Prenatal Lead Exposure and Schizophrenia: Further Evidence and More Neurobiological Connections

Tomás R. Guilarte

In 2004, Opler et al. published a study in Environmental Health Perspectives (EHP) suggesting an association between prenatal lead (Pb2+) exposure and schizophrenia (Opler et al. 2004). In the November 2008 issue of EHP, Opler et al. (2008) further supported this association using a different cohort of subjects. In a letter published in EHP in 2004 (Guilarte 2004), I indicated that a plausible neurobiological connection between prenatal Pb2+ exposure and schizophrenia may be that Pb2+ is a potent antagonist of the N-methyl d-aspartate (NMDA) receptor (NMDAR), and NMDAR hypofunction is thought to be involved in the pathophysiology of the disease. Since then, another plausible neurobiological connection has surfaced, and this relates to hippo campal neurogenesis. Neurogenesis occurs not only during development but is also prominent in the adult brain (Laplagne et al. 2006). A well-characterized neurogenic zone in the adult brain is the subgranular zone of the dentate gyrus (DG) in the hippocampus (Zhao et al. 2008). Although the significance of newly born neurons in the adult hippocampus is currently under investigation, the overwhelming evidence supports a role in hippocampus-dependent learning (Dupret et al. 2008; Imayoshi et al. 2008).

Schizophrenia patients express cognitive deficits that may be related to hippocampal dysfunction (Gothelf et al. 2000; Sweatt 2004). So, what is the new neurobiological connection between Pb2+ exposure and schizophrenia? Recent evidence indicates that neurogenesis is decreased in schizophrenia patients, and this decrease may contribute to their cognitive dysfunction (Kempermann et al. 2008; Reif et al. 2006). In an animal model using the NMDAR antagonist phencyclidine (PCP) to induce schizophrenia-like symptoms in mice, Maeda et al. (2007) observed reduced DG neurogenesis that was reversed by the atypical anti-psychotic drug clozapine. Co-administration of d-serine and glycine also inhibited the PCP-induced decrease in neurogenesis. PCP, like Pb2+, is an NMDAR antagonist, and D-serine and glycine activate NMDAR; this suggests that chronic NMDAR hypofunction decreases neurogenesis in the hippo campus, an observation consistent with my comments in 2004 (Guilarte 2004). Models of developmental Pb2+ exposure have also shown decreased DG neurogenesis and are associated with deficits in learning (Jaako-Movits et al. 2005; Verina et al. 2007). Therefore, reduced DG neuro genesis appears to be a common factor in schizophrenia and in animal models of schizophrenia and developmental Pb2+ exposure.

Schizophrenia is a neurodevelopmental disorder that is expressed later in life. Pb2+ is a neurotoxicant that is known to cause developmental abnormalities. Animal models of developmental Pb2+ exposure express a behavioral phenotype with features that overlap with those in animal models of schizophrenia, including increased spontaneous activity, decreased social interaction, and learning deficits (Moreira et al. 2001; Nihei et al. 2000). Also, some of the behavioral effects described in adolescents with early-life Pb2+ exposure are similar to those expressed in schizophrenia patients (Opler and Susser 2005). Thus, although the environmental causes of schizophrenia have not evaluated environmental toxicants, the emerging evidence from the human studies by Opler and colleagues and animal studies suggest that prenatal Pb2+ exposure may be an environmental risk factor for schizophrenia.

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Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses.

Neurotoxicology. 2012 Jun;33(3):560-74. Epub  2011 Dec 9.


Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, United States.


Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb(2+)) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb(2+) exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb(2+) exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders.

Copyright © 2011 Elsevier Inc. All rights reserved.

Organic lead encephalopathy: behavioral change and movement disorder following gasoline inhalation.

J Clin Psychiatry. 1982 Feb;43(2):70-2.


A 15 year old boy was evaluated in the psychiatric emergency room for the acute onset of “confusion,”insomnia, headache, and shaking of one week’s duration. Two days later hallucinations, formication and a movement disorder emerged characterized by action tremor, myoclonus, chorea and ataxia. Further history revealed inhalation of gasoline for its euphoric effects. Plasma lead levels were in the toxic range. Chelation therapy reversed the clinical symptoms. Behavioral changes and a movement disorder in the context of gasoline inhalation are highly suggestive of organic lead encephalopathy. Recognition of this syndrome is important as chelation therapy is effective.

