the functional maturation of the cerebral cortex, especially the prefrontal cortex (PFC) [23]. This is particularly relevant during adolescence since this is when PFC exhibits protracted development that defines the maturation of cognitive functions and affective responses in adults [23,24]. Developmental disruption of cortical inhibitory neurons contributes to cognitive deficits in SZ [25–27]. Postmortem studies in the SZ brain indicate the loss of cortical and hippocampal GABAergic interneurons, in particular those containing the calcium-binding protein parvalbumin (PV) [28,29]. Pharmacological, biochemical, and gene deletion studies converge to support hypofunction of the N-methyl-D-aspartate subtype of excitatory amino acid receptors (NMDAR) as a central player in the pathophysiology of SZ [30–32]. NMDAR hypoactivity can mechanistically explain the positive, negative, and cognitive function deficits in SZ at the cellular, network, and behavioral levels [25,26]. NMDAR hypofunction during brain development has been shown to result in the loss of cortical and hippocampal PV+ GABAergic interneurons (PVGI) disrupting the excitatory/inhibitory (E/I) balance, altering network activity and circuit connectivity leading to cognitive deficits [26,27]. NMDAR antagonists decrease levels of the GABA synthesizing enzyme glutamic acid decarboxylase-67 (GAD67) and PV expression in cortical PVGI [33,34]. Further, NMDAR play an important role in the maturation and maintenance of PV and GAD67 protein levels in PVGI [35] via activation of the brain-derived neurotrophic factor (BDNF)-trypomyosin receptor kinase B (TrkB) system [36]. This is consistent with the selective loss of PVGI in the SZ brain [37,38]. Thus, disruption of brain GABAergic circuits resulting from NMDAR hypofunction has emerged as a key player in the pathophysiology of cognitive dysfunction in SZ [26,27].

We became interested in a putative association between CELLE and SZ following two seminal studies by Opler and colleagues [18,39]. Based on these studies, we proposed that an association between CELLE and SZ was based on the ability of Pb²⁺ to produce NMDAR hypofunction [40], the leading hypothesis in SZ pathophysiology. Seminal studies in the early 1990s provided the initial evidence that Pb²⁺ is a potent and selective inhibitor of the NMDAR [41,42]. Subsequent studies showed that CELLE altered the ontogeny of NMDAR subunits [43], disrupting NMDAR-dependent downstream signaling leading to deficits in synaptic plasticity in the form of long-term potentiation (LTP) in the hippocampus (HIPP) and impaired cognitive function [44]. CELLE dysregulates the normal developmental switch of GluN2B subunit-containing NMDARs to GluN2A subunit-containing NMDARs [45,46], an event that is important for brain development and maturation of important inhibitory brain circuits including PVGI [35]. In a review article, we delineated the remarkable similarities at the behavioral, neurochemical, and neuropathological level between CELLE and SZ [9]. We also proposed that based on the NMDAR hypofunction hypothesis of SZ, CELLE should produce the loss of Parvalbumin-positive GABAergic interneurons (PVGI) [9], one of the most consistent pathologies in preclinical animal models of SZ and in SZ subjects. We later showed a highly significant decrease in the number of PVGI in the medial prefrontal cortex (mPFC) and HIPP in CELLE animals [8]. Importantly, in the same publication, we also showed that in the same CELLE animals that exhibited a loss of PVGI in the mPFC and HIPP, they also expressed a hyperactive subcortical dopaminergic system consistent with what is observed in animal models of SZ and in SZ subjects [8]. Therefore, CELLE produces PVGI loss and subcortical dopaminergic system hyperactivity, two important aspects of SZ pathophysiology. Following the landmark studies by Opler and colleagues of an association between CELLE and SZ, an increasing number of human studies continue to provide evidence supporting this association [7,20–22,47]. Consistent with the notion that CELLE may be an environmental risk factor for SZ and PVGI loss is associated with cognitive deficits and may share similar pathophysiological mechanisms, another study showed that a decrease (25%) in PVGI in the mPFC using shRNAi during adolescence reduced local GABAergic transmission to pyramidal cells disrupting excitatory/inhibitory (E/I) balance leading to an impairment in extinction learning of conditioned fear in adult animals [48]. This is remarkably similar to the 35% decrease in PVGI in the mPFC of CELLE rats [8] that also exhibit a deficit in extinction learning of conditioned fear [49].

