REVIEW URRENT C OPINION

Environmental exposure to metals, neurodevelopment, and psychosis Amirhossein Modabbernia a,b, Manish Arora c, and Abraham Reichenberg a,b,c,d

Purpose of review This article presents a new hypothesis about the possible relation between early life exposure to metals and psychosis. We review limitations of available research, and discuss novel approaches to overcome previous methodological barriers. Recent findings Mechanistic studies suggest a possible association between excess lead, manganese, cadmium, arsenic, or copper, and zinc deficiency, and several biochemical disturbances related to psychosis, such as altered neurotransmitters levels, excitotoxicity, and inflammation. Furthermore, studies suggest that some metals (lead, manganese, cadmium excess, and zinc deficiency) are associated with schizophrenia or psychosisrelated phenotype. However, previous studies had multiple methodological limitations. Importantly, metal exposure was often measured after disease development and seldom determined during critical developmental periods. Most studies fell short of depicting the exact timing of exposure and the change in exposure over time. Here, we propose several methods to overcome these methodological limitations. Summary There is a plausible role of early life exposure to metals in the cause of psychosis. Owing to methodological limitations in exposure measurement, this has not been well characterized. Considering the wide exposure to metals and the high cost of psychosis to society, this hypothesis should be rigorously examined. Keywords laser ablation-inductively coupled plasma-mass spectrometry, metal, psychosis, schizophrenia, tooth

INTRODUCTION Psychotic disorders typically emerge in late adolescence or early adulthood and are characterized by altered perception, changes in the form and content of thoughts, social and emotional deficits, and cognitive dysfunction. There is strong evidence that both genetic and environmental factors play important roles in the cause of psychotic disorders [1,2]. The largest study to date, using populationbased information on siblings and cousins, has found that environmental factors are responsible for one third of the risk for psychosis [3]. Evidence strongly suggests that psychosis is a neurodevelopmental disorder that starts in utero but remains latent until late adolescence or early adult life. According to the neurodevelopmental model, psychosis is the behavioral manifestation of abnormal brain development and occurs as the result of a combination of genetic and environmental factors. Current etiological models suggest that early life

environmental factors, such as birth complications, social adversities, and early nutritional deficiency, are particularly important [4]. However, fetuses and young children are exposed to many environmental hazards, and for most of those hazards, their effect on the risk of psychosis has scarcely been characterized.

a

Department of Psychiatry, bSeaver Center for Autism Research and Treatment, cDepartment of Preventive Medicine and dFriedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA Correspondence to Amirhossein Modabbernia, MD, Department of Psychiatry and Preventive Medicine, Seaver Autism Center, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA. E-mail: [email protected] Curr Opin Pediatr 2016, 28:243–249 DOI:10.1097/MOP.0000000000000332

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Therapeutics and toxicology

KEY POINTS
Mechanistic studies suggest that excessive exposure to some metals (lead, manganese, arsenic, and cadmium), as well as a deficiency of others (zinc), might mimic biochemical and phenotypic manifestations of psychosis.
Because psychosis is a neurodevelopmental phenomenon, studies of environmental exposure to metals should focus on neurodevelopmental period.
Previous studies were limited in determining the exact timing of exposure, the changes in exposure over time, and measuring exposure during critical neurodevelopmental period.
Tooth acts as a chemical repository where many metals will accumulate, leading researchers to use this tissue to estimate cumulative metal exposure.
Laser ablation technology can be used to generate weekly metal-exposure profiles pre and postnatally.

METALS AS ENVIRONMENTAL RISK FACTORS FOR PSYCHOSIS Metals and elemental minerals have long been known to have toxic, and in some cases, nutritive effects at different doses. Many reports have identified fetal and early childhood exposure to metals as being particularly relevant to later neurodevelopmental phenotypes [5 ,6]. The current review focuses on six metals that mechanistically are the most relevant to psychosis (namely lead, copper, cadmium, manganese, arsenic, and zinc) and their possible mechanisms of action [7,8 ,9–13,14 ,15–25]. We will also review the limitations of the current research, challenges for environmental research on psychotic disorders, and discuss an innovative approach to overcome previous methodological barriers. &&

&

&

Lead (Pb) Pb is efficiently transferred from mother to fetus, and its well established neurotoxicity makes it a paradigm metal to study. Exposure to Pb during development can result in significant behavioral and cognitive impairments in childhood, and the effects can persist into adult life [26,27]. Needleman et al. [28] showed that Pb exposure was associated with lower IQ, poorer working memory and attention, and behavioral problems in children. Subsequent studies confirmed the relationship between Pb exposure and cognitive and behavioral functioning [5 ,6]. Pb and schizophrenia show multiple parallel biological and psychological features [24] (Table 1). In &&