[PubMed – indexed for MEDLINE]

Blood Lead Level in Children with Encephalopathy

Javed H Hussain

Children’s Hospital, Boston; Harvard Medical School, 300, Longwood Ave, Boston, MA 02215, USA.

No other heavy metal toxicity has gained as much public attention as lead – due to its impact on the developing brain of young children. Lead is ubiquitous in our environment but has no physiologic role in our biological systems. Lead became part of our daily life due to its easy workability, low melting point and corrosion-resistance. Later in our industrial society, it became part of house paint due its shining and lasting function and also used in gasoline for its anti-knock properties.

The toxicity of lead comes from its ability to mimic other biologically important metals, most notably calcium, iron and zinc, which act as cofactors in many enzymatic reactions. Lead is able to bind to enzymes delta-aminolevulinic acid dehydratase, and ferrochelatase, affecting the biosynthesis of heme causing anemia.

Lead also interferes with excitatory neuro-transmission by glutamate, which is the transmitter at more than half the synapses in the brain and is critical for learning. N-methyl-D-aspartate (NMDA) receptor, thought to be associated with neuronal development and plasticity, is blocked selectively by lead. This disrupts long-term potentiation, which compromises the permanent retention of newly learned information(1). Lead exposure also decreases the amount of NMDA receptor gene and protein in hippocampus(2).

Continue reading “Blood Lead Level in Children with Encephalopathy”

Mental Health Advocacy: Has it contributed to a medication management monopoly?

By Maria Mangicaro

This ad, sponsored in part by NAMI, is one that I find very disturbing.  It was published weekly in the Sunday newspaper in Naples, Florida.

The term “Mental Illness” involves a broad spectrum of conditions and disorders.  Main stream mental health advocates promote a “treatment” approach that focuses on a medication management regime.  They have contributed to a medication management monopoly in mental health care.

Many psychiatric patients are not afforded equal protection under the law, due in part to the advocacy agenda of NAMI.

A forced psychiatric treatment agenda interferes with a patient’s right to contract services for appropriate, cost-effective care.

Advocacy for forced psychiatric treatment proliferates the belief “mental illness” can only be diagnosed and treated effectively by psychiatrists using a medication management protocol.  Advocates in favor of forced psychiatric treatment fail to recognize psychiatric diagnoses are descriptive labels only for phenomenology, not etiological or mechanistic explanation for syndromes.  Coercive psychiatry forces patients labeled “mentally ill” to contract costly services of selected providers and facilities, as well as forces patients to purchase and consume products that have potentially lethal side effects.
Individuals labeled with “severe mental illness” are a marginalized population who are being strategically deprived equal protection and liberty to contract by their advocates.   Mental health advocacy must support informed consent, treatment options and the right to contract.

Mainstream mental health advocates ignore critical evidence between childhood exposure to lead and criminal behavior later in life.   Author Pete Earley recently posted the salaries of nonprofit mental health leaders.  Click here to read more.  Pete also makes a living from the topic of severe mental illness and has deliberately ignored the fact underlying medical conditions and substances can be contributing factors.

Association of Prenatal and Childhood Blood Lead Concentrations with Criminal Arrests in Early Adulthood


Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses.

Methods and Findings

Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead.


Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.

Neurotoxicity and aggressiveness triggered by low-level lead in children: a review

Kelly Polido Kaneshiro Olympio,1 Claudia Gonçalves,2
Wanda Maria Risso Günther,1 and Etelvino José Henriques Bechara 3

Lead-induced neurotoxicity acquired by low-level long-term exposure has special relevance for
children. A plethora of recent reports has demonstrated a direct link between low-level lead exposure
and deficits in the neurobehavioral-cognitive performance manifested from childhood
through adolescence. In many studies, aggressiveness and delinquency have also been suggested
as symptoms of lead poisoning. Several environmental, occupational and domestic
sources of contaminant lead and consequent health risks are largely identified and understood,
but the occurrences of lead poisoning remain numerous. There is an urgent need for public
health policies to prevent lead poisoning so as to reduce individual and societal damages and
losses. In this paper we describe unsuspected sources of contaminant lead, discuss the economic
losses and urban violence possibly associated with lead contamination and review the
molecular basis of lead-induced neurotoxicity, emphasizing its effects on the social behavior,
delinquency and IQ of children and adolescents.
Lead poisoning; neurotoxicity syndromes; oxidative stress; juvenile delinquency