2.3. Developmental lead exposure and susceptibility to drugs of abuse

The comorbidity of neuropsychiatric disorders and drugs of abuse is high. A meta-analysis including data from epidemiological studies, cohort studies, and clinical studies shows a 42% comorbidity of SZ and substance use disorder (SUD) [50]. SUD-SZ comorbidity reduces the quality of life and increases SZ symptomatology. This includes the use of cannabis, psychostimulants, opioids, and alcohol [50,51]. Data from this meta-analysis also showed that males have a 2 to 3 fold higher risk of comorbidity than females [50].

Bellinger et al. [52] proposed a developmental cascade starting with an early neurotoxic event affecting the individual, consequently altering their neurocognitive development and triggering a myriad of psychological impairments. Examples of this may be externalizing behaviors observed in adolescents exposed to Pb²⁺, including increased impulsivity, criminal behavior, and substance use [53–55]. Data from a multidecade longitudinal study in a Pb²⁺ exposed population [22] suggest an association between long term consequences for adult mental health and childhood BLL. Other evidence suggests a link between CELLE and proclivity to substance abuse and criminal behavior [56–58]. Data from population-based studies have shown a relationship between Pb²⁺ exposure and heroin use in inner-city women [59]. Studies have shown higher BLL in opioid users (children and adults), albeit this could be due to Pb²⁺ contamination of the drug [60,61].

Recent work from our laboratory has provided evidence of the role of CELLE on the brain opioid system, showing increased u-opiod receptor (MOR) levels during the adolescent period in the striatum, nucleus accumbens, basolateral amygdala, and medial thalamus of the rat brain [62]. The MOR plays a key role in opioid use disorders [63] and act as a reinforcer of different drugs of abuse [64]. In addition, the increase on MOR levels present in brain regions involved in reward and seeking behaviors is of special interest given the increased susceptibility in humans to engage in drug-seeking behavior at this age [62]. In summary, evidence from human and animal studies suggest that there is an increased risk for individuals developmentally exposed to Pb²⁺ to be affected later in life with an increased susceptibility to engage in drug use and express psychiatric symptoms (Figure 1).

Figure 1.

Factors influencing health outcomes of Pb²⁺ exposure. Current evidence of childhood Pb²⁺ exposure indicates that the adverse neurodevelopmental outcomes of Pb²⁺ exposure could vary based on the developmental window of exposure, duration of exposure, and magnitude of exposure. This evidence comes from population-based studies, animal studies (in vivo, ex vivo, in vitro). These findings suggest a potential role of Pb²⁺ exposure in the onset of neuropsychiatric disorders and increased susceptibility to drug use and abuse.

3. CONCLUDING REMARKS

Despite the many successes to lower BLL in the United States (US) and many other high-income countries, exposure to Pb²⁺ in early life remains a public health problem in the US. There remains a greater impact on low and middle-income countries due to the higher number of children with increased BLL, producing devastating consequences to mental health [4]. The full impact of Pb²⁺ exposure on the onset of neurodevelopmental disorders is not yet fully understood nor appreciated [65]. Nevertheless, there is increasing evidence that early life Pb²⁺ exposure is a risk factor for psychiatric disorders and substance abuse. Further studies are needed to understand the underlying neurobiology in order to devise putative therapeutic strategies.

HIGHLIGHTS.

• Lead (Pb²⁺) exposure is a public health problem of global proportions, with 157-574 million children estimated to have blood lead levels > 10 >g/dL.

• There is increasing evidence of an association between Pb²⁺ exposure and psychiatric disorders.

• Animal studies provide evidence that Pb²⁺ exposure may also play an important role in proclivity to substance use disorder.