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addition to impaired cognition, there are analogous abnormalities in gray and white matter and disrupted dopamine neurotransmission [24]. Recent evidence suggests that cognitive and behavioral effects of Pb are also mediated through N-methylD-aspartate receptor (NMDAR) hypofunction, which is associated with schizophrenia [24]. According to a recent study, Pb exposure leads to selective loss of parvalbumin-positive GABAergic interneuron (PVGI), which subsequently causes subcortical dopaminergic hyperactivity, similar to what is seen in schizophrenia [29 ]. Opler et al. [30,31] measured levels of delta aminolevulinic acid (d-ALA), a marker of Pb exposure, in archived maternal serum of women whose offspring were diagnosed with schizophrenia as adults and found that higher d-ALA levels were associated with higher risk of schizophrenia in the offspring. Although these findings are consistent with the hypothesis that Pb increases psychosis risk and are related to psychosis-related phenotypes, the studies did not characterize the specific timing of exposure, and lacked a direct measure of fetal exposure. &&

Copper (Cu) Cu is an essential nutritive element and an integral component of several biological pathways, including neurotransmitter synthesis, antioxidant activity, and oxidative phosphorylation [32]. Cu excess or deficiency can lead to human disease. Genetically based excessive Cu accumulation, known as Wilson’s disease, can cause significant cognitive dysfunction, behavioral disturbances, and psychosis, often misdiagnosed as schizophrenia [33,34]. Despite the evidence of a potential association between Cu exposure and psychotic disorders, few studies have directly studied such a link (Table 1). Recent evidence suggests that high Cu levels in the sera of healthy individuals might be associated with cognitive decline [35]. Moreover, hair Cu levels were higher in patients with schizophrenia than controls [36]. Cu excess likely impairs neuropsychological function by disrupting neurotransmission and inducing mitochondrial dysfunction [37]. Conversely, a recent study of blood Cu levels suggested an inverse association between Cu levels and risk of schizophrenia [38 ]. &&

Cadmium (Cd) Cd is another neurotoxin that is widespread in the environment. The main sources of Cd exposure in humans are industrial pollution and cigarette smoke. Interestingly, it has been shown that maternal smoking during pregnancy increases the Volume 28
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Metals, neurodevelopment, and psychosis Modabbernia et al. Table 1. Pathophysiological similarities between exposure to metals and psychosis Findings in schizophrenia [58,59]

Pb

Cd

As

Mn

Cu

Zn (deficiency)

IQ

þ

þ

þ

þ

þ

þ

Working memory

þ

þ

þ

þ

þ

þ

Attention

þ

þ

þ

þ

þ

þ

Processing speed

þ

N

þ

þ

þ

N

[5 ,6]

[50,60,61 ]

[5 ,6,60]

[60,62]

[33,35,63]

[64,65]

Dopamine

þ

þ

þ

þ

þ

þ

Serotonin

þ

þ

þ

þ

þ

þ

Core neuropsychological dysfunctions

References

&&

&&

&&

Core neurotransmitter disturbances

Glutamate References Clinical evidence of association with psychosis References

þ

þ

þ

þ

þ

þ

[20,66,67]

[68–70]

[71,72]

[73–75]

[76]

[77–79]

þ

þ

þ

þ

þ

þ

[30,31]

[36,80]

[81]

[44,45]

[36,82]

[36]

IQ, intelligence quotient; N, no evidence.

risk of schizophrenia [39]. Cd causes oxidative stress, induces apoptosis, and interferes with Zn and calcium-dependent neuronal processes [40]. Moreover, Cd appears to affect the metabolism and release of neurotransmitters (e.g., dopamine and serotonin) [40]. Several studies have shown neurobehavioral disturbances, impaired attention, and memories in individuals exposed to Cd (Table 1). Elevated levels of Cd were found in hair samples of patients with schizophrenia [36].

&&

processing speed, and memory [5 ,6]. Similar to Pb, As crosses the placenta readily. The neurotoxic effects of As are thought to be mediated through enzyme inactivation and interference with cytoskeletal proteins [49]. An important aspect of As neurotoxicity is its interaction with other metals. A pilot study has shown that As and Mn interaction predicted deficits in children’s general intelligence scores, particularly verbal IQ scores [50], whereas a larger study did not confirm such interaction [51] (Table 1).