Effects of Toxic Metals on Learning Ability and Behavior

B. Windham (Ed)

I. Mechanisms of Developmental Damage by Toxic Metals.

The human brain forms and develops over a long period of time compared to other organs, with neuron proliferation and migration continuing in the postnatal period.  The blood-brain barrier is not fully developed until the middle of the first year of life.  Similarly there is postnatal activity in the development of neuronal receptors and transmitter systems, as well as in the production of myelin.  The fetus has been found to get significant exposure to toxic substances through maternal blood and across the placenta, with fetal levels of toxic metals often being higher than that of maternal blood(19,30-32,41,42,169b).  Likewise infants have been found to get significant exposure to toxics, such as mercury and organochlorine compounds that their mother is exposed to, through breast-feeding(26,30-32,101,107,169b).  Other toxic exposures are also extremely common as documented in Section IV.

The incidence of neurotoxic or  immune reactive conditions such as autism, schizophrenia, ADD, dyslexia, learning disabilities, etc. have been increasing rapidly in recent years(2,80-82,113-115,143,144,149,169).  A recent report by the National Research Council found that 50% of all pregnancies in the U.S. are now resulting in prenatal or postnatal mortality, significant birth defects, developmental neurological problems, or otherwise chronically unhealthy babies(82).  There has been a similar sharp increase in developmental conditions in Canadian children(132), including increases in learning disabilities and behavioral problems, asthma and allergies, and childhood cancer.  Not all children are equally affected by a given level of toxic exposures, and susceptibility factors such as immune reactivity, genetic factors affecting ability to excrete toxic metals, and other toxic exposures have major influences on toxicity effects.

A 2009 study found that inorganic mercury levels in people have been increasing rapidly in recent years(177). It used data from the U.S. Centers for Disease Control and Prevention’s National Health Nutrition Examination Survey (NHANES) finding that while inorganic mercury was detected in the blood of 2 percent of women aged 18 to 49 in the 1999-2000 NHANES survey, that level rose to 30 percent of women by 2005-2006. Surveys in all states using hair tests have found dangerous levels of mercury in an average of 22 % of the population, with over 30% in some states like Florida and New York(178).

Studies and clinical experience at treatment clinics have found consistently that gastrointestinal, immunologic and metabolic problems are found in children with ADHD, that are related to prenatal and neonatal exposure to toxic substances with much of these being related to vaccinations.(173) Lower GI dysfunction, enzyme deficiencies and impairments of hepatic detoxification pathways are very common. Many ADHD/autism patients have “leaky gut” syndrome, and inability to digest wheat gluten and milk casein, resulting in neurotoxic substances being dumped in the blood with significant adverse behavioral impacts.

Continue reading “Effects of Toxic Metals on Learning Ability and Behavior”

Auditory and visual dysfunction following lead exposure.

Neurotoxicology. 1993 Summer-Fall;14(2-3):191-207.


Human Studies Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.


The effects of lead exposure on cognitive function have been intensively studied during the past decade, but relatively little effort has been made to understand the impact on sensory function. Subtle impairments of visual and/or auditory processing, however, could have profound effects on learning. The objectives of this paper are to review what is known about the effects of lead exposure on visual and auditory function and to identify related research needs. In particular, the effects of lead exposure on sensory function in children, which have not been studied adequately, will be discussed. Evidence from human and animal studies reveal that lead exposure impairs auditory function. The cochlear nerve and more central structures appear to be preferentially sensitive in both developing and mature humans and experimental animals.

Elevations in hearing thresholds and increased latencies of brainstem auditory evoked potential have been reported at low-moderate levels of lead exposure. Higher doses of lead increase the threshold of the auditory nerve action potential, produce segmental demyelination and axonal degeneration of the cochlear nerve, but appear to have no effect on cochlear microphonics or structure.

Lead exposure affects both the retina and visual cortex of the developing and mature visual system.

Low to moderate level developmental lead exposure produces selective rod deficits which can be detected with electrophysiological and behavioral techniques. At slightly higher levels of lead exposure the visual cortex is affected. A wide range of functional and neurochemical effects on retinal function occurring at blood lead levels below 20 micrograms/dl, the current level of concern, have been observed in rats. Structural, biophysical and photochemical similarities of rods in rats, monkeys and humans argue the relevance of this data for pediatric lead screening.

To date, however, rod-mediated visual functions have not been examined in lead-exposed children. Undetected sensory deficits of these kinds may have profound impact on the motor and mental development of children as well as on the quality of life of affected adults.

There is clearly a need for more extensive sensory testing in children and workers to screen for lead-induced health effects and in animal models to clarify the mechanisms of lead neurotoxicity

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