Manganese (Mn) Mn is an essential element at low doses but is neurotoxic at higher levels and crosses the placenta to reach the fetus. Maternal levels of Mn increase markedly during pregnancy, peaking in the third trimester [41,42]. Excessive exposure to Mn has been associated with reduced educational achievement, behavioral problems, decreased IQ, and frontal lobe abnormalities [43]. Psychosis after occupational Mn exposure is a well-known toxicological entity [44,45] and higher Mn levels have been observed in the blood of patients with schizophrenia compared with controls [38 ] (Table 1). &&

Arsenic (As) As is one of the most hazardous environmental toxicants [46] and has multiple exposure routes. Studies of 6 to 10-year-old children from Bangladesh showed an inverse association between cognitive function and As levels in the water [47,48], and other studies reported links between urine or blood As measurements and impaired attention,

Zinc (Zn) Zn is nutritive at low doses and toxic at high doses [52]. Zn deficiency has long been known to adversely impact neurodevelopment, but the effects of excess Zn on perinatal neurodevelopment are not well studied. Animal models have shown that Zn supplementation can mitigate the effects of Pb, As, and Cd toxicity [53–56]. Although data on the association between high or low Zn and psychosis are scarce, one study found lower Zn levels in the hair of patients with schizophrenia compared with controls [36] (Table 1). Zinc finger proteins are key transcriptional elements that regulate the cellular response to metal toxicity, among other processes. Animal studies found that excess Zn is involved in neuronal injury observed in cerebral ischemia, epilepsy, and brain trauma [52]. Toxic Zn accumulation can result from either trans-synaptic Zn movement or mobilization from intracellular sites, such as Zn flux through receptor-associated calcium channels, voltage-sensitive calcium channels, or Zn-sensitive membrane transporters [57].

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POTENTIAL BIOLOGICAL MECHANISMS Metals might affect neural function by causing inflammation in the brain [7,8 ]. Importantly, early-life inflammation has been suggested as a common mediator of several environmental risk factors for psychosis such as chemicals, infection, and social stress [9–13,14 ], all of which augment inflammation. Other risk factors for psychosis, including preterm birth, maternal diabetes, and maternal smoking have also been linked to inflammation [15–18]. Further support for the idea that inflammation contributes to psychosis risk are the elevated levels of C-reactive protein, interleukin-8, and tumor necrosis factor-a reported in mothers whose offspring develop psychosis as adults [10,13,14 ]. Metals are also drivers of oxidative stress, by catalyzing redox reactions (e.g., Fenton reaction), replacing cofactors in enzymatic reactions, or binding to sulfhydryl groups, thereby inactivating antioxidant enzymes [19]. Oxidative stress during discrete windows of susceptibility might be another potential mechanism to understand the relationship between metal exposure and the development of psychosis-related processes. Metals such as Pb and Mn can also lead to brain abnormalities through excitotoxic mechanisms that damage neuronal and glial populations or by disrupting the development, assembly, and function of NMDARs [20]. Glutamate, an excitatory neurotransmitter, is the primary endogenous agonist for the NMDAR system [21]. Reduced Glutamate transmission is considered crucial for psychosis [22] and metals, in particular lead, blocks excitation via inhibition of its calcium voltage gated channel or by impeding the normal NMDAR assembly [20,23–25]. &

&

&

LIMITATIONS OF THE CURRENT STUDIES Although many studies have found adverse early neurodevelopmental outcomes associated with one or more of metals, the very few studies that have examined them in relation to later developmental outcome (such as psychosis) have several important methodological limitations. Importantly, metal exposure is mostly measured after disease development and seldom during critical developmental periods. Most studies relied on samples that do not reflect the exact timing of exposure during the high-risk developmental period, and fell short of depicting the change in exposure over time. In addition, most samples studied are not representative of the population and have limited sample size, which limits their generalizability and increases the risk of selection bias. Furthermore, 246

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various metals often interact with each other, and any analysis of metal exposure must take these interactions into considerations. With these limitations, studies to date have been unable to clearly delineate the role of metal exposure in psychosis. Taken together, these limitations dictate the need to employ new methods for the measurement of early life metal exposure.

CHALLENGES FOR RESEARCH ON EARLY LIFE ENVIRONMENTAL EXPOSURE AND PSYCHOSIS Although the neurodevelopmental model of schizophrenia postulates that events taking place in pregnancy and early life play a significant etiological role, the prevalence of schizophrenia and related disorders (1–3%), coupled with the fact that the incidence of schizophrenia peaks in early adult life, make research on early life environmental exposures a substantial challenge. A rigorous study would require a large sample to be followed for 3 decades and for biological samples to be stored throughout this period. One way to overcome this barrier is to use existing cohort studies, initially designed to study other hypotheses and outcomes, and to capitalize on the availability of long follow-ups and originally collected bio-samples. Although such an approach is cost-effective and has been applied [10–12], the ranges of exposures that can be measured, and the ability to map timing of exposure, are limited. Traits that form a continuum with psychosis and can be measured in the general population could be studied. Subclinical psychotic experiences in childhood have been associated with later psychotic disorders, and share risk factors with psychotic illness, including factors operating early in life such as preterm birth. Because psychotic experiences can be measured in general population samples, and first manifest earlier in life they allow for smaller samples to be followed for shorter periods. However, such studies do not provide a direct test of the hypothesized role of exposures in schizophrenia. Alternatively, if the history of exposure could be reliably reconstructed this could offer a way to overcome the substantial barrier to research. Although self-report on the history of exposures, as well as a review of medical histories, have been used to collect individual-level exposure data, these methods are prone to recall and other biases, limiting their utility and generalizability. An objective, reliable methodology would be superior and present a unique opportunity. Volume 28
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Metals, neurodevelopment, and psychosis Modabbernia et al.

TOOTH AS A BIOMARKER OF METAL EXPOSURE The skeletal compartment, including teeth, acts as a chemical repository. Many metals (Pb, Mn, Cd, Zn, etc.) accumulate in teeth, leading researchers to use this tissue to estimate cumulative metal exposure. Notably, in two studies, Pb levels in dentine fragments showed stronger associations with health outcomes than bone Pb concentrations (a validated marker of cumulative Pb exposure), suggesting that teeth may accumulate metals more proficiently than bone [83,84]. For example, Gulson and Wilson [85] measured stable Pb isotopes in enamel to estimate prenatal exposure. A brief overview of the embryology of tooth formation merits consideration. Between the 14th and 19th week of intrauterine development, the tooth germ enters the advanced bell stage characterized by the appearance of enamel and dentine at the future dentine–enamel junction on the cusp tip [86]. Subsequently, enamel and dentine deposition occurs in a rhythmic manner, forming incremental lines, akin to growth rings of a tree. At birth, an accentuated incremental line, called the ‘neonatal’ line [87], is formed because of stunting of the ameloblasts and odontoblasts that deposit enamel and dentine matrix, respectively. This line forms a clear histological landmark that demarcates pre and postnatally formed parts of the tooth, thereby orienting the assay in time [87].

AN INNOVATIVE APPROACH TO RECONSTRUCTING PAST EXPOSURE IN TEETH &&

Arora and colleagues [88 ] developed laser ablation technology to generate weekly metal-exposure profiles pre and postnatally (This method is described in detail elsewhere in this issue). Validation work was conducted in prospective birth cohorts that collected metal exposure data in pregnancy and childhood. Tooth measures were validated using maternal blood during pregnancy, cord blood at birth, and repeated childhood blood samples. Several tooth biomarkers were also validated using controlled experiments in primates [88 ]. This new method allows researcher not only to measure cumulative metal exposure, but also to parse out precise information on the timing of metal exposure. Researchers can essentially estimate the dose of each metal and the week of life at which that dose was deposited in teeth. Arora et al. [89] published the first study using the proposed method to develop a detailed temporal map of prenatal metal exposure during the 2nd and 3rd trimesters. Recently, the same authors also &&

developed multielement imaging methods that allow for the assessment of coexposures at specific developmental times with weekly temporal resolution [90].

Methodological considerations The proposed method for the measurement of metals in teeth requires careful sampling, validation, and statistical analyses procedures. Furthermore, we need to consider how the genetic background modifies handling the metal balance in the body. Therefore, studies of metal exposure in teeth in patients with psychosis would benefit from a sibling or twin control design.

Analysis of tooth samples The analysis of tooth samples involves three key steps, including sample preparation [91], identifying specific temporal developmental zones in teeth, and measuring metals in specific regions of teeth at micrometer resolution. Using the neonatal line as a reference, we can identify parts of the tooth formed at different times by using daily growth rings that are visible in enamel and dentine. The sophisticated theoretical and practical framework of this method was described recently [92]. Precise measurement of metals can be done using laser ablation-inductively coupled plasma-mass spectrometry [89,90,93].

Biomarker validation Arora and colleagues [90] developed a multielement imaging method that generates spatial distribution maps of metals in teeth. This method has been validated extensively for metals. This method can be used to identify specific times of major transitions in metal uptake, giving us the resolution to construct exposure histories over a selected month, week, or even over a few days. Tooth type does not affect the analysis.

Data analysis Measurement of multiple metals across multiple time-points requires a specialized statistical approach. Critical windows of susceptibility can be detected for each metal individually using distributed lag models. The statistical methods have been described in details elsewhere [94].

CONCLUSION In summary, although a role for environmental factors in causing psychosis is now widely accepted, to date only a few specific environmental exposures

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have been linked to psychosis. Metals have well known effects on early neurodevelopment, but effects later in life are not well characterized. Although there are plausible mechanisms linking metals and psychosis, only few studies have investigated this association. Considering the wide exposure to metals and the high cost of psychosis to society, this hypothesis should be rigorously examined. Identifying the timing and dose of metal exposure during critical neurodevelopmental periods is the key to understanding the effects of metals on risk of psychosis. This can now be achieved using new technology to reconstruct past exposure in deciduous teeth. Acknowledgements The authors would like to thank Dr Eva Velthorst for her assistance with the review. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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